Method for treating obesity with an MC4R agonist

Abstract

The present disclosure relates to a method of treating non-genetic obesity (e.g., hypothalamic obesity) in a subject using a melanocortin-4 receptor (MC4R) agonist. The present disclosure features, inter alia, the treatment of obesity, e.g., non-genetic obesity, e.g., hypothalamic obesity, using a compound (e.g., an MC4R agonist) or a composition thereof. In some embodiments, the MC4R agonist is a compound of any one of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) (e.g., as described herein), or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] Claim of Priority This application claims priority to U.S. Application No. 63 / 388,580, filed Jul. 12, 2022, and U.S. Application No. 63 / 426,610, filed Nov. 18, 2022, the entire contents of each of the foregoing applications being incorporated herein by reference.

Background Art

[0002] There is a need for the treatment of obesity and obesity-related disorders, including non-genetic obesity and related disorders (e.g., hypothalamic obesity).

Summary of the Invention

[0003] The present disclosure features, inter alia, the treatment of obesity, e.g., non-genetic obesity, e.g., hypothalamic obesity, using a compound (e.g., an MC4R agonist) or a composition thereof. In some embodiments, the MC4R agonist is a compound of any one of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) (e.g., as described herein), or a pharmaceutically acceptable salt thereof. The MC4R agonist, e.g., a compound of any one of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt thereof, may be provided as a composition (e.g., a pharmaceutical composition) comprising a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutically acceptable excipient comprises polyethylene glycol (e.g., modified polyethylene glycol) or a lipid (e.g., a neutral lipid or a phospholipid). In one embodiment, the pharmaceutically acceptable excipient comprises modified polyethylene glycol. In one embodiment, the pharmaceutically acceptable excipient comprises a lipid such as a neutral diacyl lipid or a phospholipid.

[0004] The MC4R agonist or its composition may be provided in unit dosage forms. For example, the unit dosage form may contain from about 0.01 mg to 100 mg of the MC4R agonist. In one embodiment, the unit dosage form contains from 0.1 mg to 100 mg, such as from 0.1 mg to 50 mg, from 0.1 mg to 25 mg, from 0.1 mg to 10 mg, from 1 mg to 100 mg, from 1 mg to 50 mg, from 1 mg to 25 mg, from 1 mg to 10 mg, from 5 mg to 100 mg, from 5 mg to 50 mg, from 5 mg to 25 mg, from 5 mg to 15 mg, or from 5 mg to 10 mg.

[0005] The MC4R agonist or its composition may be administered to a subject daily, weekly, or monthly. In one embodiment, the MC4R agonist or its composition is administered daily, for example, once a day, twice a day, or three times a day. In one embodiment, the MC4R agonist or its composition is administered weekly, for example, once a week, once every two weeks, or once every three weeks. In an embodiment, the MC4R agonist or its composition is administered daily over a period of at least 3 weeks, for example, at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more, or at least 1, 2, 3, 4 years or more.

[0006] In an embodiment, the method includes administering the MC4R agonist or its composition in a unit dosage form suitable for injection into a subject, such as subcutaneous injection. In an embodiment, the unit dosage form is placed in a delivery device, such as a syringe (e.g., a pre-filled syringe), an implantable device, a needleless subcutaneous injection device, an infusion pump (e.g., an implantable infusion pump), or an osmotic delivery system. In an embodiment, the MC4R agonist is administered subcutaneously, for example, by subcutaneous injection.

[0007] In an embodiment, the subject is obese, for example, severely obese. In an embodiment, in the subject, severe obesity has started early. In an embodiment, the subject has bulimia. In an embodiment, the subject experiences severe hunger. In an embodiment, the subject has a body mass index (BMI) of greater than 25 kg / m 2 2 (e.g., ≥25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 2 or more) prior to administration of the MC4R agonist, for example, when the MC4R agonist is prescribed or at the time of the first administration. In an embodiment, the subject has a body mass index (BMI) of greater than 35 kg / m 2 2 (e.g., ≥36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 2 or more) prior to administration of the MC4R agonist, for example, when the MC4R agonist is prescribed or at the time of the first administration. In an embodiment, the subject has a body mass index (BMI) of greater than 40 kg / m 2 2 (e.g., ≥41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m 2 2 or more) prior to administration of the MC4R agonist, for example, when the MC4R agonist is prescribed or at the time of the first administration. In an embodiment, the subject has a body mass index (BMI) of greater than 45 kg / m 2 2 (e.g., ≥46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m 2 2 or more) prior to administration of the MC4R agonist or a composition thereof, for example, when the MC4R agonist is prescribed or at the time of the first administration. In an embodiment, the subject has a BMI greater than the 85th to 95th percentile prior to administration of the MC4R agonist or its composition, for example, when the MC4R agonist is prescribed or at the time of the first administration.

[0008] In an embodiment, the subject has failed one or more previous therapies, such as exercise, diet, or behavioral therapy, before administration of the MC4R agonist or its composition, for example, when the agonist is prescribed or at the first administration.

[0009] In an embodiment, the subject has a lower body weight after administration of the MC4R agonist or its composition than before administration of the agonist.

[0010] In an embodiment, administration of the MC4R agonist or its composition results in a weight loss of about 1 kg to 3 kg after 1 week of treatment, or about 1 kg to 6 kg after 2 weeks of treatment, or about 2 kg to 12 kg after 4 weeks of treatment, or about 4 kg to 24 kg after 8 weeks of treatment, or about 8 kg to 48 kg after 16 weeks of treatment, compared to the weight of the subject before treatment. In an embodiment, administration of the MC4R agonist or its composition results in a decrease in BMI of about 1%, 2%, 3%, 5%, 6%, 7%, 8%, 9%, 10% or more over a period of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks or more.

[0011] In an embodiment, administration of the MC4R agonist or its composition does not result in a detectable / significant decrease in the resting energy expenditure (REE) in the subject over a period of, for example, 24 hours, 1 week, or 30 days or more, compared to, for example, a control REE (e.g., when expressed as REE per kg of fat-free mass, for example, in a subject with a similar pre-treatment BMI, e.g., the REE of the subject before treatment or a predetermined REE).

[0012] In an embodiment, administration of an MC4R agonist or a composition thereof results in a reduction in food intake of at least 5 kcal / kg / day, such as 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90 kcal / kg / day or more. In an embodiment, the reduction in food intake is relative to the food intake at baseline. In an embodiment, the baseline food intake is at least 100 kcal / kg / day, for example, for a pediatric subject at an age of about 1 year. In an embodiment, the baseline food intake is at least 40 kcal / kg / day, for example, for a pediatric subject in late adolescence.

[0013] In an embodiment, administration of an MC4R agonist or a composition thereof results in a reduction in the abdominal circumference of a subject as compared to a control (e.g., the abdominal circumference of the subject before treatment) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after the start of treatment.

[0014] In an embodiment, administration of an MC4R agonist or a composition thereof does not result in a detectable increase in the blood pressure of a subject (e.g., diastolic and / or systolic blood pressure) as compared to the blood pressure of the subject before treatment when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after the start of treatment. In an embodiment, administration of an MC4R agonist or a composition thereof results in a detectable decrease in the blood pressure of a subject (e.g., diastolic and / or systolic blood pressure) as compared to the blood pressure of the subject before treatment when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after the start of treatment. In an embodiment, administration of an MC4R agonist or a composition thereof results in a decrease in the systolic blood of the subject of at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg or more) as compared to the blood pressure of the subject before treatment when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after the start of treatment. In an embodiment, administration of an MC4R agonist or a composition thereof results in a decrease in the diastolic blood pressure of the subject of at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg or more) as compared to the blood pressure of the subject before treatment when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after the start of treatment.

[0015] In an embodiment, administration of an MC4R agonist or a composition thereof results in a reduction of fasting in a subject. The reduction of fasting can result in a decrease in food intake, a decrease in resting energy expenditure (REE), weight loss, a decrease in abdominal circumference, and / or a decrease in blood pressure in the subject.

[0016] In an embodiment, the subject is a mammal, such as a human. In one embodiment, the subject is an adult (e.g., 18 years of age or older). In one embodiment, the subject is a pediatric subject, such as a child.

[0017] In an embodiment, the method further includes obtaining knowledge about the genotype of the subject, for example, obtaining knowledge about the genotype of a gene that can activate the MC4R pathway, such as the genes listed in Table 1. In an embodiment, the knowledge is obtained directly from a sample of the subject (e.g., a serum, urine, or tissue (e.g., biopsy) sample).

[0018] In an embodiment, the MC4R agonist or its composition is administered in response to the detection of a predetermined sequence, for example, a mutation, a gene capable of activating the MC4R pathway, for example, a gene listed in Table 1. In an embodiment, the predetermined sequence, for example, the mutation, is detected in a nucleic acid by a method selected from one or more of nucleic acid hybridization assays, amplification-based assays, PCR-RFLP assays, real-time PCR, sequencing (for example, DNA sequencing, for example, next-generation sequencing or Sanger sequencing, bisulfite sequencing, or pyrosequencing), screening assays, FISH, spectral karyotyping or MFISH, comparative genomic hybridization, in situ hybridization, SSP, HPLC, or mass spectrometry genotyping. In an embodiment, the predetermined sequence, for example, the mutation, is detected in a subject. In an embodiment, the predetermined sequence, for example, the mutation, is detected in a nucleic acid molecule or polypeptide in a sample derived from the subject. In an embodiment, the sample includes cells derived from serum, urine, or tissue (for example, a biopsy) from the subject. In an embodiment, the method includes obtaining knowledge about the genotype of the subject, for example, obtaining knowledge of the genotype of the mutation in the genes listed, for example.

[0019] In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) is hydantoin (C(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 148) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound according to any one of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) is formulated as a pharmaceutical composition.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features, objects, and advantages of the present disclosure will become apparent from the description and drawings, as well as from the claims.

Brief Description of the Drawings

[0021]

Figure 1

Modes for Carrying Out the Invention

[0022] The present disclosure is based, at least in part, on the discovery that non-genetic obesity, including hypothalamic obesity, and other related disorders can be treated in a subject by administering a therapeutic agent that targets the melanocortin 4 receptor (MC4R) pathway, such as an MC4R agonist. In one embodiment, the subject has hypothalamic obesity. In one embodiment, the subject has been identified as having or diagnosed with hypothalamic obesity. In one embodiment, administering an MC4R agonist to the subject results in significant weight loss, decreased appetite, and / or increased metabolic rate in the subject. Exemplary MC4R agonists, as well as related formulations and methods of use, are described in more detail herein.

[0023] Definitions As used herein, "about" and "approximately" generally mean an acceptable degree of error for the measured quantity considering the nature and precision of the measurement. Exemplary degrees of error are within twenty percent (20%) of a given value or range of values, typically within ten percent (10%), and more typically within five percent (5%).

[0024] As used herein, the term "obtain" or "obtaining" refers to obtaining a physical entity, value, or knowledge, e.g., by "directly obtaining" or "indirectly obtaining", a physical entity or value, e.g., a numerical value, or knowledge of a genotype or nucleic acid or polypeptide (e.g., knowledge of their sequences or mutant states). "Directly obtaining" means performing a physical process (e.g., performing a synthesis method or an analysis method) to obtain a physical entity, value, or knowledge. "Indirectly obtaining" refers to receiving a physical entity, value, or knowledge from another entity or source (e.g., a third party laboratory that has directly obtained a physical entity, value, or knowledge). Directly obtaining a physical entity includes performing a process involving a physical change of a physical substance, e.g., a starting material. Exemplary changes include making a physical entity from two or more starting materials, shearing or fragmenting a substance, separating or purifying a substance, combining two or more separate entities into a mixture, and performing a chemical reaction including cleaving or forming a covalent or non-covalent bond. Directly obtaining a value or knowledge includes performing a process involving a physical change in a sample or another substance. Examples include performing an analysis process involving a physical change in a substance, e.g., a sample, analyte, or reagent (sometimes referred to herein as a "physical analysis"), an analysis method, e.g., separating or purifying the following substances, e.g., an analyte, or fragment, or other derivatives thereof, from another substance, combining an analyte, or fragment, or other derivatives thereof, with another substance, e.g., a buffer, solvent, or reactant, or changing the structure of an analyte, or fragment, or other derivatives thereof, e.g., by cleaving or forming a covalent or non-covalent bond between a first and a second atom of the analyte, or changing the structure of a reagent, or fragment, or other derivatives thereof, e.g., by cleaving or forming a covalent or non-covalent bond between a first and a second atom of the reagent, including performing one or more of the methods mentioned above.

[0025] As used herein, for example, the term "functional", when applied to an allele of a gene capable of activating the MC4R pathway, means an allele having, for example, at least 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, such as a wild-type allele.

[0026] As used herein, the term "non-functional", when applied to an allele, for example, of a gene capable of activating the MC4R pathway, means an allele having less than 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, such as a wild-type allele. In one embodiment, a non-functional allele is an allele of a gene other than a functional allele (the term "functional allele" being as defined herein). By way of example, in one embodiment, if a functional allele has at least 20% of the activity of a reference allele, a non-functional allele is an allele having less than 20% of the activity.

[0027] As used herein, the term "gene capable of activating the MC4R pathway" means a gene associated with a phenotype that can be controlled, for example, improved or alleviated, for example, by an MC4R agonist, for example, by controlling, for example, activating the MC4R. In one embodiment, the phenotype is bulimia, appetite, unwanted appetite, obesity, weight, body mass, or metabolic syndrome (e.g., diabetes), and the phenotype is, for example, controlled, for example, alleviated or improved.

[0028] In one embodiment, the term "gene capable of activating the MC4R pathway" does not include the melanocortin 4 receptor (MC4R) gene. In one embodiment, the term "gene capable of activating the MC4R pathway" does not include POMC. In one embodiment, the gene capable of activating the MC4R pathway does not include any one of POMC, proprotein convertase subtilisin / kexin type 1 (PCSK1, also called PC1 / 3), MAGE-like 2 (MAGEL2), leptin receptor (leptin-R), leptin, 5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-HT2c receptor), nescient helix-loop-helix 2 (NhHL2, also called NSCL2), prohormone convertase, carboxypeptidase E (CPE), and single-minded 1 (Sim1). In one embodiment, the gene capable of activating the MC4R pathway does not include any gene disclosed in WO2013 / 102047 or WO2017 / 059076, the entire contents of which are incorporated herein by reference.

[0029] In one embodiment, at least one of the MC4R alleles is functional, for example, having at least 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, such as a wild-type allele, as measured by a functional assay. In one embodiment, one of the MC4R alleles is functional. In one embodiment, both of the MC4R alleles are functional. In one embodiment, the subject is heterozygous for the MC4R gene and both alleles are functional. In one embodiment, the subject is homozygous for the MC4R gene with respect to the functional allele.

[0030] In one embodiment, both of the MC4R alleles are non-functional (a non-functional allele is an allele that is not functional, where functional is as defined herein). In one embodiment, the subject is heterozygous for the MC4R gene and both alleles are non-functional. In one embodiment, the subject is homozygous for the MC4R gene with respect to the non-functional allele.

[0031] In one embodiment, at least one allele of a gene capable of activating the MC4R pathway other than MC4R is functional, e.g., having at least 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, e.g., a wild-type allele, as measured by a functional assay. In one embodiment, one allele of a gene capable of activating the MC4R pathway other than MC4R is functional. In one embodiment, both alleles of a gene capable of activating the MC4R pathway other than MC4R are functional. In one embodiment, the subject is heterozygous for a gene capable of activating the MC4R pathway other than MC4R, and both alleles are functional. In one embodiment, the subject is homozygous for a gene capable of activating the MC4R pathway other than MC4R with respect to the functional allele.

[0032] In one embodiment, both MC4R alleles are non-functional (a non-functional allele is an allele that is not functional, where functional is as defined herein). In one embodiment, the subject is heterozygous for the MC4R gene, and both alleles are non-functional. In one embodiment, the subject is homozygous for the MC4R gene with respect to the non-functional allele.

[0033] In one embodiment, there is an epigenetic modification, e.g., a histone modification, e.g., acetylation or methylation of a nucleic acid base, e.g., methylation of cytosine, that is associated with the phenotype of a gene capable of activating the MC4R pathway, e.g., hyperphagia, appetite, unwanted appetite, obesity, weight, body mass, or metabolic syndrome (e.g., diabetes).

[0034] In one embodiment, the epigenetic modification is associated with a gene capable of activating the MC4R pathway. In one embodiment, the epigenetic modification is associated with MC4R.

[0035] In one embodiment, the epigenetic modification is associated with a gene other than MC4R that can activate the MC4R pathway. In one embodiment, the gene that can activate the MC4R pathway does not include any one of proopiomelanocortin (POMC), proprotein convertase subtilisin / kexin type 1 (also called PCSK1, PC1 / 3), MAGE-like 2 (MAGEL2), leptin receptor (leptin-R), leptin, 5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-HT2c receptor), nescient helix-loop-helix 2 (also called NhHL2, NSCL2), prohormone convertase, carboxypeptidase E (CPE), and single-minded 1 (Sim1). In one embodiment, the gene that can activate the MC4R pathway does not include any gene disclosed in WO2013 / 102047 or WO2017 / 059076, the entire contents of which are incorporated herein by reference. As used herein, the term "obesity" refers to a subject having a body mass index (BMI) within the range defined as "obesity" by the Centers for Disease Control and Prevention in the United States (for example, see URL.cdc.gov / obesity / defining.html, and www.cdc.gov / obesity / childhood- / defining.html: last access on August 26, 2012), or by the "Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults" of the National Institutes of Health in the United States. BMI is obtained by dividing the weight of the subject (for example, in kilograms (kg)) by the square of the height of the subject (for example, in meters (m)). For example, an adult with a BMI of 30 kg / m 2 or more is considered obese. For example, an adult with a BMI of 25.0 - 29.9 kg / m 2 is considered overweight, and an adult with a BMI of 18.5 - 24.9 kg / m 2 is considered to have a normal or healthy weight range, and an adult with a BMI of 18.5 kg / m 2Adults with a BMI below are considered underweight. For example, an adult with a weight of 203 pounds or more and a height of 5 feet 9 inches is considered obese. For pediatric subjects, such as children and adolescents, obesity means having a BMI at or above the 85th to 95th percentile for pediatric subjects of the same age and sex, such as children and adolescents.

[0036] As used herein, the term "BMI Z-score" refers to the number of standard deviations by which an absolute BMI value deviates from the mean BMI of the target population. For example, a BMI Z-score of +1.0 indicates that the subject's BMI is 1 standard deviation higher than the mean BMI of the target population (e.g., a BMI at approximately the 84th percentile of the parent population). In one embodiment, the BMI Z-score of an obese pediatric patient is at or above a BMI Z-score of +1.04 to +1.65 or more, which corresponds to the subject's BMI being at or above the 85th to 95th percentile for a population of pediatric subjects of the same age and sex.

[0037] As used herein, the terms "IWQOL (Impact of Weight on Quality of Life)" and "Impact of Weight on Quality of Life-Lite" refer to psychometric questionnaires for assessing the impact of obesity on the ability of an obese and overweight subject to lead a satisfying life, the scores of which are individually evaluated by the subject or the subject's guardian. In one embodiment, the IWQOL or IWQOL-Lite score decreases when the subject develops hypothalamic obesity compared to a reference IWQOL or IWQOL-Lite score, such as the IWQOL or IWQOL-Lite score before the onset of hypothalamic obesity. In one embodiment, the IWQOL or IWQOL-Lite score increases after administration of a therapy that improves the symptoms of hypothalamic obesity compared to a reference IWQOL or IWQOL-Lite score, such as the IWQOL or IWQOL-Lite score before administration of the therapy.

[0038] As used herein, the "weekly average of the maximum fasting score per day" refers to the average or mean value of the maximum fasting score per day of a subject over a period of one week or seven days.

[0039] A subject with "severe obesity" or having "severe obesity disorder" means a subject having a BMI of 35 kg / m 2 or more, for example, 40 kg / m 2 or more. For example, a subject with severe obesity exceeds 100% of the ideal (normal, healthy) weight.

[0040] As used herein, for example, "early onset" such as in early onset obesity means the onset (e.g., a disorder, such as a disorder described herein, e.g., the first occurrence of one or more symptoms of obesity) that occurs in a subject before adulthood, for example, during childhood, for example, when the age of the subject is 18 years or less (e.g., the age is 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 year or less, or during adolescence, for example, when the age of the child is less than 12 years, or when the age of the child is less than 6 years).

[0041] As used herein, the term "metabolic syndrome" means a group of symptoms that occur together and increase the risk of coronary artery disease, stroke, and type 2 diabetes. According to the American Heart Association and the National Heart, Lung, and Blood Institute, metabolic syndrome, also referred to as syndrome X, occurs when a subject has three or more of the following symptoms: 1) Blood pressure of 130 / 85 mmHg or higher; 2) Fasting blood glucose level (glucose) of 100 mg / dL or higher; 3) Large waist circumference (length around the abdomen): 40 inches or more for men and 35 inches or more for women; 4) Low HDL cholesterol: less than 40 mg / dL for men and less than 50 mg / dL for women; 5) Triglycerides of 150 mg / dL or higher. Metabolic syndrome can be diagnosed by examining the subject's blood pressure, blood glucose level, HDL cholesterol level, LDL cholesterol level, total cholesterol level, and triglyceride level.

[0042] As used herein, the term "agonist" means any chemical compound, whether natural or synthetic, that produces a MC4R signaling activity above its baseline value when interacting with (e.g., binding to) its target, e.g., MC4R. An agonist can be a superagonist (i.e., a compound that can produce a greater maximal response than an endogenous agonist for the target receptor and thus has an efficacy greater than 100%), a full agonist (i.e., a compound that induces a maximal response after receptor occupancy and activation), or a partial agonist (i.e., a compound that can activate the receptor but cannot induce a maximal response of the receptor system).

[0043] As used herein, "treating" means achieving one or more of the following results: for example, reducing weight (e.g., as measured by body mass index (BMI) and / or weight) compared to a control (e.g., pre-treatment weight or a predetermined weight); for example, reducing abdominal circumference compared to a control (e.g., pre-treatment abdominal circumference or a predetermined abdominal circumference); for example, reducing fasting compared to a control (e.g., pre-treatment fasting or a predetermined fasting); for example, increasing resting energy expenditure (REE) compared to a control (e.g., pre-treatment REE or a predetermined REE); for example, reducing food intake compared to a control concentration (e.g., pre-treatment or a predetermined food intake); improving or ameliorating clinical symptoms or markers associated with the disorders described herein, such as obesity, Prader-Willi syndrome, Smith-Magenis syndrome, type II diabetes, prediabetic state, blood concentration of hemoglobin A1C (Hb1Ac) exceeding 6%, hyperinsulinemia, hyperlipidemia, insulin resistance, or impaired glucose tolerance; delaying, inhibiting, or preventing the progression of obesity and / or obesity-related markers; or partially or completely delaying, inhibiting, or preventing the onset or progression of obesity or obesity-related markers. Delaying, inhibiting, or preventing the progression of obesity includes, for example, delaying, inhibiting, or preventing the progression of a subject with a normal weight to obesity. In an embodiment, the control is the value of a parameter measured prior to treatment with the MC4R agonist described herein or a predetermined value. The term "treating" further includes partially or completely reducing the risk of coronary artery disease, stroke, and type 2 diabetes associated with metabolic syndrome, and in addition, improving or ameliorating clinical symptoms or signs of metabolic syndrome associated with metabolic syndrome, such as any one or more of the five factors described above. For example, the term "treating" includes delaying, inhibiting, or preventing the progression of parameters associated with metabolic syndrome, including insulin resistance, glucose clearance, and cardiovascular disease parameters including heart rate and blood pressure.

[0044] As used herein, "inhibit" or "inhibiting" can include a decrease in a particular parameter, such as the parameters described herein. For example, inhibition of a parameter, such as activity, can be at least 5%, 10%, 20%, 30%, 40% or more, and is encompassed by this term. Thus, inhibition need not be 100%.

[0045] "Preventive treatment" means treatment before the onset of obesity that prevents, inhibits, or reduces its occurrence.

[0046] As used herein, the term "subject" means a mammal, such as a human. A subject also means an animal in need of veterinary treatment, such as a companion animal (e.g., dog, cat, etc.), a livestock animal (e.g., cow, sheep, pig, horse, etc.), and a laboratory animal (e.g., rat, mouse, guinea pig, etc.). In one embodiment, the subject is a pediatric subject (e.g., a subject less than 21 years old or less than 18 years old). In one embodiment, the subject is an adult subject (e.g., a subject 18 years old or older or 21 years old or older).

[0047] As used herein, the term "mutation" can mean an altered nucleic acid sequence of a gene or a fragment thereof as compared to the wild-type sequence. For example, a mutation can include a point mutation, a frameshift mutation, a missense mutation, an inversion, a deletion, an insertion, a cleavage, a chromosomal translocation. In embodiments, a mutation can result in a gene or a fragment thereof that encodes a non-functional protein, a protein with reduced activity (or a partially functional protein), or a protein with altered activity. For example, a "loss-of-function" mutation means a mutation that results in a gene or a fragment thereof that encodes a non-functional protein with substantially reduced activity as compared to its wild-type activity (e.g., the non-functional protein has an activity of less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less as compared to its wild-type activity). For example, a "partial loss-of-function" mutation means a mutation that results in a gene or a fragment thereof that encodes a partially functional protein with reduced activity as compared to its wild-type activity (e.g., the partially functional protein has an activity of less than 50% and more than 10% of its wild-type activity).

[0048] As used herein, "heterozygous" means that in a given gene of interest, two different alleles (having different nucleic acid sequences) are present. In some embodiments, a "heterozygous mutation" can mean that a mutation is present in one allele of a given gene and the absence of a mutation is present in the other allele of the same gene in the subject (e.g., for a given gene, one mutant allele and one wild-type allele). In other embodiments, a "heterozygous mutation" can be a "compound heterozygous" mutation, which means that in one allele of a given gene, a mutation (e.g., a loss-of-function mutation, or a partial loss-of-function mutation), and in the other allele of the same gene (e.g., two different alleles that are both mutated, e.g., non-functional or partially functional), a different mutation (e.g., a loss-of-function mutation, or a partial loss-of-function mutation) is present. In embodiments, when the compound heterozygous mutation includes two non-functional alleles, the genotype can be a null genotype or a loss-of-function genotype.

[0049] As used herein, "homozygous" means that two identical alleles are present for a given gene. In some embodiments, a "homozygous mutation" means that two mutant alleles are present for a given gene and these two mutant alleles are identical.

[0050] As used herein, "null genotype" means that in a subject, two non-functional alleles of a gene are present.

[0051] As used herein, "unit dosage form" means a physically discrete unit suitable as a single dosage for a subject to be treated. Each unit contains a predetermined amount of the active compound calculated to produce the desired therapeutic effect together with the necessary pharmaceutical carrier.

[0052] As used herein, "dose" means the quantity or amount of a therapeutic agent. In some embodiments, a dose is the amount administered to a subject in a single administration of one or more unit doses, e.g., a single injection, a single infusion, or a single administration. In embodiments, a dose is the amount administered to a subject in multiple administrations of one or more unit doses, e.g., multiple injections, multiple infusions, or multiple administrations. In other embodiments, a dose can mean the total amount administered to a subject over a given period, e.g., per day. In such an example, the dose is typically referred to as a "daily dose" or a dose in terms of the quantity per day.

[0053] As used herein, "fasting" or "fasting level" means the appetite of a subject, the desire to eat food, or the perception of a need for food. In embodiments, the fasting or fasting level of a subject can be quantified by using a scale for obtaining a fasting score. In embodiments, the scale for fasting assigns a high score to a subject who more frequently (e.g., often, or always) experiences unendurable hunger and a low score to a subject who less frequently (e.g., rarely, or never) experiences unendurable hunger. See, e.g., Sibilia. Psychological Topics 19(2010),2,341-354. For example, a Likert scale for fasting that assigns a score from 0 to 10 points (0 = no hunger; 10 = severe hunger) can be used. In other examples, a Likert scale for fasting that assigns a score from 1 to 4 points can be used, where a score of 1 is assigned to a subject who never experiences unendurable hunger, a score of 2 is assigned to a subject who sometimes experiences unendurable hunger, a score of 3 is assigned to a subject who often experiences unendurable hunger, and a score of 4 is assigned to a subject who always experiences unendurable hunger. See Id.

[0054] Selected Chemical Definitions The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. (inside cover), and specific functional groups are generally defined as described therein. Further, the general principles of organic chemistry, in addition to specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0055] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The chemical structures and formulas described herein are interpreted in accordance with the standard rules of chemical valency known in the chemical arts. Also, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0056] The nomenclature used to define peptides is that commonly used in the art, with the N-terminal amino group appearing on the left and the C-terminal carboxyl group appearing on the right. When an amino acid has D and L isomeric forms, the L form of the amino acid is represented unless otherwise specified.

[0057] When a range of values is recited, each value and sub-ranges within that range are intended to be included. For example, "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0058] Compounds useful for carrying out the methods described herein may have one or more chiral centers and thus may exist as a number of stereoisomers. All stereoisomers and mixtures thereof are within the scope of the present disclosure. Racemic compounds may be separated using preparative HPLC and columns with chiral stationary phases or resolved using methods known to those skilled in the art to obtain the individual enantiomers. Further, chiral intermediate compounds may be resolved and used to prepare the chiral compounds of the present disclosure.

[0059] Compounds useful for carrying out the methods described herein may also include one or more isotope substitutions. For example, H may be 1 H, 2 H (D or deuterium), and 3 H (T or tritium) in any isotopic form, C may be 12 C, 13 C, and 14 C in any isotopic form, O may be 16 O and 18 O in any isotopic form, and so on.

[0060] As used herein, the term "pharmaceutically acceptable salt" means salts of the active compounds prepared using relatively non-toxic acids or bases, depending on the particular substituents found in the compounds described herein. When the compounds used in the present disclosure contain relatively acidic functional groups, the base addition salts can be obtained by contacting the neutral form of such compounds, either neat or in any suitable inert solvent, with a sufficient amount of the desired base. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When the compounds used in the present disclosure contain relatively basic functionality, the acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, or phosphorous acid, and salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as alginate salts, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al, Journal of Pharmaceutical Science 66:1-19 (1977)). The particular specific compounds used in the present disclosure contain both basic and acidic functionality that allows the compound to be converted to either a base or an acid addition salt. These salts can be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for use in the present disclosure.

[0061] Compounds useful for carrying out the methods described herein can exist in unsolvated forms, as well as in solvated forms including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Compounds useful for carrying out the methods described herein can exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent with respect to the uses contemplated by the present disclosure and are encompassed within the scope of the present disclosure.

[0062] The term "solvate" typically refers to a form of a compound associated with a solvent, usually by solvolysis. This physical association can include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates, including both stoichiometric and non-stoichiometric solvates.

[0063] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in a hydrate of a compound is within a limited ratio relative to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0.

[0064] As used herein, the term "tautomer" means a compound having interchangeable forms of its structure, with a change in the replacement of a hydrogen atom and an electron. Thus, the two structures can be in equilibrium through the movement of π electrons and an atom (usually H). For example, enol and ketone are tautomers because they are rapidly interconverted by treatment with either an acid or a base. Tautomeric forms can be relevant to achieving the optimal chemical reactivity and biological activity of the desired compound. Table 1 shows the definitions of chemical abbreviations used herein.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

[0065] Unless otherwise specified, with the exception of the N-terminal amino acid, all abbreviations of amino acids in the present disclosure (e.g., Ala) have the structure of -NH-C(R)(R’)-CO- [wherein R and R’ are each independently hydrogen or the side chain of an amino acid (e.g., for Ala, R = CH3 and R’ = H), or R and R’ may be joined to form a ring system.].

[0066] For the N-terminal amino acid, the abbreviation has the structure of

Chemical formula

[0067] For example, in the case of Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 13), the notation “NH2” indicates that the C-terminus of the peptide is amidated. Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys) (SEQ ID NO: 107), or Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH (SEQ ID NO: 107) indicates that the C-terminus is a free acid.

[0068] “-c(Cys-Cys)-” or “-cyclo(Cys-Cys)-” represents the following structure:

Chemical formula

[0069] 「-c(Cys-Pen)-」, or 「-cyclo(Cys-Pen)-」, represents the following structure:

Chem.

[0070] 「-c(Asp-Lys)-」, or 「-cyclo(Asp-Lys)-」, represents the following structure:

Chem.

[0071] The following abbreviations are used throughout this disclosure: 「Hydantoin-(C(O)-(A a -A b ))」 refers to the following structure:

Chem.

Chem.

Chem.

[0072] ))」 has the following structure: b

Chem.

[0073] For example, 「Hydantoin-(C(O)-(Arg-Gly))」 has the following structure:

Chem.

[0074] For example, the compound represented as "c[hydantoin" (C(O)-(Cys-A b ))-A 1 -A 2 -A 3 -A 4 -Cys]-" has the following structure:

Chemical formula

Chemical formula

[0075] As a further guide, "c[hydantoin (C(O)-(Asp-A b ))-A 1 -A 2 -A 3 -A 4 -Lys]-" represents the following compound:

Chemical formula

Chemical formula

[0076] "Acyl" means R''-(C(O)-, where R'' is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, aryl, alkylaryl, or substituted alkylaryl, and is represented in the general formula in certain embodiments as "Ac".

[0077] "Alkyl" means a hydrocarbon group containing one or more carbon atoms, and where present, the plurality of carbon atoms are bonded by single bonds. The alkyl hydrocarbon group may be straight-chain or may contain one or more branched or cyclic groups.

[0078] "Hydroxyalkyl" means an alkyl group in which one or more hydrogen atoms of the hydrocarbon group are substituted with one or more hydroxy radicals (such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, etc.).

[0079] "Substituted alkyl" means an alkyl in which one or more hydrogen atoms of the hydrocarbon group are substituted with one or more substituents selected from the group consisting of halogen (i.e., fluorine, chlorine, bromine, and iodine), -OH, -CN, -SH, amine (e.g., -NH2, -NHCH3), -NO2, guanidine, urea, amidine, and -(C1-C 20 )alkyl [the above -(C1-C 20 )alkyl may optionally be substituted with one or more substituents independently selected from the group consisting of halogen, -CF3, -OCH3, -OCF3, and -(CH2) 0-20 -COOH for each occurrence]. In different embodiments, 1, 2, 3, or 4 substituents are present. The presence of -(CH2) 0-20 -COOH results in the production of alkyl acids. Non-limiting examples of alkyl acids containing or consisting of -(CH2) 0-20 -COOH include 2-norbornaneacetic acid, tert-butyric acid, 3-cyclopentylpropionic acid, etc.

[0080] The term "halo" includes fluoro, chloro, bromo, and iodo.

[0081] Guanidine refers to a group of organic compounds sharing a common functional group with the general structure (R 1 R 2 N)(R 3 R 4 N)C=N-R 5 The central bond in this group is an imine, and the group is structurally related to amidine and urea.

[0082] "Heteroalkyl" means an alkyl in which one or more of the carbon atoms in the hydrocarbon group are substituted with one or more of the following groups: amino, amide, -O-, -S-, or carbonyl. In different embodiments, one or two heteroatoms are present.

[0083] "Substituted heteroalkyl" means a heteroalkyl in which one or more hydrogen atoms of the hydrocarbon group are substituted with one or more substituents selected from the group consisting of halogen (i.e., fluorine, chlorine, bromine, and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2, and -(C1-C 20 )alkyl [the above -(C1-C 20 )alkyl may optionally be substituted with one or more substituents independently selected from the group consisting of halogen, -CF3, -OCH3, -OCF3, and -(CH2) 0-20 -COOH for each occurrence]. In different embodiments, 1, 2, 3, or 4 substituents are present.

[0084] "Alkenyl" means a hydrocarbon group composed of two or more carbons in which one or more carbon-carbon double bonds are present. The alkenyl hydrocarbon group may be linear or may contain one or more branched or cyclic groups.

[0085] "Substituted alkenyl" means that one or more hydrogens are replaced by halogen (i.e., fluorine, chlorine, bromine, and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2, and -(C1-C20 ) Alkyl [the above -(C1-C 20 ) Alkyl is optionally, for each occurrence, halogen, -CF3, -OCH3, -OCF3, and -(CH2) 0-20 -COOH, and may be substituted with one or more substituents independently selected from the group consisting of] and is substituted with one or more substituents selected from the group consisting of alkenyl substituted with. In different embodiments, 1, 2, 3, or 4 substituents are present.

[0086] "Aryl" means an optionally substituted aromatic group having at least one ring with a conjugated π electron system, containing up to 3 conjugated or fused ring systems. Aryl includes carbocyclic aryl, heterocyclic aryl, and biaryl groups. Preferably, aryl is a 5- or 6-membered ring. Preferred atoms for heterocyclic aryl are one or more sulfur, oxygen, and / or nitrogen. Non-limiting examples of aryl include phenyl, 1-naphthyl, 2-naphthyl, indole, quinoline, 2-imidazole, 9-anthracene, etc. Aryl substituents are -(C1-C 20 ) alkyl, -(C1-C 20 ) alkoxy, halogen (i.e., fluorine, chlorine, bromine, and iodine), -OH, -CN, -SH, -NH2, -NO2; halogen, -CF3, -OCF3, and -(CH2) 0-20 -COOH substituted -(C1-C 20 ) alkyl selected from the group consisting of. In different embodiments, aryl contains 0, 1, 2, 3, or 4 substituents.

[0087] "Alkylaryl" means "alkyl" bonded to "aryl".

[0088] The term "(C1-12) hydrocarbon moiety" includes alkyl, alkenyl, and alkynyl, and in the case of alkenyl and alkynyl, C2-C 12 is present.

[0089] For the avoidance of doubt, unless stated otherwise, the term "substituted" means substituted by one or more defined groups. When a group may be selected from a number of alternative groups, the selected groups may be the same or different. For the avoidance of doubt, the term "independently" means that when two or more substituents are selected from a number of possible substituents, these substituents may be the same or different.

[0090] The notation "(amino acid) n " means that the amino acid is repeated n times. For example, the notations "(Pro)2" or "(Arg)3" mean that the proline or arginine residues are repeated 2 or 3 times, respectively.

[0091] MC4R hMC4R is a protein encoded by the genomic sequence having GenBank accession number CH471077.2. Mutations in the MC4R receptor are a cause associated with severe childhood obesity. The carrier prevalence of MC4R mutations in the juvenile-onset obesity population is stated to be about 2.5%, and among children with severe obesity, the highest prevalence is 6%. Humans having MC4R mutations exhibit more or less similar phenotypes to those observed in mice having mutations in the MC4R gene. MC4R-deficient patients show hyperphagia, hyperinsulinemia, increased fat mass, accompanied by decreased fat-free mass, and increased bone mineral density and linear growth rate, with no changes in cortisol levels, gonadotropin, thyroid, and sex steroid levels. In contrast to MC4R deficiency, hyperphagia and hyperinsulinemia tend to resolve as the human subjects age. Similar to MC4R knockout mice, the phenotype in heterozygous carriers is intermediate compared to homozygous carriers. The hyperphagia shown during a test meal is not as severe as that observed in people with leptin deficiency. The severity of MC4R dysfunction seen in in vitro assays can predict the amount of food consumed in a test meal by subjects having that specific mutation, and correlates with the onset and severity of the obesity phenotype. At least 90 different MC4R mutations are associated with obesity, and it is highly likely that additional mutations in MC4R that result in a similar obesity phenotype will be discovered.

[0092] Examples of MC4R mutations that cause obesity in humans are described, for example, in Farooqi et al., The Journal of Clinical Investigation, July 2000, vol. 106(2), pp. 271-279 and Vaisse et al., The Journal of Clinical Investigation, July 2000, vol. 106(2), pp. 253-262, and the relevant portions of such documents are incorporated herein by reference.

[0093] Additional mutations that may potentially cause obesity in humans include R18H, R18L, S36Y, P48S, V50M, F51L, E61K, I69T, D90N, S94R, G98R, I121T, A154D, Y157S, W174C, G181D, F202L, A219V, I226T, G231S, G238D, N240S, C271R, S295P, P299L, E308K, I317V, L325F, and 750DelGA, as described in Xiang et al., “Pharmacological characterization of 30 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists, synthetic agonists, and the endogenous agouti-related protein antagonist.” Biochemistry, 2010 Jun 8;49(22):4583-600, the relevant parts of which are incorporated herein by reference.

[0094] Further examples of mutations that may in some cases cause obesity in humans are listed in the Online Mendelian Inheritance in Man (OMIM), a database of human genes and genetic diseases, under accession number 155541 (MC4R), more precisely under accession numbers 155541.0001 to 155541.0023, at the URL http: / / omim.org / entry / 155541. Representative examples include 4-BP DEL, NT631; 4-BP INS, NT732; TYR35TER; ASP37VAL; SER58CYS; ILE102SER; ASN274SER; 1-BP INS, 112A; 4-BP DEL, 211CTCT; ILE125LYS; ALA175THR; ILE316SER; TYR287TER; ASN97ASP; 15-BP DEL (codons δ88-92); and SER127LEU. The relevant part of the OMIM database is incorporated herein by reference. Further exemplary mutations in MC4R are described in Lee, Annals Acad. Med. 38.1 (2009): 34-44.

[0095] In an exemplary embodiment, the MC4R mutation results in the maintenance of MC4R signaling activity. Mutations in the genomic sequence encoding MC4R can be detected by methods known to those skilled in the art. For example, the genomic sequence can be cloned using nucleotide primers such as those described in Farooqi et al., The Journal of Clinical Investigation, July 2000, vol. 106(2), pp. 271-279, and Vaisse et al., The Journal of Clinical Investigation, July 2000, vol. 106(2), pp. 253-262, and the cloned sequence can be analyzed using commercially available sequencers and software.

[0096] The activity of MC4R can be measured by methods known to those skilled in the art. For example, cells can be transiently transfected with cloned MC4R DNA, and the transfected cells are contacted with an agonist of MC4R (e.g., α-MSH), and the intracellular concentration of cAMP, which is a secondary messenger of MC4R, is measured by, for example, the electrochemiluminescence assay described in Roubert et al., Journal of Endocrinology (2010) 207, pp. 177-183. A decrease in MC4R signaling can be confirmed by comparing the intracellular concentration of cAMP produced in response to a given agonist by wild-type MC4R with the intracellular concentration of cAMP produced by mutant MC4R.

[0097] An MC4R agonist can bind directly or indirectly to MC4R. In one embodiment, the MC4R agonist binds to MC4R in or near the ligand-binding pocket. In one embodiment, the MC4R agonist binds to MC4R in or near the G-protein binding cavity. In one embodiment, the MC4R agonist binds to MC4R in or near a transmembrane domain or an extracellular loop, such as TM2, TM3, TM5, TM7, EL2, and / or EL3. Further interactions between the MC4R agonist and MC4R may be exemplified in Nat Cell Research (2021) 31:1176-1189, which is incorporated herein by reference.

[0098] Melanocortin-4 receptor (MC4R) pathway gene The melanocortin (MC) system, including agouti, agouti-related protein, and their receptors, integrates hormonal, metabolic, and neural signals to control energy homeostasis and regulate appetite, metabolic rate, and body weight. MCs, including α-melanocyte-stimulating hormone (α-MSH), β-MSH, γ-MSH, and ACTH, are a family of peptide hormones derived from a precursor protein called proopiomelanocortin (POMC). Activation of the MC4 receptor (MC4R) in the POMC-MC4R pathway increases metabolic rate and decreases food intake. See, for example, Fan et al. Nature 1997;385:165-68. The POMC-MC4R pathway contributes to the control of energy homeostasis, for example, by regulating appetite and metabolic rate, and includes multiple proteins such as melanocortin (MC), MC4 receptor (MC4R), POMC, proprotein convertase subtilisin / kexin type 1 (PCSK1, also called PC1 / 3), MAGE-like 2 (MAGEL2), leptin receptor (leptin-R), leptin, 5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-HT2c receptor), nescient helix-loop-helix 2 (NhHL2, also called NSCL2), prohormone convertase, carboxypeptidase E (CPE), and single-minded 1 (Sim1). MC4R and other components of the POMC-MC4R pathway play important roles in body weight regulation. Mutations in the MC4R gene have been reported to cause early-onset and severe obesity. Other genetic defects in the POMC-MC4R pathway are also likely to cause early-onset and severe obesity. These genes are collectively referred to as "genes capable of activating the MC4R pathway," and examples are shown below.In one embodiment, the gene capable of activating the MC4R pathway does not include any one of POMC, proprotein convertase subtilisin / kexin type 1 (also called PCSK1, PC1 / 3), MAGE-like 2 (MAGEL2), leptin receptor (leptin-R), leptin, 5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-HT2c receptor), nescient helix-loop-helix 2 (also called NhHL2, NSCL2), prohormone convertase, carboxypeptidase E (CPE), and single-minded 1 (Sim1). In one embodiment, the subject does not exhibit a gene mutation or genetic defect in a gene capable of activating the MC4R, such as a gene capable of activating the MC4R described below.

[0099] ADP ribosylation factor-like GTPase 6 (ARL6) ADP ribosylation factor-like GTPase 6 (ARL6), also known as BBS3, is a member of the ARF-like (ADP ribosylation factor-like) subfamily of the ARF family of GTP-binding proteins, which is involved in the regulation of intracellular transport. ARL6 is involved in membrane protein transport at the base of the ciliary organelle and mediates the mobilization of the BBSome complex to the plasma membrane. Together with BBS1, ARL6 is required to correctly transport PKD1 mainly to the cilia. Together with the BBSome complex and LTZL1, ARL6 controls the ciliary transport of SMO and contributes to sonic hedgehog (SHH) pathway regulation. ARL6 is thought to be able to regulate ciliary integration and disassembly, as well as subsequent ciliary signaling events such as the Wnt signaling cascade. ARL6 isoform 2 may be required for proper retinal function and organization. A vision-specific transcript encoding the long isoform BBS3L has also been described.

[0100] Mutations in the ARL6 gene are associated with Bardet-Biedl syndrome (BBS), a genetically heterogeneous disorder. BBS is a form of Laurence-Moon-Biedl syndrome and is characterized by obesity, retinitis, learning disabilities, polydactyly, genital hypoplasia, and retinitis pigmentosa 55 (see, e.g., Young et al. Am. J. Med. Genet. 78(5):461-7(2002)).

[0101] The human ARL6 gene sequence is shown at GenBank accession number NG_008119.2 and is incorporated herein by reference. Exemplary human ARL6 nucleic acid sequences are shown at GenBank accession number NM_001278293.3 and are incorporated herein by reference. An exemplary amino acid sequence of human ARL6 is shown by Q9H0F7 and is incorporated herein by reference. In one embodiment, the subject is identified as not having or not being identified as having a genetic mutation or genetic defect in the ARL6 gene.

[0102] Retinoic acid-induced 1 (RAI1) Retinoic acid-induced 1 (RAI1) is a transcription factor that regulates the circadian clock components: CLOCK, ARNTL / BMAL1, ARNTL2 / BMAL2, PER1 / 3, CRY1 / 2, NR1D1 / 2, and RORA / C. RAI1 positively regulates the transcriptional activity of CLOCK, a core component of the circadian clock (see, e.g., Williams et al. Am. J. Hum. Genet. 90(6):941-9(2012)). RAI1 also regulates transcription by interacting with other proteins in chromatin and by chromatin remodeling through interaction with proteins in the basal transcription machinery. RAI1 is thought to be important for embryonic and postnatal growth and may be involved in neuronal cell differentiation.

[0103] Mutations in RAI1 (e.g., resulting in haploinsufficiency) are associated with Smith-Magenis syndrome, a disorder characterized by cognitive and behavioral abnormalities, including self-injurious behavior and sleep disturbances, obesity, and distinctive craniofacial and skeletal anomalies, which are associated with deletions involving chromosome 17p11.2 (see, e.g., Slager et al. Nat Genet. 33(4):466-468 (2003)).

[0104] The human RAI1 gene sequence is set forth at GenBank accession number NG_007101.2 and is incorporated herein by reference. Exemplary human RAI1 nucleic acid sequences are set forth at GenBank accession number NM_030665.4 and are incorporated herein by reference. An exemplary amino acid sequence of human RAI1 is set forth by Q7Z5J4-1 and is incorporated herein by reference. In one embodiment, a subject is not identified as having or being likely to have a genetic mutation or defect in the RAI1 gene.

[0105] Steroid receptor coactivator 1 (SRC1) Steroid receptor coactivator 1 (SRC1), also known as nuclear receptor coactivator 1 (NCOA1), is a transcriptional coactivator for steroid and nuclear hormone receptors. SRC1 is a member of the p160 / SRC family and, like other family members, has histone acetyltransferase activity and contains a nuclear localization signal, in addition to bHLH and PAS domains. SRC1 binds directly to nuclear receptors and stimulates transcriptional activity in a hormone-dependent manner. SRC1 is involved, for example, in the coactivation of different nuclear receptors for steroids, retinoids, thyroid hormones, and prostaglandins. SRC1 is also involved in coactivation mediated by the STAT3, STAT5A, STAT5B, and STAT6 transcription factors. SRC1 plays a central role in the formation of multi-subunit coactivator complexes that act by chromatin remodeling and, in some cases, acts by being involved in both chromatin remodeling and the recruitment of general transcription factors. SRC1 associates with NCOA2, controls the metabolic balance between white and brown adipose tissues, and mediates the steroid hormone response. Transcriptional variants that have undergone alternative splicing to encode different isoforms have also been identified.

[0106] Mutations in SRC1 are associated with obesity. Although not bound by theory, SRC-1 is thought to control the function of hypothalamic proopiomelanocortin (Pomc) neurons, which regulate feeding and body weight. Rare heterozygous variants of SRC1 have been found in severely obese individuals in which there was a defect in leptin-mediated Pomc reporter activity in cells (see, for example, Yang et al. Nat. Commun. 10(1):1718 (2019)).

[0107] The human SRC1 gene sequence is shown in GenBank accession number NG_029014.2 and is incorporated herein by reference. An exemplary human SRC1 nucleic acid sequence is shown in GenBank accession number NM_003743.5 and is incorporated herein by reference. An exemplary amino acid sequence of human SRC1 is shown by Q15788-1 and is incorporated herein by reference. In one embodiment, the subject is not identified as having or having a genetic mutation or genetic defect in the SRC1 gene.

[0108] Bardet-Biedl syndrome 19 (BBS19) Also known as intraflagellar transport protein 27 homolog (IFT27), Bardet-Biedl syndrome 19 (BBS19) is a small GTPase-like component of the intraflagellar transport complex B and is essential for cilia biogenesis and maintenance. BBS19 promotes the exit of the BBSome complex from cilia through interaction with ARL6. BBS19 forms a partial complex with IFT25 within the IFT complex B and prevents the aggregation of GTP-free ARL6, but is not thought to be involved in the entry of the BBSome complex into cilia (see, for example, Liew et al. Dev. Cell 31(3):265-278 (2014)). BBS19 is also required for Hedgehog signaling. The role of BBS19 in intraflagellar transport is mainly confirmed in tissues rich in ciliated cells such as the kidney and testis. BBS19 is essential for male fertility, spermatogenesis, and sperm flagella formation, plays a role in early kidney development, and may be involved in the regulation of ureteric bud initiation.

[0109] Mutations in the BBS19 gene are associated with Bardet-Biedl syndrome (see, for example, Aldahmesh et al. Hum. Mol. Genet. 23(12):3307-15 (2014)).

[0110] The human BBS19 gene sequence is shown in GenBank accession number NG_034205.1 and is incorporated herein by reference. An exemplary human BBS19 nucleic acid sequence is shown in GenBank accession number NM_001177701.3 and is incorporated herein by reference. An exemplary amino acid sequence of human BBS19 is shown by Q9BW83-1 and is incorporated herein by reference. In one embodiment, the subject is not identified as having or having a gene mutation or genetic defect in the BBS19 gene.

[0111] Bardet-Biedl syndrome 21 (BBS21) Also known as chromosome 8 open reading frame 37 (C8orf37), Bardet-Biedl syndrome 21 (BBS21) encodes a protein of unknown function that is widely expressed. Large amounts of BBS21 mRNA can be found in the brain, heart, and retina. The protein has been shown to co-localize mainly with polyglutamylated tubulin at the base of the cilia in human retinal pigment epithelial cells. Mutations in the BBS21 gene are associated with Bardet-Biedl syndrome, autosomal recessive cone-rod dystrophy (arCRD), and retinitis pigmentosa (see, for example, Heon et al. Hum. Mol. Genet. 25(11):2283-2294 (2016)).

[0112] The human BBS21 gene sequence is shown in GenBank accession number NG_032804.1 and is incorporated herein by reference. An exemplary human BBS21 nucleic acid sequence is shown in GenBank accession number NM_177965.4 and is incorporated herein by reference. An exemplary amino acid sequence of human BBS21 is shown by Q96NL8-1 and is incorporated herein by reference. In one embodiment, the subject is not identified as having or having a gene mutation or genetic defect in the BBS21 gene.

[0113] Centrosomal protein 290 (CEP290) Centrosomal protein 290 (CEP290), also known as BBS14, encodes a protein that contains 13 putative coiled-coil domains, an SMC chromosome segregation ATPase, six KID motifs, three tropomyosin homology domains, and a region homologous to ATP / GTP-binding site motif A. The protein is localized to the centrosome and cilia and has sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation.

[0114] CEP290 is involved in the early and late steps in ciliogenesis, and its association with CCP110 is required to inhibit primary cilia formation by CCP110. CEP290 may play a role in the initial ciliogenesis in the disappearance of centriolar satellites and in the transition of primary ciliary vesicles (PCVs) to ciliary capping vesicles (CCVs). CEP290 is also required for the centrosomal recruitment of RAB8A and for targeting centriolar satellite proteins to the centrosome, such as those in PCM1. CEP290 is required for the correct localization of cilia and phototransduction proteins in retinal photoreceptor cells and may play a role in the ciliary transport process. It is required for the efficient recruitment of RAB8A to the primary cilium. In the ciliary transition zone, CEP290 is required for tissue-specific ciliogenesis and is part of a structural-like complex that may regulate the ciliary membrane composition. CEP290 is involved in the regulation of the complex integrity of the BBSome, particularly in the presence of BBS2, BBS5, and BBS8 / TTC8 within the complex, and in the ciliary targeting of selected BBSome cargo. CEP290 may play a role in the control of the entry of the BBSome complex into the cilium.

[0115] Mutations in this gene are associated with several ciliopathies, including Bardet-Biedl syndrome, retinitis pigmentosa, nephronophthisis (NPHP), Joubert syndrome, Senior-Loken syndrome (SLSN), and neonatal lethal Meckel-Gruber syndrome (MKS) (see, e.g., Zhang et al. Hum. Mol. Genet. 23(1):40-51 (2014), and Leitch et al. Nat. Genet. 40(4):443-448 (2008)).

[0116] The human CEP290 gene sequence is shown at GenBank accession number NG_008417.2 and is incorporated herein by reference. An exemplary human CEP290 nucleic acid sequence is shown at GenBank accession number NM_025114.4 and is incorporated herein by reference. An exemplary amino acid sequence of human CEP290 is shown by O15078-1 and is incorporated herein by reference. In one embodiment, the subject is identified as not having or not being identified as having a gene mutation or genetic defect in the CEP290 gene.

[0117] Intraflagellar transport 74 (IFT74) Intraflagellar transport 74 (IFT74) is a core component of intraflagellar transport (IFT), a multi-protein complex involved in transporting ciliary proteins along axonemal microtubules. IFT proteins are found at the base of the cilium, in addition to within the cilium, where the IFT proteins aggregate into long arrays between the base and the tip of the cilium. Specifically, IFT74 forms a tubulin-binding molecule with IFT81 within the cilium that mediates, in particular, the transport of tubulin. IFT74 binds to β-tubulin via its basal domain and is required for photoreceptor development.

[0118] Naturally occurring mutations within this gene are associated with Bardet-Biedl syndrome and amyotrophic lateral sclerosis-frontotemporal dementia (see, e.g., Lindstrand et al. Am. J. Hum. Genet. 99(2):318-336 (2016)).

[0119] The human IFT74 gene sequence is shown in GenBank accession number NG_053083.1 and is incorporated herein by reference. An exemplary human IFT74 nucleic acid sequence is shown in GenBank accession number NM_001099222.2 and is incorporated herein by reference. An exemplary amino acid sequence of human IFT74 is shown by Q96LB3-1 and is incorporated herein by reference. In one embodiment, the subject is not identified as having or having a gene mutation or genetic defect in the IFT74 gene.

[0120] Leucine zipper transcription factor-like 1 (LZTFL1) Leucine zipper transcription factor-like 1 (LZTFL1), also known as BBS17, encodes a ubiquitously expressed protein that localizes to the cytoplasm. This protein interacts with Bardet-Biedl syndrome (BBS) proteins and regulates protein transport to the ciliary membrane through its interaction with the BBS protein complex. LZTFL1 regulates the ciliary localization of the BBSome complex and, together with the BBSome complex, controls SMO ciliary transport and contributes to sonic hedgehog (SHH) pathway regulation.

[0121] Nonsense mutations within this gene are associated with a form of Bardet-Biedl syndrome (see, for example, Deffert et al. Am. J. Med. Genet. A. 143A(2):208-213(2007)). LZTFL1 may also function as a tumor suppressor, in part, by interacting with E-cadherin and the actin cytoskeleton and thereby regulating the transition of epithelial cells to mesenchymal cells. Alternative splicing of LZTFL1 results in multiple transcriptional variants.

[0122] The human LZTFL1 gene sequence is shown in GenBank accession number NG_033917.1 and is incorporated herein by reference. An exemplary human LZTFL1 nucleic acid sequence is shown in GenBank accession number NM_020347.4 and is incorporated herein by reference. An exemplary amino acid sequence of human LZTFL1 is shown by Q9NQ48-1 and is incorporated herein by reference. In one embodiment, the subject is not identified as having or having a gene mutation or genetic defect in the LZTFL1 gene.

[0123] MKS transition zone complex subunit 1 (MKS1) MKS transition zone complex subunit 1 (MKS1), also known as BBS13, is a component of a structural-like complex that localizes to the transition zone of the primary cilium and acts as a barrier to prevent the diffusion of transmembrane proteins between the cilium and the plasma membrane. MKS1 localizes to the basal body and is involved in the movement of the centrosome to the apical cell surface during early ciliogenesis and is required for the formation of primary cilia in ciliated epithelial cells. It is required for functions including roles in controlling the length and proper number by regulating ciliary structure, as well as centrosome duplication. MKS1 is also required for cell branching morphology.

[0124] Mutations within this gene result in Meckel syndrome type 1 and Bardet-Biedl syndrome type 13 (see, e.g., Xing et al. PLoS One 9(3):e90599 (2014)). Multiple transcript variants encoding different isoforms have been identified for this gene.

[0125] The human MKS1 gene sequence is shown in GenBank accession number NG_013032.1 and is incorporated herein by reference. An exemplary human MKS1 nucleic acid sequence is shown in GenBank accession number NM_017777.4 and is incorporated herein by reference. An exemplary amino acid sequence of human MKS1 is shown by Q9NXB0-1 and is incorporated herein by reference. In one embodiment, the subject is not identified as having or having a gene mutation or genetic defect in the MKS1 gene.

[0126] Tripartite motif-containing 32 (TRIM32) Tripartite motif-containing 32 (TRIM32), also known as BBS11, is a member of the tripartite motif (TRIM) family. The protein encoded by the TRIM32 gene contains three zinc-binding domains, RING, B-box type 1, and B-box type 2; as well as a coiled-coil region. The protein encoded by TRIM32 localizes to the cytoplasmic body and the nucleus, where the protein interacts with the activation domain of the HIV-1 Tat protein. The TRIM32 protein also has E3 ubiquitin ligase activity and has been shown to ubiquitinate DTNBP1 (dysbindin), promoting the degradation of DTNBP1. The TRIM32 protein may also ubiquitinate BBS2.

[0127] Mutations in TRIM32 are associated with muscular dystrophy, limb-girdle, autosomal recessive 8, and Bardet-Biedl syndrome (see, for example, Chiang et al. Proc. Natl. Acad. Sci. U.S.A. 103(16):3287-92(2006)).

[0128] The human TRIM32 gene sequence is shown in GenBank accession number NG_011619.1 and is incorporated herein by reference. An exemplary human TRIM32 nucleic acid sequence is shown in GenBank accession number NM_012210.4 and is incorporated herein by reference. An exemplary amino acid sequence of human TRIM32 is shown by Q13049-1 and is incorporated herein by reference. In one embodiment, the subject is not identified as having or having a gene mutation or genetic defect in the TRIM32 gene.

[0129] WD repeat-containing planar cell polarity effector (WDPCP) The WD repeat-containing planar cell polarity effector (WDPCP), also known as BBS15, is a cytoplasmic WD40 repeat protein. WDPCP has been shown to act as a planar cell polarity protein, which plays an important role in collective cell migration and ciliogenesis by mediating septin localization. Together with FUZ, WDPCP has been shown to function as a core component of the CPLANE (ciliogenesis and planar polarity effector) complex, which is involved in the recruitment of peripheral IFT-A proteins to the basal body.

[0130] Mutations within this gene are associated with Bardet-Biedl syndrome and may also play a role in Meckel-Gruber syndrome (see, e.g., Kim et al. Science 329(5997):1337-40(2010)). Alternative splicing results in multiple transcript variants.

[0131] The human WDPCP gene sequence is shown in GenBank accession number NG_028144.2 and is incorporated herein by reference. An exemplary human WDPCP nucleic acid sequence is shown in GenBank accession number NM_001042692.3 and is incorporated herein by reference. An exemplary amino acid sequence of human WDPCP is shown by O95876-1 and is incorporated herein by reference. In one embodiment, the subject is not identified as having or having a gene mutation or genetic defect in the WDPCP gene.

[0132] Ribosomal protein S6 kinase A3 (RPS6KA3) Ribosomal protein S6 kinase A3 (RPS6KA3) acts downstream of ERK (MAPK1 / ERK2 and MAPK3 / ERK1) signaling, mediates the mitotic and stress-induced activation of transcription factors CREB1, ETV1 / ER81, and NR4A1 / NUR77, controls translation by phosphorylating RPS6 and EIF4B, regulates mTOR signaling, and suppresses the pro-apoptotic functions of BAD and DAPK1, thereby mediating cell proliferation, survival, and differentiation. It is a member of the RSK (ribosomal S6 kinase) family of serine / threonine kinases. In fibroblasts, RPS6KA3 is required for EGF-stimulated phosphorylation of CREB1 and histone H3 at "Ser-10", which results in subsequent transcriptional activation of several early genes. RPS6KA3 phosphorylates and activates the NR4A1 / NUR77 and ETV1 / ER81 transcription factors as well as the co-factor CREBBP in response to mitogenic stimuli (EGF and PMA). During insulin-driven signaling, RPS6KA3 acts indirectly in the transcriptional regulation of several genes by phosphorylating GSK3B at "Ser-9" and inhibiting its activity. RPS6KA3 promotes translation initiation by phosphorylating RPS6 in response to serum or EGF through a mechanism independent of mTOR and facilitating the assembly of the pre-initiation complex. In response to insulin, RPS6KA3 phosphorylates EIF4B, improves the affinity of EIF4B for the EIF3 complex, and stimulates cap-dependent translation. RPS6KA3 is involved in the mTOR nutrient sensing pathway by directly phosphorylating TSC2 at "Ser-1798" (which potently inhibits the ability of TSC2 to suppress mTOR signaling) and mediates the phosphorylation of RPTOR (which can regulate mTORC1 activity and promote rapamycin-sensitive signaling independently of the PI3K / AKT pathway). RPS6KA3 phosphorylates the pro-apoptotic proteins BAD and DAPK1 and mediates cell survival by suppressing their pro-apoptotic functions. RPS6KA3 promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4).RPS6KA3 is also involved in cell cycle control by phosphorylating CDKN1B, a CDK inhibitor, thereby promoting the association of CDKN1B with 14-3-3 proteins and preventing the translocation of CDKN1B to the nucleus and the inhibition of G1 progression. In LPS-stimulated dendritic cells, RPS6KA3 is involved in TLR4-induced macropinocytosis, and in myeloma cells, RPS6KA3 acts as an effector of FGFR3-mediated transformation signaling after direct phosphorylation at Tyr-529 by FGFR3. RPS6KA3 negatively regulates EGF-induced MAPK1 / 3 phosphorylation by phosphorylating SOS1. RPS6KA3 phosphorylates SOS1 at "Ser-1134" and "Ser-1161" (thereby creating YWHAB and YWHAE binding sites that contribute to the negative regulation of MAPK1 / 3 phosphorylation), phosphorylates EPHA2 at "Ser-897", and the RPS6KA-EPHA2 signaling pathway controls cell migration.

[0133] Mutations in this gene are associated with Coffin-Lowry syndrome (CLS), a rare X-linked semi-dominant syndrome characterized by profound psychomotor retardation, facial dysmorphism, finger anomalies, and progressive skeletal deformities (see, for example, Delaunoy et al. Clin. Genet. 70(2):161-6 (2006)).

[0134] The human RPS6KA3 gene sequence is shown in GenBank accession number NG_007488.1 and is incorporated herein by reference. An exemplary human RPS6KA3 nucleic acid sequence is shown in GenBank accession number NM_004586.3 and is incorporated herein by reference. An exemplary amino acid sequence of human RPS6KA3 is shown by P51812-1 and is incorporated herein by reference. In one embodiment, the subject is identified as not having or not being identified as having a gene mutation or genetic defect in the RPS6KA3 gene.

[0135] 5-Hydroxytryptamine receptor 2C (HTR2C) 5-Hydroxytryptamine receptor 2C (HTR2C) is a seven-transmembrane G protein-coupled receptor for 5-hydroxytryptamine (serotonin). HTR2C also functions as a receptor for various drugs and psychoactive substances, including ergoline derivatives, 1-2,5,-dimethoxy-4-iodophenyl-2-aminopropane (DOI), and lysergic acid diethylamide (LSD). Ligand binding causes a conformational change that induces signal transduction via guanine nucleotide-binding protein (G protein), regulating the activity of downstream effectors. β-Arrestin family members inhibit signal transduction via G protein and mediate the activity of alternative signal transduction pathways. Signal transduction activates the phosphatidylinositol-calcium second messenger system, which regulates the activity of phosphatidylinositol 3-kinase and downstream signal transduction cascades, promoting the release of Ca 2+ ions from intracellular stores. HTR2C also regulates neuronal activity by activating transient receptor potential calcium channels in the brain, thereby regulating the activation of proopiomelanocortin neurons and the release of corticotropin-releasing hormone (CRH), which subsequently regulates the release of corticosterone. HTR2C plays a role in the regulation of appetite and feeding behavior, responds to anxiety-provoking stimuli and stress, and also plays a role in insulin sensitivity and glucose homeostasis.

[0136] The mRNA of HTR2C is subjected to multiple RNA editing events, where adenosine residues encoded by the genome are converted to inosine. RNA editing is expected to alter the structure of the second intracellular loop, resulting in the generation of alternative protein forms with reduced ability to interact with G proteins. Abnormalities in the RNA editing of HTR2C have been detected in suicide victims with depression. Furthermore, naturally occurring changes in the promoter and 5' non-coding and coding regions of HTR2C may show a statistically significant association with mental disorders and behavioral disorders. Alternative splicing results in multiple different transcript variants. Mutations in HTR2C are associated with bulimia, hyperactivity, and obesity (see, for example, Xu et al. Neuron. 60(4):582-9 (2008)).

[0137] The human HTR2C gene sequence is shown at GenBank accession number NG_012082.2 and is incorporated herein by reference. An exemplary human HTR2C nucleic acid sequence is shown at GenBank accession number NM_001256760.2 and is incorporated herein by reference. An exemplary amino acid sequence of human HTR2C is shown by P28335-1 and is incorporated herein by reference. In one embodiment, the subject is not identified as having or having a genetic mutation or genetic defect in the HTR2C gene.

[0138] Kinase suppressor of Ras2 (KSR2) The kinase suppressor of Ras2 (KSR2) is an intracellular scaffold protein that is involved in multiple signaling pathways. In particular, KSR2 is a positional control scaffold that links MEK to RAF. KSR2 has been shown to have very low protein kinase activity and can phosphorylate MAP2K1 at several Ser and Thr residues with very low efficiency in vitro. KSR2 functions as a MAP2K1 / MEK1-dependent allosteric activator of BRAF, and upon binding to MAP2K1 / MEK1, KSR2 dimerizes with BRAF and promotes BRAF-mediated phosphorylation of MAP2K1 / MEK1 (see, for example, Lavoie et al. Nature 554:549-553 (2018)). Interaction with BRAF improves KSR2-mediated phosphorylation of MAP2K1 in vitro. KSR2 blocks MAP3K8 kinase activity and MAP3K8-mediated signaling. KSR2 also functions as a negative regulator of the activation of the ERK, JNK, and NF-κB pathways mediated by MAP3K3 and inhibits MAP3K3-mediated interleukin-8 production.

[0139] Mutations in KSR2 are associated with childhood hyperphagia, low heart rate, reduced basal metabolic rate, and severe insulin resistance, suggesting that KSR2 is an important regulator of energy intake, metabolism, and substrate utilization in humans (see, for example, Pearce et al. Cell. 155(4):765-77(2013)).

[0140] The human KSR2 gene sequence is shown at GenBank accession number NC_000012.12 and is incorporated herein by reference. An exemplary human KSR2 nucleic acid sequence is shown at GenBank accession number NM_173598.6 and is incorporated herein by reference. An exemplary amino acid sequence of human KSR2 is shown by Q6VAB6-1 and is incorporated herein by reference. In one embodiment, the subject is not identified as having or not having a genetic mutation or genetic defect in the KSR2 gene.

[0141] Prokineticin 2 (PROK2) The prokineticin 2 (PROK2) gene encodes a protein that is expressed in the suprachiasmatic nucleus (SCN) circadian clock and can function as an output component of the circadian clock. The secreted form of the encoded protein can also function as a chemoattractant for neural progenitor cells in the olfactory bulb. Proteins from other vertebrates similar to the PROK2 gene product were isolated based on homology to snake venom. Secretions from frog skin have been shown to have various functions.

[0142] Mutations in PROK2 are associated with hypogonadotropic hypogonadism type 4, with or without anosmia and Kallmann syndrome. Multiple transcript variants encoding different isoforms have been found for this gene (see, for example, Dode et al. PLoS Genet. 2(10):e175 (2006)).

[0143] The human PROK2 gene sequence is shown in GenBank accession number NG_008275.1 and is incorporated herein by reference. An exemplary human PROK2 nucleic acid sequence is shown in GenBank accession number NM_001126128.2 and is incorporated herein by reference. An exemplary amino acid sequence of human PROK2 is shown by Q9HC23-1 and is incorporated herein by reference. In one embodiment, the subject is not identified as having or not having a gene mutation or genetic defect in the PROK2 gene.

[0144] Ras-related protein Rab-23 (RAB23) The Ras-related protein Rab-23 (RAB23) is a small GTPase of the Ras superfamily. Small GTPase Rab is involved in the regulation of diverse cellular functions related to intracellular membrane trafficking, including autophagy and the immune response to bacterial infections. Rab cycles between an inactive GDP-bound form and an active GTP-bound form that can recruit a different set of downstream effectors directly responsible for vesicle formation, movement, tethering, and fusion to the membrane. Together with SUFU, the protein encoded by RAB23 prevents the nuclear import of GLI1, thereby inhibiting the transcriptional factor activity of GLI1. RAB23 also regulates GLI1 during chondrocyte differentiation, regulates GLI3 proteolytic processing, and regulates GLI2 and GLI3 transcriptional factor activities. RAB23 also plays a role in the aggregation of autophagosomes and then mediates defense against pathogens, such as S. aureus, by promoting their capture by autophagosomes that emerge by lysosomes. RAB23 may play a role in the development of the central nervous system by attenuating Sonic hedgehog signaling.

[0145] Mutations in RAB23 are associated with cancer and Carpenter syndrome, a pleiotropic disorder with autosomal recessive inheritance (basic features include premature cranial suture fusion, polysyndactyly, obesity, and heart defects. See, for example, Jenkins et al. Am. J. Hum. Genet. 80(6):1162-70 (2007)). Alternative splicing results in multiple transcript variants.

[0146] The human RAB23 gene sequence is shown in GenBank accession number NG_012170.1 and is incorporated herein by reference. An exemplary human RAB23 nucleic acid sequence is shown in GenBank accession number NM_016277.5 and is incorporated herein by reference. An exemplary amino acid sequence of human RAB23 is shown by Q9ULC3-1 and is incorporated herein by reference. In one embodiment, the subject is identified as not having or not being identified as having a gene mutation or genetic defect in the RAB23 gene.

[0147] Melanocortin 2 receptor accessory protein 2 (MRAP2) Melanocortin 2 receptor accessory protein 2 (MRAP2) is a G protein-coupled receptor accessory protein that modulates melanocortin receptor signaling and is involved in energy homeostasis. The encoded protein has been shown to interact with all known melanocortin receptors and can regulate both receptor transport and activation in response to ligands. MRAP2 is thought to play a central role in the control of energy homeostasis and body weight regulation by increasing the ligand sensitivity of MC4R and the production of cAMP mediated by MC4R. MRAP2 can also act as a negative regulator of MC2R (e.g., by competing with MRAP for binding to MC2R and impairing the binding of adrenocorticotropic hormone (ACTH) to MC2R). MRAP2 can also control the activity of other melanocortin receptors (MC1R, MC3R, and MC5R). MRAP2 has been implicated in metabolic control in rodents, particularly via the melanocortin-4 receptor.

[0148] Defects in MRAP2 are associated with obesity (e.g., monogenic hyperphagic obesity, hyperglycemia, and hypertension) in both children and adults (see, e.g., Baron et al. Nat. Med. 25(11):1733-1738 (2019)).

[0149] The human MRAP2 gene sequence is shown in GenBank accession number NG_051944.1 and is incorporated herein by reference. An exemplary human MRAP2 nucleic acid sequence is shown in GenBank accession number NM_138409.4 and is incorporated herein by reference. An exemplary amino acid sequence of human MRAP2 is shown by Q96G30-1 and is incorporated herein by reference. In one embodiment, the subject has not been identified as having or having a genetic mutation or genetic defect in the MRAP2 gene.

[0150] AF4 / FMR2 family member 4 (AFF4) AF4 / FMR2 family member 4 (AFF4) is a component of the positive transcription elongation factor b (P-TEFb) complex, a core component of the super elongation complex (SEC) required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient interruptions by polymerase at multiple sites along DNA. In the SEC complex, AFF4 functions as a central scaffold for recruiting other factors through direct interaction with ELL proteins (e.g., ELL, ELL2, or ELL3) and the P-TEFb complex. In the case of infection by the HIV-1 virus, the SEC complex is recruited by the viral Tat protein to stimulate viral gene expression.

[0151] Chromosomal abnormalities involving ATF4 have been found in acute lymphoblastic leukemia (ALL). Missense mutations in AFF4 are associated with the CHOPS (C for cognitive impairment and coarse facies, H for heart defects, O for obesity, P for lung lesions, and S for short stature and skeletal dysplasia) syndrome (see, e.g., Izumi et al. Nat. Genet. 47(4):338-44 (2015)).

[0152] The human AFF4 gene sequence is shown in GenBank accession number NG_030340.1 and is incorporated herein by reference. An exemplary human AFF4 nucleic acid sequence is shown in GenBank accession number NM_014423.4 and is incorporated herein by reference. An exemplary amino acid sequence of human AFF4 is shown by Q9UHB7-1 and is incorporated herein by reference. In one embodiment, the subject is identified as not having or not being identified as having a gene mutation or genetic defect in the AFF4 gene.

[0153] Adenylate cyclase 3 (ADCY3) Adenylate cyclase 3 (ADCY3) is a membrane-associated enzyme that catalyzes the formation of the second messenger cyclic adenosine monophosphate (cAMP). ADCY3 catalyzes the formation of the signaling molecule cAMP in response to G protein signaling and is involved in the signal transduction cascade triggered by olfactory receptors through its function in cAMP biosynthesis. ADCY3 is required for the perception of smell, sperm motility, and normal male reproduction. ADCY3 also plays a role in regulating insulin concentration and body fat accumulation in response to a high-fat diet. ADCY3 is widely expressed in various human tissues and may be involved in a number of physiological and pathophysiological metabolic processes. Two transcript variants encoding different isoforms have been identified for ADCY3.

[0154] Loss-of-function mutations in ADCY4 have been associated with severe monogenic obesity (see, for example, Saeed et al. Nat. Genet. 50(2):175-179 (2018)).

[0155] The human ADCY3 gene sequence is shown in GenBank accession number NC_000002.12 and is incorporated herein by reference. An exemplary human ADCY3 nucleic acid sequence is shown in GenBank accession number NM_001320613.2 and is incorporated herein by reference. An exemplary amino acid sequence of human ADCY3 is shown by O60266-1 and is incorporated herein by reference. In one embodiment, the subject is identified as not having or not being identified as having a gene mutation or genetic defect in the ADCY3 gene.

[0156] TUB bipartite transcription factor (TUB) The TUB bipartite transcription factor (TUB) is a member of the Tubby family of bipartite transcription factors that functions in signal transduction from heterotrimeric G protein-coupled receptors. The crystal structure has been measured for a similar protein in mouse and functions as a membrane-bound transcriptional regulator that translocates to the nucleus in response to phosphoinositide hydrolysis. TUB has been shown to bind to membranes containing phosphatidylinositol 4,5-bisphosphate and to bind DNA in vitro. TUB may contribute to transcriptional control in the nucleus and may be involved in hypothalamic control of body weight. TUB contributes to the stimulation of phagocytosis in apoptotic retinal pigment (RPE) cells and macrophages. Two transcript variants encoding different isoforms have been identified for this gene.

[0157] Mutations in TUB are associated with obesity and retinal dystrophy (e.g., characterized by obesity and electrophysiological features of rod-cone dystrophy such as night blindness, reduced visual acuity, and see, e.g., Borman et al. Hum. Mutat. 35(3):289-93 (2014)).

[0158] The human TUB gene sequence is shown in GenBank accession number NG_029912.1 and is incorporated herein by reference. An exemplary human TUB nucleic acid sequence is shown in GenBank accession number NM_003320.4 and is incorporated herein by reference. An exemplary amino acid sequence of human TUB is shown by P50607-1 and is incorporated herein by reference. In one embodiment, the subject is identified as not having or not being identified as having a gene mutation or genetic defect in the TUB gene.

[0159] Orthopedia homeobox (OTP) Orthopedia homeobox (OTP) is a member of the homeodomain (HD) family. HD family proteins are helix-turn-helix transcription factors that play important roles in cell fate specification. OTP can function during brain development, particularly in the differentiation of hypothalamic neuroendocrine cells. OTP is thought to be involved in mammalian energy homeostasis and behavior.

[0160] Disruption of OTP has been associated with obesity, cachexia, kwashiorkor, and anxiety (see, for example, Moir et al. Mol. Metab. 6(11):1419-1428 (2017)).

[0161] The human OTP gene sequence is shown in GenBank accession number NC_000005.10 and is incorporated herein by reference. An exemplary human OTP nucleic acid sequence is shown in GenBank accession number NM_032109.3 and is incorporated herein by reference. An exemplary amino acid sequence of human OTP is shown by Q5XKR4-1 and is incorporated herein by reference. In one embodiment, the subject is identified as not having or not being identified as having a gene mutation or genetic defect in the OTP gene.

[0162] G protein-coupled receptor 101 (GPR101) G protein-coupled receptor 101 (GPR101) is an orphan G protein-coupled receptor with many unknown functions. The encoded protein is a member of a family of proteins containing seven transmembrane domains and transduces extracellular signals via heterotrimeric G proteins.

[0163] Diseases associated with GPR101 include pituitary adenoma type 2, growth hormone secretion, and chromosome Xq26.3 duplication syndrome. Although neuronal GLP1R has been shown to mediate the weight and anorectic effects of liraglutide, it is not required for the glucose-lowering effect (see, for example, Sisley et al. J. Clin. Invest. 124(6):2456-63 (2014)).

[0164] The human GPR101 gene sequence is shown in GenBank accession number NG_016367.1 and is incorporated herein by reference. Exemplary human GPR101 nucleic acid sequences are shown in GenBank accession number NM_054021.2 and are incorporated herein by reference. An exemplary amino acid sequence of human GPR101 is shown by Q96P66-1 and is incorporated herein by reference. In one embodiment, the subject is identified as not having or not being identified as having a gene mutation or genetic defect in the GPR101 gene.

[0165] T-Box transcription factor 3 (TBX3) T-Box transcription factor 3 (TBX3) is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of growth processes. TBX3 is a transcriptional repressor and is thought to play a role in the anterior / posterior axis of the forelimbs. TBX3 functions as a negative regulator of the PML function in cellular senescence. TBX3 may also play a role in limb pattern formation. Alternative splicing of this gene results in three transcript variants encoding different isoforms.

[0166] Mutations that disrupt the DNA-binding domain of TBX3 are associated with ulnar-mammary syndrome (UMS), a Carpenter syndrome that affects the development of the limbs, apocrine glands, teeth, hair, and genitalia (see, for example, Bamshad et al. Am. J. Hum. Genet. 64(6):1550-62 (1999)).

[0167] The human TBX3 gene sequence is shown at GenBank accession number NG_008315.1 and is incorporated herein by reference. An exemplary human TBX3 nucleic acid sequence is shown at GenBank accession number NM_016569.4 and is incorporated herein by reference. An exemplary amino acid sequence of human TBX3 is shown by O15119-1 and is incorporated herein by reference. In one embodiment, a subject is not identified as having or having a genetic mutation or genetic defect in the TBX3 gene.

[0168] In embodiments of any of the methods described herein, the method includes treating a subject having a mutation in a gene described in Table 2 below. In embodiments, the methods described herein include the use of an MC4R agonist described herein for treating non-genetic obesity in a subject, such as a subject who does not have a mutation in a gene capable of activating the MC4R pathway, as described in Table 2, for example. In embodiments, the methods described herein include the use of an MC4R agonist described herein for treating a subject having a mutation in a gene capable of activating the MC4R pathway, as described in Table 2, for example. Table 2 lists exemplary genes, alleles, transcripts, and proteins, but other genes, alleles, transcripts, and proteins may also be included. [Table 2]

[0169] Additional genes capable of activating the MC4R pathway Additional genes that can activate the MC4R pathway and are useful in the methods disclosed herein are described as follows: Acyl-CoA binding domain containing 7 (ACBD7), also known as BA455B2.2, is associated with food intake, metabolic rate, and body weight in preclinical models (see, for example, Lanfray et al. Elife. 15;5:e11742 (2016)).

[0170] Agouti-related neuropeptide (AGRP), also known as ASIP2, is associated with hyperphagia and obesity (see, for example, Carroll et al. Clin. Dermatol. 22(4):345-9 (2004)).

[0171] Cell adhesion molecule 1 (CADM1), also known as TSLC1 or IGSF4, is associated with obesity (see, for example, Rathjen et al. Nat. Neurosci. 20(8):1096-1103 (2017)).

[0172] Cell adhesion molecule 2 (CADM2), also known as IGSF4D, is associated with obesity (see, for example, Li et al. Hum. Genet. 132(7):793-801 (2013)).

[0173] Cocaine- and amphetamine-regulated transcript protein (CARTPT), also known as CART, is associated with obesity (see, for example, Asnicar et al. Endocrinology. 42(10):4394-400 (2001)).

[0174] Coiled-coil domain containing 28B (CCDC28B) is associated with Bardet-Biedl syndrome (see, for example, Novas et al. Sic. Rep. 14;8(1):3019 (2018)).

[0175] Cholecystokinin (CCK), also known as preprocholecystokinin, is associated with obesity and body mass index (see, e.g., Namjou et al. Front. Genet. 3;4:268 (2013)).

[0176] Cannabinoid receptor 1 (CNR1), also known as CNR, is associated with obesity, as well as body fat mass and distribution (see, e.g., Russo et al. J. Endocrinol. Metab. 92(6):2382-6 (2007)).

[0177] CREB-binding protein (CREBBP), also known as RSTS, is associated with Rubinstein-Taybi syndrome (see, e.g., Stevens et al. Am. J. Med. Genet. A. 155A(7):1680-4 (2011)).

[0178] CREB3 regulator (CREBRF), also known as C5orf41, is associated with obesity and diabetes (see, e.g., Hanson et al. Diabetologia. 62(9):1647-1652 (2019)).

[0179] Cullin 4B (CUL4B), also known as KIAA0695, MRXHF2, MRXS15, MRXSC, and SFM2, is associated with mental retardation, X-linked, syndromic 15 (Cabezas type) (see, e.g., Tarpey et al. Am. J. Hum. Genet. 80(2):345-52 (2007)).

[0180] DNA methyltransferase 3α (DNMT3A), also known as HESJAS and TBRS, encodes a protein involved in de novo methylation (see, e.g., Xie S. et al. Gene 236(1):87-95 (1999)).

[0181] Dual specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B), also known as minibrain-related kinase, is associated with abdominal obesity metabolic syndrome 3 (see, e.g., Keramati et al. N. Engl. J. Med. 15; 370(20):1909-1919 (2014)).

[0182] Ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1), also known as NPPS, M6S1, and PDNP1, is associated with obesity (see, e.g., Valli-Jaakola et al. Obesity. 16(9):2113-9 (2008)).

[0183] E1A-binding protein P300 (EP300), also known as histone acetyltransferase P300, is associated with Rubinstein-Taybi syndrome (see, e.g., Stevens et al. Am. J. Med. Genet. A. 155A(7):1680-4 (2011)).

[0184] FMRP translational regulator 1 (FMR1), also known as POF1 and POF, is associated with fragile X syndrome (see, e.g., Raspa et al. Am. J. Intelelct. Devv. Disabil. 115(6):482-95 (2010)).

[0185] FTO alpha-ketoglutarate-dependent dioxygenase (FTO), also known as FTO alpha-ketoglutarate-dependent dioxygenase, is associated with obesity-related characteristics including body mass index, hip circumference, and body weight (see, e.g., Scuteri et al. PLoS. Genet. 3(7):e115 (2007)).

[0186] Ghrelin and obestatin prepropeptide (GHRL), also known as prepro appetite-regulating hormone, is associated with obesity (see, for example, J. Clin. Endocrinol. Metab. 87(8):4005-8(2002)).

[0187] Gastric inhibitory polypeptide receptor (GIPR), also known as GIP-R and PGQTL2, is associated with body mass index, as well as energy intake and metabolic pathways in obesity (see, for example, Turcot et al. Nat. Genet. 50(1):26-41(2018)).

[0188] Glucagon-like peptide 1 receptor (GLP1R), also known as GLP-1, is associated with feeding and body weight regulation (see, for example, Sisley et al. J. Clin. Invest. 124(6):2456-63(2014)).

[0189] Inositol polyphosphate-5-phosphatase E (INPP5E), also known as JBTS1, is associated with Joubert syndrome and MORM syndrome, autosomal recessive congenital anomalies characterized by mental retardation, truncal obesity, retinal dystrophy, and micropenis (see, for example, Jacoby et al. Nat. Genet. 41(9):1027-31(2009)).

[0190] Insulin (INS), also known as IDDM2 and IDDM1, is associated with body mass index and obesity (see, for example, Antunez-Ortiz et al. Biomed. Res. Int. 2017:2432957(2017)).

[0191] Insulin-induced gene 2 (INSIG2), also known as insulin-induced protein 2, is associated with feedback control of lipid synthesis and obesity in children (see, e.g., Kaulfers et al. PLoS One 10(1):e0116340 (2015)).

[0192] Insulin receptor substrate 1 (IRS1), also known as HIRS-1, is associated with obesity, type II diabetes, and sensitivity to insulin resistance (see, e.g., Clausen et al. Lancet. 346(8972):397-402 (1995)).

[0193] Insulin receptor substrate 4 (IRS4), also known as Pp160, CHNG9, PY160, and Py160, is associated with obesity, hyperglycemia, and insulin resistance (see, e.g., Sadagurski et al. Mol. Metab. 23;3(1):55-63 (2013)).

[0194] Insulin gene enhancer protein (ISL1), also known as Islet-1 and Isl-1, is a member of the LIM / homeodomain family of transcription factors, and mutations in this gene are associated, among other things, with adult-onset diabetes (see, e.g., Tanizawa Y et al. Diabetes (1994)).

[0195] Methyl-CpG-binding protein 2 (MeCP2), also known as AUTSX3, MRXS13, MRX16, RTS, and RTT, encodes a nuclear protein associated with the onset of Rett syndrome, a progressive neurological developmental disorder. Amir, R.E. et al. Nat Genet 23(2):185-8 (1999).

[0196] Neuropilin-1 (NRP1), also known as CD304 and BDCA4, encodes one of two neuropilins involved in signal transduction pathways that control cell migration. NRP1 has been associated with cerebral arteriopathy, autosomal dominant, and tumors (see, e.g., Soker, S. et al Cell 92(6):735-745).

[0197] Neuropilin-2 (NRP2), also known as NPN2, NP2, and PRO2714, may play a role in cardiovascular development, axon guidance, and tumor formation (see, e.g., Chen, H. et al. Neuron 19(3):547-549(1997)).

[0198] RPGRIP1L-like (RPGRIP1L), also known as FTM, PPP1R134, CORS3, MKS5, JBTS7, and KIAA1005, has been found to interact with nephrocystin-4. Defects in this gene are associated with Joubert syndrome type 7 and Meckel syndrome type 5 (Nagase, T et al DNA Res 6(1):63-70(1999).

[0199] Plexin A1 (PLXNA1), also known as NOV and PLXN1, is associated with hereditary congenital facial paresis and medullary cystic kidney 4 (see, e.g., Maestrini, E. et al. Proc Natl Acad Sci USA 93(2):674-678(1996)).

[0200] Plexin A2 (PLXNA2), also known as OCT, KIAA0463, and FLJ11751, is a member of the plexin-A family thought to be involved in signal transduction from semaphorin-3A and semaphorin-3B (see also, e.g., Coric, V. et al. Depress Anxiety 27(5):417-425(2010)).

[0201] Plexin A3 (PLXNA3), also known as XAP-6, is involved in cytoskeleton remodeling and apoptosis. This gene has been shown to be important in axonal pathfinding during nervous system development and is associated with tumor progression (see, for example, Maestrini, L. et al. Proc Natl Acad Sci USA 93(2):674-678(1996)).

[0202] Plexin A4 (PLXNA4), also known as FAYV2820, KIAA1550, and PRO34003, is associated with signaling pathways that are involved in various, particularly, semaphorin-3A and semaphorin-3B (see, for example, Imboden, M. J Allergy Clin Immunol 129(5):1218-1228(2012)).

[0203] Potassium channel tetramerization domain containing 15 (KCTD15), also known as BTB / POZ domain-containing protein KCTD15, is associated with body mass index and childhood obesity (see, for example, Zhao et al. Obesity 17(12):2254-7(2009)).

[0204] Kinase D interacting substrate 220 (KIDINS220), also known as ARMS, KIAA1250, and SINO, is associated with spastic paraplegia, intellectual disability, nystagmus, and obesity (see, for example, Josifova et al. Hum.Mol.Genet.25(11):2158-2167(2016)).

[0205] Melanin-concentrating hormone receptor 1 (MCHR1), also known as GPR24, is associated with the control of feeding and body weight (see, for example, Marsh et al. Proc.Natl.Acad.Sci.U.S.A.5;99(5):3240-5(2002)).

[0206] Methionine sulfoxide reductase A (MSRA), also known as PMSR, has been associated with several obesity-related features in children (see, e.g., Albuquerque et al. J. Hum. Genet. 59(6):307-13 (2014)).

[0207] Necdin (NDN), a member of the MAGE family, also known as PWCR, has been associated with Prader-Willi syndrome (see, e.g., Jay et al. Nat. Genet. 17(3):357-61 (1997)).

[0208] Neuronal growth regulator 1 (NEGR1), also known as neurotractin, IGLON4, DMML2433, KILON, and Ntra, has been associated with body mass index (see, e.g., Zhao et al. Obesity. 17(12):2254-7 (2009)).

[0209] Neuromedin 2 (NLGN2), also known as KIAA1366, has been associated with anxiety, autism, intellectual disability, bulimia, and obesity (see, e.g., Am. J. Med. Genet. A. 173(1):213-216 (2017)).

[0210] Neuropeptide Y (NPY), also known as PYY4, has been associated with obesity (see, e.g., van Rossum et al. Int. J. Obes. 30(10):1522-8 (2006)).

[0211] Nuclear receptor subfamily 0 group B member 2 (NR0B2), also known as SHP1, has been associated with moderate early-onset obesity (see, e.g., Nishigori et al. PNAS. 16;98(2):575-80 (2001)).

[0212] Neurotrophic tyrosine kinase receptor type 2 (NTRK2), also known as Trk-B, is associated with severe obesity and developmental delay (e.g., NTRK2-deficient obesity) (see, e.g., Yeo et al. Nat. Neurosci. 7(11):1187-9 (2004)).

[0213] Opioid receptor mu 1 (OPRM1), also known as MOR1, MOP, LMOR, OPRM, and HMOP, is associated with metabolism and the MC4R pathway (see, e.g., Olszewski et al. Neuroreport 12(8):1727-1730 (2001)).

[0214] Pericentrin (PCNT), also known as kendrin and PCNT2, is associated with Majewski osteodysplastic primordial dwarfism type II (see, e.g., Rauch et al. Science. 8;319(5864):816-9 (20008)).

[0215] Pleckstrin homology domain interaction protein (PHIP), also known as WDR11, Ndrp, DCAF14, BRWD2 (see, e.g., Webster et al. Cold Spring Harb Mol Case Stud 2(6):a001172 (2016)).

[0216] Proprotein convertase subtilisin / kexin type 2 (PCSK2), also known as NEC2, is associated with glucose homeostasis, feeding, and ultimately body mass (see, e.g., Anini et al. Int. J. Obes. 34(11):1599-607 (2010)).

[0217] PHD finger protein 6 (PHF6), also known as BFLS and BORJ, is associated with Borjeson-Forssman-Lehmann syndrome, a syndrome characterized by moderate to severe mental retardation, epilepsy, hypogonadism, hypometabolism, obesity with prominent gynecomastia, swelling of the facial subcutaneous tissue, narrow palpebral fissures, and large but un-deformed ears (see, e.g., Lower et al. Nat. Genet. 32(4):661-5 (2002)).

[0218] Pro-melanin concentrating hormone (PMCH), also known as MCH and PpMCH, is associated with the control of feeding and body weight (see, e.g., Shimada et al. Nature. 396(6712):670-4 (1998)).

[0219] Peroxisome proliferator-activated receptor gamma (PPARG), also known as NR1C3, PPARG1, PPARG2, CIMT1, and GLM1, is associated with obesity in children and adolescence (see, e.g., Ochoa et al. Int. J. Obes. Relat. Metab. Disord. 28 Suppl 3:S37-41 (2004)).

[0220] Peptide YY (PYY), also known as peptide tyrosine tyrosine, is associated with the control of feeding and obesity (see, e.g., Ahituv et al. Hum. Mol. Genet. 1;15(3):387-91 (2006)).

[0221] Syndecan 3 (SDC3), also known as SDCN, is associated with metabolic balance, obesity, body mass index, and LHDL cholesterol (see, e.g., Chang et al. Int. J. Endocrinol. 30;2018:9282598 (2018)).

[0222] The endoplasmic reticulum export factor of SEC16 homolog B (SEC16B), also known as LZTR2, is associated with body mass index (see, for example, Felix et al. Hum. Mol. Genet. 15;25(2):389-403(2016)).

[0223] Solute carrier family 6 member 14 (SLC6A14), also known as BMIQ11, is associated with body mass index and obesity (see, for example, Suviolahti et al. J. Clin. Invest. 112(11):1762-72(2003)).

[0224] Small nuclear ribonucleoprotein polypeptide N (SNRPN), also known as PWCR, is associated with Prader-Willi syndrome (see, for example, Kuslich et al. Am. J. Hum. Genet. 64(1):70-6(1999)).

[0225] Thyroid hormone receptor beta (THRB), also known as ERBA2 and PRTH, is associated with the control of feeding and body weight (see, for example, Amorim et al. J. Endocrinol. 203(2):291-9(2009)).

[0226] Transient receptor potential cation channel subfamily C member 5 (TRPC5), also known as PPP1R159, TRP-5, and HTRP5 (see, for example, Sossey-Alaoui, K et al. Genomics 60(3):330-3340(1999)).

[0227] Transmembrane protein 18 (TMEM18), also known as LncND, is associated with body mass index and body weight control (see, for example, Willer et al. Nat. Genet. 41(1):25-34(2009)).

[0228] Transmembrane protein 67 (TMEM67), also known as MKS3, is associated with Bardet - Biedl syndrome (see, for example, Leitch et al. Nat. Genet. 40(4):443 - 8 (2008)).

[0229] Transport protein particle complex 9 (TRAPPC9), also known as NIBP, is associated with mental retardation, autosomal recessive 13 (see, for example, Marangi et al. Eur. J. Hum. Genet. 21(2):229 - 32 (2013)).

[0230] Uncoupling protein 1 (UCP1), also known as thermogenin, SLC25A7, and UCP, is associated with obesity (see, for example, Ramos et al. BMC Med. Genet. 7;13:101 (2012)).

[0231] Uncoupling protein 3 (UCP3), also known as SLC25A9, is associated with metabolic fuel partitioning and obesity (see, for example, Argyropoulos et al. J. Clin. Invest. 1;102(7):1345 - 51 (1998)).

[0232] Vacuolar protein sorting 13 homolog B (VPS13B), also known as CHS and COH1, is associated with Cohen syndrome, an autosomal recessive disorder characterized by mental retardation, postnatal microcephaly, facial dysmorphism, retinitis pigmentosa, myopia, and cyclic neutropenia with variable clinical manifestations (see, for example, Seifert et al. J. Med. Genet. 43(5):e22 (2006)).

[0233] In one embodiment, genes capable of activating the MC4R pathway include POMC, PCSK1, LEPR, LEP, SDCCAG8, SH2B1, CPE, ALMS1, BBS1, BBS2, BBS4, BBS5, BBS6, BBS7, BBS8, BBS9, BBS10, BBS12, BBS18, BBS20, GNAS, MC3R, NHLH2, SIM1, BDNF, NTRK2, MAGEL2, or a 16p11.2 deletion. In one embodiment, the subject does not have a gene mutation or gene variant of a gene selected from POMC, PCSK1, LEPR, LEP, SDCCAG8, SH2B1, CPE, ALMS1, BBS1, BBS2, BBS4, BBS5, BBS6, BBS7, BBS8, BBS9, BBS10, BBS12, BBS18, BBS20, GNAS, MC3R, NHLH2, SIM1, BDNF, NTRK2, and MAGEL2, or a 16p11.2 deletion.

[0234] Obesity The present disclosure features methods for treating a subject having obesity, such as non - genetic obesity. In one embodiment, the obesity is hypothalamic obesity. In one embodiment, the obesity is caused by a disease, disorder, or medical condition associated with a gene capable of activating the MC4R pathway. In one embodiment, the disease, disorder, or medical condition is characterized by a mutation (e.g., substitution mutation, deletion mutation, or polymorphism) in a gene capable of activating the MC4R pathway. In an embodiment, the method comprises administering to the subject an MC4R agonist or a composition described herein, e.g., a compound of any one of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) (e.g., as described herein), or a pharmaceutically acceptable salt thereof. In one embodiment, the MC4R agonist is setmelanotide (i.e., Ac - Arg - c(Cys - D - Ala - His - D - Phe - Arg - Trp - Cys)-NH2 (SEQ ID NO: 140)).

[0235] Hypothalamic obesity Hypothalamic obesity (HO) is a form of obesity caused by physical or genetic damage to the hypothalamus, resulting in symptoms such as uncontrollable hunger, rapid and / or excessive weight gain, and a low metabolic rate. The hypothalamus plays a role in regulating energy balance and body weight by integrating metabolic information that controls the driving forces of feeding and energy consumption, mainly through signal transduction via the melanocortin 4 receptor (MC4R). MC4R has been identified as an important melatonin receptor involved in the regulation of body weight, hunger, and energy homeostasis (Holland 2019). Recently, MRI findings in HO patients have shown anatomical disruption of the hypothalamus, including MC4 receptors and POMC neurons present in the arcuate nucleus and paraventricular nucleus, respectively.

[0236] Damage to the arcuate nucleus, paraventricular nucleus, dorsomedial nucleus, and dorsal hypothalamic area frequently results in disorders in the regulation of both peripheral energy consumption and satiety (Abuzzahab 2019). Such dysfunction of the MC4R pathway can lead to severe, sudden, profound, and persistent weight gain that is refractory to general lifestyle changes or current anti-obesity pharmacotherapy (Sterkenburg 2015). Approximately 50% of HO patients also exhibit a significant increase in hunger. The main difference from other diseases that may be caused by dysfunction of the MC4 pathway is that in the case of HO, the dysfunction is due to structural damage, whereas in other diseases, it is due to genetic dysfunction. Several genetic variants have been associated with reduced signal transduction via the MC4 pathway, reduced α-MSH, and resulting hyperphagia and obesity.

[0237] Tumors (e.g., craniopharyngioma, glioma, pituitary adenoma, error tumor), and / or in addition to surgery or radiotherapy used to treat tumors (Hochberg 2010), other causes of injury are very rare but include inflammatory conditions or trauma related to the hypothalamus. Craniopharyngioma is the most common tumor associated with the onset of HO and accounts for 5% - 15% of intracranial tumors in children (Muller 2022). A bimodal age distribution is observed in new cases of craniopharyngioma, with the first peak seen in children aged 4 - 14 years and the second peak in adults over 40 years old (Ostrom 2021).

[0238] Other causes of this condition include brain swelling, head trauma, brain surgery, or the presence of specific gene mutations. Gene mutations in the LEP, LEPR, POMC, MC4R, and CART genes may also lead to this disease (see, for example, Kim et al. Ann Pediatr Endocrinol Metab (2013) 18(4):161 - 167). Hypothalamic obesity is also associated with a decrease in α-MSH concentration (see, for example, Roth et al. Metabol Clin Exper (2010) 59:186 - 194).

[0239] Hypothalamic obesity is a distinct disease different from general obesity (e.g., genetic obesity, or other non - genetic obesity or symptomatic diseases). For example, HO is often the result of acquired injury rather than a genetic defect in the MC4R pathway that leads to a decrease in the hormone α-MSH. Furthermore, subjects with or identified as having HO may show dramatic changes in clinical phenotypes such as rapid weight gain starting at the time of injury, increased hunger, and decreased energy, compared to subjects with general obesity (e.g., genetic obesity, or other non - genetic obesity or symptomatic diseases). Additionally, subjects with or identified as having HO often do not present secondary or additional disease symptoms that are often characteristic of some genetic obesities.

[0240] In one embodiment, the subject has obesity, such as hypothalamic obesity, and the fasting peripheral blood α-MSH is about 4 to about 10 fmol / mL as compared to the fasting peripheral blood α-MSH of healthy non-obese subjects, which is about 15 to about 30 fmol / mL. In one embodiment, the subject has obesity, such as hypothalamic obesity, and the fasting peripheral blood α-MSH is about 4 to about 9, 4 to about 8, 4 to about 7, 4 to about 6, or 4 to about 5 fmol / mL as compared to the fasting peripheral blood α-MSH of healthy non-obese subjects, which is about 15 to about 30 fmol / mL. In one embodiment, the subject has obesity, such as hypothalamic obesity, and the fasting peripheral blood α-MSH is about 4 to about 9 fmol / mL as compared to the fasting peripheral blood α-MSH of healthy non-obese subjects, which is about 15 to about 30 fmol / mL. In one embodiment, the subject has obesity, such as hypothalamic obesity, and the fasting peripheral blood α-MSH is about 4 to about 8 fmol / mL as compared to the fasting peripheral blood α-MSH of healthy non-obese subjects, which is about 15 to about 30 fmol / mL. In one embodiment, the subject has obesity, such as hypothalamic obesity, and the fasting peripheral blood α-MSH is about 4 to about 7 fmol / mL as compared to the fasting peripheral blood α-MSH of healthy non-obese subjects, which is about 15 to about 30 fmol / mL. In one embodiment, the subject has obesity, such as hypothalamic obesity, and the fasting peripheral blood α-MSH is about 4 to about 6 fmol / mL as compared to the fasting peripheral blood α-MSH of healthy non-obese subjects, which is about 15 to about 30 fmol / mL. In one embodiment, the subject has obesity, such as hypothalamic obesity, and the fasting peripheral blood α-MSH is about 4 to about 5 fmol / mL as compared to the fasting peripheral blood α-MSH of healthy non-obese subjects, which is about 15 to about 30 fmol / mL.

[0241] In one embodiment, the subject has obesity, such as hypothalamic obesity, and the fasting peripheral blood α-MSH is less than 10 fmol / mL compared to the fasting peripheral blood α-MSH of healthy non-obese subjects, which is about 15 to about 30 fmol / mL. In one embodiment, the subject has obesity, such as hypothalamic obesity, and the fasting peripheral blood α-MSH is less than 9, 8, 7, 6, 5 or 4 fmol / mL compared to the fasting peripheral blood α-MSH of healthy non-obese subjects, which is about 15 to about 30 fmol / mL. In one embodiment, the subject has obesity, such as hypothalamic obesity, and the fasting peripheral blood α-MSH is less than 9 fmol / mL compared to the fasting peripheral blood α-MSH of healthy non-obese subjects, which is about 15 to about 30 fmol / mL. In one embodiment, the subject has obesity, such as hypothalamic obesity, and the fasting peripheral blood α-MSH is less than 8 fmol / mL compared to the fasting peripheral blood α-MSH of healthy non-obese subjects, which is about 15 to about 30 fmol / mL. In one embodiment, the subject has obesity, such as hypothalamic obesity, and the fasting peripheral blood α-MSH is less than 7 fmol / mL compared to the fasting peripheral blood α-MSH of healthy non-obese subjects, which is about 15 to about 30 fmol / mL. In one embodiment, the subject has obesity, such as hypothalamic obesity, and the fasting peripheral blood α-MSH is less than 6 fmol / mL compared to the fasting peripheral blood α-MSH of healthy non-obese subjects, which is about 15 to about 30 fmol / mL. In one embodiment, the subject has obesity, such as hypothalamic obesity, and the fasting peripheral blood α-MSH is less than 5 fmol / mL compared to the fasting peripheral blood α-MSH of healthy non-obese subjects, which is about 15 to about 30 fmol / mL. In one embodiment, the subject has obesity, such as hypothalamic obesity, and the fasting peripheral blood α-MSH is less than 4 fmol / mL compared to the fasting peripheral blood α-MSH of healthy non-obese subjects, which is about 15 to about 30 fmol / mL.

[0242] In one embodiment, the subject has obesity, such as hypothalamic obesity, and the fasting peripheral blood α-MSH is less than 4 fmol / mL compared to the fasting peripheral blood α-MSH of healthy non-obese subjects, which is about 15 to about 30 fmol / mL.

[0243] In one embodiment, the subject has obesity, such as hypothalamic obesity, that is refractory to lifestyle changes (e.g., dietary or exercise modifications). In one embodiment, the subject has obesity, such as hypothalamic obesity, that is refractory to dietary changes. In one embodiment, the subject has obesity, such as hypothalamic obesity, that is refractory to calorie restriction. In one embodiment, the subject has obesity, such as hypothalamic obesity, that is refractory to reduced food intake. In one embodiment, the subject has obesity, such as hypothalamic obesity, that is refractory to increased exercise, such as an increase in calorie consumption achieved during exercise.

[0244] In one embodiment, the subject has obesity characterized by a decrease in resting energy expenditure (REE) without hyperphagia, such as hypothalamic obesity. In one embodiment, the subject has obesity characterized by a decrease in resting energy expenditure (REE) without hyperphagia, such as hypothalamic obesity, and the subject's maximum daily fasting score is, for example, within the standard error of measurement and statistically equivalent to the subject's maximum daily fasting score before the onset of hypothalamic obesity in the subject. In one embodiment, the subject has obesity characterized by a decrease in resting energy expenditure (REE) without hyperphagia, such as hypothalamic obesity, and the weekly average of the subject's maximum daily fasting score is, for example, within the standard error of measurement and statistically equivalent to the weekly average of the subject's maximum daily fasting score before the onset of hypothalamic obesity in the subject. In one embodiment, the subject has obesity characterized by a decrease in resting energy expenditure (REE) without hyperphagia, such as hypothalamic obesity, and the subject's maximum daily fasting score is not clinically significant compared to the subject's maximum daily fasting score before the onset of hypothalamic obesity in the subject, for example, less than 2 points. In one embodiment, the subject has obesity characterized by a decrease in resting energy expenditure (REE) without hyperphagia, such as hypothalamic obesity, and the weekly average of the subject's maximum daily fasting score is not clinically significant compared to the weekly average of the subject's maximum daily fasting score before the onset of hypothalamic obesity in the subject, for example, less than 2 points. In one embodiment, the subject has obesity characterized by a decrease in resting energy expenditure (REE) without hyperphagia, such as hypothalamic obesity, and the change in the subject's IWQOL or IQWOL-Lite score is not clinically significant compared to the subject's IWQOL or IQWOL-Lite score before the onset of hypothalamic obesity in the subject.

[0245] In one embodiment, the subject has obesity characterized by overeating and a reduced resting metabolic rate, such as hypothalamic obesity. In one embodiment, the subject has obesity characterized by overeating and a reduced resting energy expenditure (REE), such as hypothalamic obesity, and an increase in the subject's maximum daily fasting score is clinically significant compared to the subject's maximum daily fasting score prior to the onset of hypothalamic obesity in the subject, for example, more than 2 points. In one embodiment, the subject has obesity characterized by overeating and a reduced resting energy expenditure (REE), such as hypothalamic obesity, and an increase in the weekly average of the subject's maximum daily fasting score is clinically significant compared to the weekly average of the subject's maximum daily fasting score prior to the onset of hypothalamic obesity in the subject, for example, more than 2 points. In one embodiment, the subject has obesity characterized by overeating and a reduced resting energy expenditure (REE), such as hypothalamic obesity, and a decrease in the subject's IWQOL or IQWOL-Lite score is clinically significant compared to the subject's IWQOL or IQWOL-Lite score prior to the onset of hypothalamic obesity in the subject.

[0246] In one embodiment, the subject has obesity characterized by a decrease in resting metabolic rate and a decrease in physical activity without bulimia, such as hypothalamic obesity. In one embodiment, the subject has obesity characterized by a decrease in resting energy expenditure (REE) and a decrease in physical activity without bulimia, such as hypothalamic obesity, and the subject's maximum daily fasting score is, for example, within the standard error of measurement and statistically equivalent to the subject's maximum daily fasting score prior to the onset of hypothalamic obesity in the subject. In one embodiment, the subject has obesity characterized by a decrease in resting energy expenditure (REE) and a decrease in physical activity without bulimia, such as hypothalamic obesity, and the weekly average of the subject's maximum daily fasting score is, for example, within the standard error of measurement and statistically equivalent to the weekly average of the subject's maximum daily fasting score prior to the onset of hypothalamic obesity in the subject. In one embodiment, the subject has obesity characterized by a decrease in resting energy expenditure (REE) and a decrease in physical activity without bulimia, such as hypothalamic obesity, and the subject's maximum daily fasting score is not clinically significant compared to the subject's maximum daily fasting score prior to the onset of hypothalamic obesity in the subject, for example, less than 2 points. In one embodiment, the subject has obesity characterized by a decrease in resting energy expenditure (REE) and a decrease in physical activity without bulimia, such as hypothalamic obesity, and the weekly average of the subject's maximum daily fasting score is not clinically significant compared to the weekly average of the subject's maximum daily fasting score prior to the onset of hypothalamic obesity in the subject, for example, less than 2 points. In one embodiment, the subject has obesity characterized by a decrease in resting energy expenditure (REE) and a decrease in physical activity without bulimia, such as hypothalamic obesity, and the change in the subject's IWQOL or IQWOL-Lite score is not clinically significant compared to the subject's IWQOL or IQWOL-Lite score prior to the onset of hypothalamic obesity in the subject.

[0247] In one embodiment, the subject has obesity characterized by hyperphagia, decreased resting metabolic rate, and decreased physical activity, such as hypothalamic obesity. In one embodiment, the subject has obesity characterized by hyperphagia, decreased resting energy expenditure (REE), and decreased physical activity, such as hypothalamic obesity, and an increase in the subject's maximum daily fasting score is clinically significant compared to the subject's maximum daily fasting score before the onset of hypothalamic obesity in the subject, e.g., more than 2 points. In one embodiment, the subject has obesity characterized by hyperphagia, decreased resting energy expenditure (REE), and decreased physical activity, such as hypothalamic obesity, and an increase in the weekly average of the subject's maximum daily fasting score is clinically significant compared to the weekly average of the subject's maximum daily fasting score before the onset of hypothalamic obesity in the subject, e.g., more than 2 points. In one embodiment, the subject has obesity characterized by hyperphagia, decreased resting energy expenditure (REE), and decreased physical activity, such as hypothalamic obesity, and a decrease in the subject's IWQOL or IQWOL-Lite score is clinically significant compared to the subject's IWQOL or IQWOL-Lite score before the onset of hypothalamic obesity in the subject.

[0248] In one embodiment, the subject has obesity that is refractory to bariatric surgery, such as hypothalamic obesity. In one embodiment, the subject has obesity that is refractory to bariatric surgery procedures, including but not limited to gastric bypass, gastric banding, gastric sleeve, duodenal switch, gastric balloon, and intestinal barrier, such as hypothalamic obesity. In one embodiment, the subject has obesity that is refractory to gastric bypass procedures, such as hypothalamic obesity. In one embodiment, the subject has obesity that is refractory to gastric banding procedures, such as hypothalamic obesity. In one embodiment, the subject has obesity that is refractory to gastric sleeve procedures, such as hypothalamic obesity. In one embodiment, the subject has obesity that is refractory to duodenal switch procedures, such as hypothalamic obesity. In one embodiment, the subject has obesity that is refractory to gastric balloon procedures, such as hypothalamic obesity. In one embodiment, the subject has obesity that is refractory to intestinal barrier procedures, such as hypothalamic obesity.

[0249] In one embodiment, the subject has obesity that is refractory to pharmacological therapies, such as sympathomimetics, somatostatin analogs, glucagon-like peptide (GLP-1) analogs, metformin, combinations of metformin and fenofibrate, combinations of metformin and diazoxide, central nervous system (CNS) stimulants, and therapy with melatonin, for example, hypothalamic obesity. In one embodiment, the subject has obesity that is refractory to pharmacological therapies that include a sympathomimetic, for example, hypothalamic obesity. In one embodiment, the subject has obesity that is refractory to pharmacological therapies that include a somatostatin analog, for example, hypothalamic obesity. In one embodiment, the subject has obesity that is refractory to pharmacological therapies that include a glucagon-like peptide (GLP-1) analog, for example, hypothalamic obesity. In one embodiment, the subject has obesity that is refractory to pharmacological therapies that include metformin, for example, hypothalamic obesity. In one embodiment, the subject has obesity that is refractory to pharmacological therapies that include a combination of metformin and fenofibrate, for example, hypothalamic obesity. In one embodiment, the subject has obesity that is refractory to pharmacological therapies that include a combination of metformin and diazoxide, for example, hypothalamic obesity. In one embodiment, the subject has obesity that is refractory to pharmacological therapies that include a central nervous system (CNS) stimulant, for example, hypothalamic obesity. In one embodiment, the subject has obesity that is refractory to pharmacological therapies that include melatonin, for example, hypothalamic obesity.

[0250] Additional diseases, disorders, or conditions treatable by administration of an MC4R agonist or a composition described herein, such as a compound of any one of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) (e.g., as described herein), or a pharmaceutically acceptable salt thereof, include 5p3 microduplication syndrome, Angelman syndrome, Chaddock-Lurie syndrome, Cornelia de Lange syndrome, Laron syndrome, Kleefstra syndrome / 9q34.3, Carpenter Marfan Cohen syndrome, Clark and Baraister XLMR syndrome, DiGeorge syndrome, velo-cardio-facial syndrome, conotruncal anomaly face syndrome, 22q11.2 deletion syndrome, rapidly progressive obesity with hypothalamic dysfunction (ROHHAD), rapidly progressive obesity with hypothalamic dysfunction, hypoventilation, dysautonomia, and neuroblastoma (ROHHAD NET), SCHARF XLMR syndrome, mental retardation, epileptic seizures, hypogonadism and genital hypoplasia, microcephaly, obesity (MEHMO) syndrome, mandibular prognathism with ocular and cutaneous anomalies (MOMES) syndrome, and MOMO syndrome. Additional diseases, disorders, or conditions treatable by administration of an MC4R agonist, such as an MC4R agonist described herein, include those summarized in Kaur et al (2017) Obesity Reviews 18:603-634.

[0251] Outcome In embodiments, the methods described herein result in one or more outcomes including, for example, a decrease in weight (e.g., body weight), a decrease in fasting, an undetectable decrease in metabolic rate (e.g., resting metabolic rate), an increase in metabolic rate (e.g., resting metabolic rate), a decrease in daily / weekly / monthly food intake, a decrease in abdominal circumference, an undetectable increase in blood pressure, or a decrease in blood pressure in a subject as compared to a control.

[0252] In an embodiment, the control is a measured value of a parameter in the subject before administration of the MC4R agonist (treatment with the MC4R agonist). In an embodiment, the control is a predetermined value, e.g., the value of a parameter in an average obese human population of approximately the same age and same sex as the subject; or a value of a parameter measured in the subject at a previous time point (e.g., at a previous visit to a doctor, medical institution, or laboratory).

[0253] In an embodiment, the outcome (e.g., a decrease, increase, undetectable decrease, or undetectable increase in a given parameter) is measured in the subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after the start of treatment with the MC4R agonist. In other embodiments, the outcome (e.g., a decrease, increase, undetectable decrease, or undetectable increase in a given parameter) is measured in the subject over a predetermined period (e.g., over 1 - 2 weeks, 2 - 4 weeks, 4 - 6 weeks, 6 - 8 weeks, 8 - 12 weeks, or 12 - 16 weeks) during the course of treatment.

[0254] In an embodiment, the method described herein results in a decrease in weight (e.g., body weight) in the subject as compared to a control (e.g., the weight of the subject before treatment, or a predetermined value, e.g., the average weight of an obese human population of approximately the same age and same sex as the subject not receiving a therapeutic intervention, or a previous measurement, e.g., the weight of the subject at a previous visit). In an embodiment, the decrease is about 1 kg - 3 kg after 1 week of treatment, about 1 kg - 6 kg after 2 weeks of treatment, about 2 kg - 12 kg after 4 weeks of treatment, about 4 kg - 24 kg after 8 weeks of treatment, or about 8 kg - 48 kg after 16 weeks of treatment. In an embodiment, the decrease is at a rate of loss of about 1 - 2 kg / week, e.g., about 2 kg / week, over a period of treatment of, e.g., 1 - 2 weeks or more of treatment, 2 - 4 weeks or more of treatment, 4 - 8 weeks or more of treatment, 8 - 16 weeks or more of treatment, or 16 - 32 weeks or more of treatment.

[0255] Measurement of weight, e.g., body weight, can be performed using standard methods in the art.

[0256] In an embodiment, weight loss is characterized by the weight of the subject compared to a control, e.g., the rate of change of weight (e.g., the weight of the subject before treatment, e.g., body weight, or the rate of change at a predetermined value, e.g., the rate of change from the average weight of an obese human population of approximately the same age and gender as the subject who does not receive a therapeutic intervention, or the rate of change from a previous measurement, e.g., the weight of the subject at a previous visit).

[0257] Subjects may experience weight loss upon administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, subjects may experience a weight loss of more than 1% upon administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 30%, 35%, 40%, or more compared to the subject's weight prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of more than 2% compared to the subject's weight prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of more than 3% compared to the subject's weight prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of more than 4% compared to the subject's weight prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of more than 5% compared to the subject's weight prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of more than 6% compared to the subject's weight prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of more than 7% compared to the subject's weight prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of more than 8% compared to the subject's weight prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a weight loss of more than 9% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of more than 10% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of more than 12.5% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of more than 15% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of more than 17.5% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of more than 20% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of more than 22.5% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of more than 25% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of more than 30% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of more than 35% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of more than 40% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0258] In one embodiment, the subject experiences a weight loss of more than 40% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0259] In one embodiment, the subject experiences a weight loss of about 1% to about 40% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 1% to about 35%, 1% to about 30%, 1% to about 25%, 1% to about 22.5%, 1% to about 20%, 1% to about 17.5%, 1% to about 15%, 1% to about 12.5%, 1% to about 10%, 1% to about 9%, 1% to about 8%, 1% to about 7%, 1% to about 6%, 1% to about 5%, 1% to about 4%, 1% to about 3%, or 1% to about 2% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 1% to about 35% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 1% to about 30% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 1% to about 25% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 1% to about 22.5% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 1% to about 20% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 1% to about 17.5% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 1% to about 15% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a weight loss of about 1% to about 12.5% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 1% to about 10% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 1% to about 9% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 1% to about 8% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 1% to about 7% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 1% to about 6% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 1% to about 5% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 1% to about 4% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 1% to about 3% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 1% to about 2% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0260] In one embodiment, the subject experiences a weight loss of about 5% to about 40% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 5% to about 35%, 5% to about 30%, 5% to about 25%, 5% to about 22.5%, 5% to about 20%, 5% to about 17.5%, 5% to about 15%, 5% to about 12.5%, 5% to about 10%, 5% to about 9%, 5% to about 8%, 5% to about 7% or about 5% to about 6% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 5% to about 35% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 5% to about 30% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 5% to about 25% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 5% to about 22.5% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 5% to about 20% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 5% to about 17.5% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 5% to about 15% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a weight loss of about 5% to about 12.5% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 5% to about 10% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 5% to about 9% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 5% to about 8% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 5% to about 7% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 5% to about 6% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0261] In one embodiment, the subject experiences a reduction in BMI of about 1% to about 40% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 10% to about 35%, 10% to about 30%, 10% to about 25%, 10% to about 22.5%, 10% to about 20%, 10% to about 17.5%, 10% to about 15%, or about 10% to about 12.5% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 10% to about 35% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 10% to about 30% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 10% to about 25% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 10% to about 22.5% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 10% to about 20% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 10% to about 17.5% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 10% to about 15% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 10% to about 12.5% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0262] In one embodiment, the subject experiences a weight loss of about 20% to 40% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in BMI of about 20% to about 35%, 20% to about 30%, 20% to 25%, or about 20% to about 22.5% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to 35% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to 30% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to 25% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to 22.5% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0263] In one embodiment, the subject experiences a weight loss of about 20% to 40% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI reduction of about 20% to about 39%, 20% to about 38%, 20% to about 37%, 20% to about 36%, 20% to about 35%, 20% to about 34%, 20% to about 33%, 20% to about 32%, 20% to about 31%, 20% to about 30%, 20% to 29%, 20% to about 28%, 20% to about 27%, 20% to about 26%, 20% to about 25%, 20% to about 24%, 20% to about 23%, 20% to about 22%, or about 20% to about 21% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to about 39% compared to the control's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to about 38% compared to the control's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to about 37% compared to the control's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to about 36% compared to the control's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to about 35% compared to the control's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to about 34% compared to the control's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to about 33% compared to the control's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a weight loss of about 20% to about 32% compared to the weight of a control before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to about 31% compared to the weight of a control before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to about 30% compared to the weight of a control before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to about 29% compared to the weight of a control before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to about 28% compared to the weight of a control before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to about 27% compared to the weight of a control before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to about 26% compared to the weight of a control before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to about 25% compared to the weight of a control before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to about 24% compared to the weight of a control before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to about 23% compared to the weight of a control before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a weight loss of about 20% to about 22% compared to the weight of the control before administration of the MC4R agonist (e.g., the MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 20% to about 21% compared to the weight of the control before administration of the MC4R agonist (e.g., the MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0264] In one embodiment, the subject experiences a weight loss of about 30% to about 40% compared to the weight of the subject before administration of the MC4R agonist (e.g., the MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 30% to about 35% compared to the weight of the subject before administration of the MC4R agonist (e.g., the MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0265] In one embodiment, the subject experiences a weight loss of about 30% to about 40% compared to the subject's weight before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 30% to about 39%, 30% to about 38%, 30% to about 37%, 30% to about 36%, 30% to about 35%, 30% to about 34%, 30% to about 33%, 30% to about 32% or about 30% to about 31% compared to the subject's weight before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 30% to about 39% compared to the subject's weight before administration of an MC4R agonist (e.g., an agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 30% to about 38% compared to the subject's weight before administration of an MC4R agonist (e.g., an agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 30% to about 37% compared to the subject's weight before administration of an MC4R agonist (e.g., an agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 30% to about 36% compared to the subject's weight before administration of an MC4R agonist (e.g., an agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 30% to about 35% compared to the subject's weight before administration of an MC4R agonist (e.g., an agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 30% to about 34% compared to the subject's weight before administration of an MC4R agonist (e.g., an agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 30% to about 33% compared to the subject's weight before administration of an MC4R agonist (e.g., an agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of about 30% to about 32% compared to the subject's weight before administration of an MC4R agonist (e.g., an agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a weight loss of about 30% to about 31% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an agonist described herein, e.g., SEQ ID NO: 140).

[0266] In one embodiment, the subject experiences a weight loss of less than 40% compared to the subject's weight before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of less than 35%, 30%, 25%, 22.5%, 20%, 17.5%, 15%, 12.5%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less than that compared to the subject's weight before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of less than 35% compared to the subject's weight before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of less than 30% compared to the subject's weight before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of less than 25% compared to the subject's weight before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of less than 22.5% compared to the subject's weight before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of less than 20% compared to the subject's weight before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of less than 17.5% compared to the subject's weight before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of less than 15% compared to the subject's weight before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of less than 12.5% compared to the subject's weight before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a weight loss of less than 10% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of less than 9% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of less than 8% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of less than 7% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of less than 6% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of less than 5% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of less than 4% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of less than 3% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of less than 2% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weight loss of less than 1% compared to the subject's weight prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0267] In an embodiment, the methods described herein include a control (e.g., the subject's kg / m prior to treatment 2Results in a decrease in the subject's body mass index (BMI), measured in units, or a predetermined value, e.g., the average BMI of an obese human population of approximately the same age and same sex as the subject who does not receive a therapeutic intervention, or the subject's BMI at a previous measurement, e.g., at a previous visit).

[0268] Subjects may experience a decrease in BMI upon administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, a subject may experience a decrease in BMI of more than 1% compared to the subject's BMI prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140) upon administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI of more than 1.5%, 2%, 2.5%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12.5%, 15%, 17.5%, 20% or greater compared to the subject's BMI prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI of more than 2% compared to the subject's BMI prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI of more than 5% compared to the subject's BMI prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI of more than 7.5% compared to the subject's BMI prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI of more than 10% compared to the subject's BMI prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI of more than 15% compared to the subject's BMI prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI of more than 18% compared to the subject's BMI prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI of more than 19% compared to the subject's BMI prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a BMI decrease of more than 20% compared to the subject's BMI prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0269] In one embodiment, the subject experiences a BMI decrease of about 1% to about 20% compared to the subject's BMI prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI decrease of about 1% to about 19%, 1% to about 18%, 1% to about 17%, 1% to about 16%, 1% to about 15%, about 1% to about 12.5%, about 1% to about 10%, about 1% to about 7.5%, about 1% to about 5% compared to the subject's BMI prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI decrease of about 1% to about 15% compared to the subject's BMI prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI decrease of about 1% to about 10% compared to the subject's BMI prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0270] In one embodiment, the subject experiences a BMI reduction of about 5% to about 20% compared to the subject's BMI prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI reduction of about 5% to about 19%, 5% to about 18%, 5% to about 17%, 5% to about 16%, 5% to about 15%, about 5% to about 12.5%, about 5% to about 10%, about 5% to about 7.5% compared to the subject's BMI prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI reduction of about 5% to about 15% compared to the subject's BMI prior to administration of an MC4R agonist. In one embodiment, the subject experiences a BMI reduction of about 5% to about 10% compared to the subject's BMI prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0271] In one embodiment, the subject experiences a BMI reduction of about 10% to about 20% compared to the subject's BMI before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI reduction of about 10% to about 19%, 10% to about 18%, 10% to about 17%, 10% to about 16%, 10% to about 14%, 10% to about 13%, 10% to about 12%, or 10% to 11% compared to the subject's BMI before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI reduction of about 10% to about 19% compared to the subject's BMI before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI reduction of about 10% to about 18% compared to the subject's BMI before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI reduction of about 10% to about 17% compared to the subject's BMI before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI reduction of about 10% to about 16% compared to the subject's BMI before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI reduction of about 10% to about 15% compared to the subject's BMI before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI reduction of about 10% to about 14% compared to the subject's BMI before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI reduction of about 10% to about 13% compared to the subject's BMI before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a BMI decrease of about 10% to about 12% compared to the subject's BMI prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI decrease of about 10% to about 11% compared to the subject's BMI prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0272] The subject may experience a decrease in BMI upon administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, the subject may experience a BMI decrease of less than 20% upon administration of the MC4R agonist, as compared to the subject's BMI prior to administration of the MC4R agonist. In one embodiment, the subject experiences a BMI decrease of less than 17.5%, 15%, 12.5%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2.5%, 2%, 1.5% or less, or smaller than that, as compared to the subject's BMI prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI decrease of less than 17.5% as compared to the subject's BMI prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI decrease of less than 15% as compared to the subject's BMI prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI decrease of less than 12.5% as compared to the subject's BMI prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI decrease of less than 10% as compared to the subject's BMI prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI decrease of less than 9% as compared to the subject's BMI prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI decrease of less than 8% as compared to the subject's BMI prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI decrease of less than 7% as compared to the subject's BMI prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a BMI decrease of less than 6% compared to the subject's BMI prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI decrease of less than 5% compared to the subject's BMI prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI decrease of less than 4% compared to the subject's BMI prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI decrease of less than 3% compared to the subject's BMI prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI decrease of less than 2% compared to the subject's BMI prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a BMI decrease of less than 1% compared to the subject's BMI prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0273] In an embodiment, the methods described herein result in a decrease in the subject's BMI Z-score compared to a control BMI Z-score (e.g., the subject's pre-treatment BMI Z-score, or a predetermined value, e.g., the mean BMI Z-score of an obese human population of approximately the same age and / or same sex who do not receive a therapeutic intervention, or a previous measurement, e.g., the subject's BMI Z-score at a previous visit), where the Z-score is calculated from the standard deviation from a reference population of the same age and sex (e.g., the Z-score of a reference population with a mean BMI of 25 and a standard deviation of 1.5).

[0274] Subjects may experience a decrease in BMI Z-score upon administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, a subject may experience a 0.1 decrease in BMI Z-score upon administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140), as compared to the subject's BMI Z-score prior to administration of the MC4R agonist. In one embodiment, the subject experiences a decrease in BMI Z-score of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.25, 2.5, 2.75, greater than 3, or more than that as compared to the subject's BMI Z-score prior to administration of the MC4R agonist. In one embodiment, the subject experiences a decrease in BMI Z-score of more than 0.2 as compared to the subject's BMI Z-score prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of more than 0.3 as compared to the subject's BMI Z-score prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of more than 0.4 as compared to the subject's BMI Z-score prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of more than 0.5 as compared to the subject's BMI Z-score prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of more than 0.6 as compared to the subject's BMI Z-score prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of more than 0.7 as compared to the subject's BMI Z-score prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a decrease in BMI Z-score of more than 0.8 as compared to the subject's BMI Z-score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of more than 0.9 as compared to the subject's BMI Z-score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of more than 1 as compared to the subject's BMI Z-score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of more than 1.1 as compared to the subject's BMI Z-score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of more than 1.2 as compared to the subject's BMI Z-score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of more than 1.3 as compared to the subject's BMI Z-score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of more than 1.4 as compared to the subject's BMI Z-score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of more than 1.5 as compared to the subject's BMI Z-score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of more than 1.6 as compared to the subject's BMI Z-score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of more than 1.7 as compared to the subject's BMI Z-score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a decrease in BMI Z-score of greater than 1.8 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of greater than 1.9 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of greater than 2 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of greater than 2.25 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of greater than 2.5 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of greater than 2.75 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of greater than 3 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0275] In one embodiment, the subject experiences a decrease in BMI z-score of from about 0.1 to about 3 as compared to the subject's BMI z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI z-score of from about 0.1 to about 2.75, 0.1 to about 2.5, 0.1 to about 2.25, 0.1 to about 2, 0.1 to about 1.9, 0.1 to about 1.8, 0.1 to about 1.7, 0.1 to about 1.6, 0.1 to about 1.5, 0.1 to about 1.4, 0.1 to about 1.3, 0.1 to about 1.2, 0.1 to about 1.1, 0.1 to about 1, 0.1 to about 0.9, 0.1 to about 0.8, 0.1 to about 0.7, 0.1 to about 0.6, 0.1 to about 0.5, 0.1 to about 0.4, 0.1 to about 0.3, or 0.1 to about 0.2 as compared to the subject's BMI z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI z-score of from about 0.1 to about 2.75 as compared to the subject's BMI z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI z-score of from about 0.1 to about 2.5 as compared to the subject's BMI z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI z-score of from about 0.1 to about 2.25 as compared to the subject's BMI z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI z-score of from about 0.1 to about 2 as compared to the subject's BMI z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI z-score of from about 0.1 to about 1.9 as compared to the subject's BMI z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a decrease in BMI Z-score of from about 0.1 to about 1.8 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of from about 0.1 to about 1.7 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of from about 0.1 to about 1.6 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of from about 0.1 to about 1.5 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of from about 0.1 to about 1.4 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of from about 0.1 to about 1.3 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of from about 0.1 to about 1.2 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of from about 0.1 to about 1.1 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of from about 0.1 to about 1 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a decrease in BMI Z-score of about 0.1 to about 0.9 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, such as SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 0.1 to about 0.8 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, such as SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 0.1 to about 0.7 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, such as SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 0.1 to about 0.6 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, such as SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 0.1 to about 0.5 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, such as SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 0.1 to about 0.4 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, such as SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 0.1 to about 0.3 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, such as SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 0.1 to about 0.2 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, such as SEQ ID NO: 140).

[0276] In one embodiment, the subject experiences a decrease in BMI Z-score of about 1 to 3 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 1 to about 2.75, 1 to about 2.5, 1 to about 2.25, 1 to about 2, 1 to about 1.9, 1 to about 1.8, 1 to about 1.7, 1 to about 1.6, 1.5, 1 to about 1.4, 1 to about 1.3, 1 to about 1.2, or 1 to about 1.1 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 1 to about 2.75 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 1 to about 2.5 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 1 to about 2.25 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 1 to about 2 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 1 to about 1.9 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 1 to about 1.8 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 1 to about 1.7 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a decrease in BMI Z - score of about 1 to about 1.6 as compared to the subject's BMI Z - score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z - score of about 1 to about 1.5 as compared to the subject's BMI Z - score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z - score of about 1 to about 1.4 as compared to the subject's BMI Z - score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z - score of about 1 to about 1.3 as compared to the subject's BMI Z - score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z - score of about 1 to about 1.2 as compared to the subject's BMI Z - score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z - score of about 1 to about 1.1 as compared to the subject's BMI Z - score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0277] In one embodiment, the subject experiences a decrease in BMI Z-score of about 2 to about 3 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 2 to about 2.75, 2 to about 2.5, or about 2 to about 2.25 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 2 to about 2.75 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 2 to about 2.5 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 2 to about 2.25 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0278] In one embodiment, the subject experiences a decrease in BMI Z-score of about 2 to about 3 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 2 to about 2.9, 2 to about 2.8, 2 to about 2.7, 2 to about 2.6, 2 to about 2.5, 2 to about 2.4, 2 to about 2.3, 2 to about 2.2, or 2 to about 2.1 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 2 to about 2.9 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 2 to about 2.8 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 2 to about 2.7 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 2 to about 2.6 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 2 to about 2.5 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 2 to about 2.4 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 2 to about 2.3 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a decrease in BMI Z-score of about 2 to about 2.2 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of about 2 to about 2.1 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0279] The subject may experience a decrease in BMI Z-score upon administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, the subject may experience a decrease in BMI Z-score of less than 3 upon administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 2.9, 2.75, 2.5, 2.25, 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or less, compared to the subject's BMI Z-score prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 2.9 compared to the subject's BMI Z-score prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 2.75 compared to the subject's BMI Z-score prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 2.25 compared to the subject's BMI Z-score prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 2 compared to the subject's BMI Z-score prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 1.9 compared to the subject's BMI Z-score prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 1.8 compared to the subject's BMI Z-score prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a decrease in BMI Z-score of less than 1.7 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 1.6 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 1.5 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 1.4 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 1.3 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 1.2 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 1.1 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 1 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 0.9 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 0.8 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a decrease in BMI Z-score of less than 0.7 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 0.6 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 0.5 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 0.4 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 0.3 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in BMI Z-score of less than 0.2 as compared to the subject's BMI Z-score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0280] In an embodiment, fasting is characterized by the weekly average of the subject's maximum daily fasting score, compared to a control (e.g., the weekly average of the subject's maximum daily fasting score prior to treatment, or a predetermined value, e.g., the average value of the weekly average of the maximum daily fasting score of an obese human population of approximately the same age and same sex as the subject who does not receive a therapeutic intervention, or a previous measurement, e.g., the weekly average of the subject's maximum daily fasting score at a previous visit).

[0281] The subject may experience a decrease in the weekly average of the maximum fasting score per day upon administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, the subject may experience a decrease in the weekly average of the maximum fasting score per day greater than 0.1 as compared to the weekly average of the maximum fasting score per day of the subject before administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day greater than 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 or greater as compared to the weekly average of the maximum fasting score per day of the subject before administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day greater than 0.2 as compared to the weekly average of the maximum fasting score per day of the subject before administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day greater than 0.3 as compared to the weekly average of the maximum fasting score per day of the subject before administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day greater than 0.4 as compared to the weekly average of the maximum fasting score per day of the subject before administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day greater than 0.5 as compared to the weekly average of the maximum fasting score per day of the subject before administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day greater than 0.6 as compared to the weekly average of the maximum fasting score per day of the subject before administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of more than 0.7 as compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of more than 0.8 as compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of more than 0.9 as compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of more than 1 as compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of more than 1.2 as compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of more than 1.4 as compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of more than 1.6 as compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of more than 1.8 as compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of more than 2 as compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day that is greater than 2.5 compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day that is greater than 3 compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day that is greater than 3.5 compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day that is greater than 4 compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day that is greater than 4.5 compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day that is greater than 5 compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day that is greater than 5.5 compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day that is greater than 6 compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day that is greater than 6.5 compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting scores of more than 7 as compared to the weekly average of the subject's daily maximum fasting scores prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0282] In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting scores of more than 7 as compared to the weekly average of the subject's daily maximum fasting scores prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0283] In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 7 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 6.5, 0.1 to about 6, 0.1 to about 6, 0.1 to about 5.5, 0.1 to about 5, 0.1 to about 4.5, 0.1 to about 4, 0.1 to about 3.5, 0.1 to about 3, 0.1 to about 2.5, 0.1 to about 2, 0.1 to about 1.8, 0.1 to about 1.6, 0.1 to about 1.4, 0.1 to about 1.2, 0.1 to about 1, 0.1 to about 0.9, 0.1 to about 0.8, 0.1 to about 0.7, 0.1 to about 0.6, 0.1 to about 0.5, 0.1 to about 0.4, 0.1 to about 0.3, or 0.1 to about 0.2 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 6.5 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 6 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 5.5 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 5 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 4.5 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 4 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 3.5 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 3 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 2.5 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 2 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 1.8 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 1.6 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 1.4 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 1.2 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 1 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 0.9 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 0.8 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 0.7 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 0.6 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 0.5 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 0.4 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 0.3 compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day of about 0.1 to about 0.2 compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0284] In one embodiment, the subject experiences a weekly average decrease in the maximum daily fasting score of about 1 to about 7 as compared to the maximum daily fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum daily fasting score of about 1 to about 6.5, 1 to about 6, 1 to about 5.5, 1 to about 5, 1 to about 4.5, 1 to about 4, 1 to about 3.5, 1 to about 3, 1 to about 2.5, 1 to about 2, 1 to about 1.8, 1 to about 1.6, 1 to about 1.4, or 1 to about 1.2 as compared to the weekly average of the maximum daily fasting score of the subject before administration of an agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum daily fasting score of about 1 to about 6.5 as compared to the maximum daily fasting score of the subject before administration of an agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum daily fasting score of about 1 to about 6 as compared to the maximum daily fasting score of the subject before administration of an agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum daily fasting score of about 1 to about 5.5 as compared to the maximum daily fasting score of the subject before administration of an agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum daily fasting score of about 1 to about 5 as compared to the maximum daily fasting score of the subject before administration of an agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum daily fasting score of about 1 to about 4.5 as compared to the maximum daily fasting score of the subject before administration of an agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum daily fasting score of about 1 to about 4 as compared to the maximum daily fasting score of the subject before administration of an agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 1 to about 3.5 as compared to the subject's maximum fasting score for a day before administration of the agonist (e.g., the MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 1 to about 3 as compared to the subject's maximum fasting score for a day before administration of the agonist (e.g., the MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 1 to about 2.5 as compared to the subject's maximum fasting score for a day before administration of the agonist (e.g., the MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 1 to about 2 as compared to the subject's maximum fasting score for a day before administration of the agonist (e.g., the MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 1 to about 1.8 as compared to the subject's maximum fasting score for a day before administration of the agonist (e.g., the MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 1 to about 1.6 as compared to the subject's maximum fasting score for a day before administration of the agonist (e.g., the MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 1 to about 1.4 as compared to the subject's maximum fasting score for a day before administration of the agonist (e.g., the MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 1 to about 1.2 as compared to the subject's maximum fasting score for a day before administration of the agonist (e.g., the MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0285] In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 2 to about 7 as compared to the maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 2 to about 6.5, 2 to about 6, 2 to about 5.5, 2 to about 5, 2 to about 4.5, 2 to about 4, 2 to about 3.5, 2 to about 3, or 2 to about 2.5. In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 2 to about 6.5 as compared to the weekly average of the maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 2 to about 6 as compared to the weekly average of the maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 2 to about 5.5 as compared to the weekly average of the maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 2 to about 5 as compared to the weekly average of the maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 2 to about 4.5 as compared to the weekly average of the maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 2 to about 4 as compared to the weekly average of the maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 2 to about 3.5 as compared to the weekly average of the maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of about 2 to about 3, as compared to the weekly average of the daily maximum fasting score of the subject prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of about 2 to about 2.5, as compared to the weekly average of the daily maximum fasting score of the subject prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0286] In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 3 to about 7 as compared to the subject's maximum fasting score of the day before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 3 to about 6.5, 3 to about 6, 3 to about 5.5, 3 to about 5, 3 to about 4.5, 3 to about 4, or 3 to about 3.5 as compared to the weekly average of the subject's maximum fasting score of the day before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 3 to about 6.5 as compared to the subject's maximum fasting score of the day before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 3 to about 6 as compared to the subject's maximum fasting score of the day before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 3 to about 5.5 as compared to the subject's maximum fasting score of the day before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 3 to about 5 as compared to the subject's maximum fasting score of the day before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 3 to about 4.5 as compared to the subject's maximum fasting score of the day before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 3 to about 4 as compared to the subject's maximum fasting score of the day before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 3 to about 3.5 as compared to the subject's maximum fasting score for a day before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0287] In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 4 to about 7 as compared to the subject's maximum fasting score for a day before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 4 to about 6.5, 4 to about 6, 4 to about 5.5, 4 to about 5, or 4 to about 4.5 as compared to the subject's maximum fasting score for a day before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 4 to about 6.5 as compared to the subject's maximum fasting score for a day before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 4 to about 6 as compared to the subject's maximum fasting score for a day before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 4 to about 5.5 as compared to the subject's maximum fasting score for a day before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 4 to about 5 as compared to the subject's maximum fasting score for a day before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 4 to about 4.5 as compared to the subject's maximum fasting score for a day before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0288] In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 5 to about 7, compared to the subject's maximum fasting score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 5 to about 6.5, 5 to about 6, or 5 to about 5.5, compared to the subject's maximum fasting score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 5 to about 6.5, compared to the subject's maximum fasting score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 5 to about 6, compared to the subject's maximum fasting score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 5 to about 5.5, compared to the subject's maximum fasting score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0289] In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 6 to about 7, compared to the subject's maximum fasting score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a weekly average decrease in the maximum fasting score of about 6 to about 6.5, compared to the subject's maximum fasting score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0290] In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of less than 7 compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In an embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of less than 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3., 2.5, 2., 1.8, 1.6, 1.4, 1.2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, or less than or smaller than that compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of less than 6.5 compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of less than 6 compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of less than 5.5 compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of less than 5 compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of less than 4.5 compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score of less than 4 compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day that is less than 3.5 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day that is less than 3 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day that is less than 2.5 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day that is less than 2 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day that is less than 1.8 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day that is less than 1.6 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day that is less than 1.4 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day that is less than 1.2 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the maximum fasting score per day that is less than 1 as compared to the weekly average of the maximum fasting score per day of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score that is less than 0.9 compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score that is less than 0.8 compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score that is less than 0.7 compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score that is less than 0.6 compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score that is less than 0.5 compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score that is less than 0.4 compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score that is less than 0.3 compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score that is less than 0.2 compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in the weekly average of the daily maximum fasting score that is less than 0.1 compared to the weekly average of the daily maximum fasting score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0291] In an embodiment, the methods described herein result in an improvement in the IWQOL or IWQOL-Lite quality of life score of a subject as compared to a control (e.g., the pre-treatment IWQOL or IWQOL-Lite score of the subject, or a predetermined value, e.g., the average IWQOL or IWQOL-Lite score of an obese human population of the same age and gender as the subject who does not receive a therapeutic intervention, or a previous measurement, e.g., the IWQOL or IWQOL-Lite score of the subject at a previous visit).

[0292] The subject may experience an improvement in the IWQOL or IWQOL-Lite Quality of Life score upon administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, the subject may experience an improvement in the IWQOL or IWQOL-Lite Quality of Life score of more than 5 points compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of more than 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40 points, or greater, compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, the subject may experience an improvement in the IWQOL or IWQOL-Lite Quality of Life score of more than 6 points compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, the subject may experience an improvement in the IWQOL or IWQOL-Lite Quality of Life score of more than 7 points compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, the subject may experience an improvement in the IWQOL or IWQOL-Lite Quality of Life score of more than 8 points compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).For example, the subject may experience an improvement in the IWQOL or IWQOL-Lite Quality of Life score of more than 9 points compared to the subject's IWQOL or IWQOL-Lite Quality of Life score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, the subject may experience an improvement in the IWQOL or IWQOL-Lite Quality of Life score of more than 10 points compared to the subject's IWQOL or IWQOL-Lite Quality of Life score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, the subject may experience an improvement in the IWQOL or IWQOL-Lite Quality of Life score of more than 12 points compared to the subject's IWQOL or IWQOL-Lite Quality of Life score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, the subject may experience an improvement in the IWQOL or IWQOL-Lite Quality of Life score of more than 14 points compared to the subject's IWQOL or IWQOL-Lite Quality of Life score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, the subject may experience an improvement in the IWQOL or IWQOL-Lite Quality of Life score of more than 16 points compared to the subject's IWQOL or IWQOL-Lite Quality of Life score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, the subject may experience an improvement in the IWQOL or IWQOL-Lite Quality of Life score of more than 18 points compared to the subject's IWQOL or IWQOL-Lite Quality of Life score before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).For example, the subject may experience an improvement in the IWQOL or IWQOL-Lite Quality of Life score of more than 20 points as compared to the IWQOL or IWQOL-Lite Quality of Life score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, the subject may experience an improvement in the IWQOL or IWQOL-Lite Quality of Life score of more than 25 points as compared to the IWQOL or IWQOL-Lite Quality of Life score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, the subject may experience an improvement in the IWQOL or IWQOL-Lite Quality of Life score of more than 30 points as compared to the IWQOL or IWQOL-Lite Quality of Life score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, the subject may experience an improvement in the IWQOL or IWQOL-Lite Quality of Life score of more than 35 points as compared to the IWQOL or IWQOL-Lite Quality of Life score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, the subject may experience an improvement in the IWQOL or IWQOL-Lite Quality of Life score of more than 40 points as compared to the IWQOL or IWQOL-Lite Quality of Life score of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0293] In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 5 to about 40 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 5 to about 35 points, 5 to about 30 points, 5 to about 25 points, 5 to about 20 points, 5 to about 18 points, 5 to about 16 points, 5 to about 14 points, 5 to about 12 points, 5 to about 10 points, 5 to about 9 points, 5 to about 8 points, 5 to about 7 points, 5 to about 6 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 5 to about 35 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 5 to about 30 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 5 to about 25 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 5 to about 20 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 5 to about 18 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 5 to about 16 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 5 to about 14 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 5 to about 12 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 5 to about 10 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 5 to about 9 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 5 to about 8 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 5 to about 7 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 5 to about 6 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140).

[0294] In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 10 to about 40 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 10 to about 35 points, 10 to about 30 points, 10 to about 25 points, 10 to about 20 points, 10 to about 18 points, 10 to about 16 points, 10 to about 14 points, or 10 to about 12 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 10 to about 35 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 10 to about 30 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 10 to about 25 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 10 to about 20 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 10 to about 18 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 10 to about 16 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 10 to about 14 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 10 to about 12 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140).

[0295] In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 20 to about 40 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 20 to about 35 points, 20 to about 30 points, or 20 to about 25 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 20 to about 35 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 20 to about 30 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 20 to about 25 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140).

[0296] In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 30 to about 40 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of about 30 to about 35 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., an MC4R agonist, e.g., SEQ ID NO: 140).

[0297] In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of less than 40 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of less than 35 points, less than 30 points, less than 25 points, less than 20 points, less than 18 points, less than 16 points, less than 14 points, less than 12 points, less than 10 points, less than 9 points, less than 8 points, less than 7 points, less than 6 points, or less than that as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of less than 35 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of less than 30 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in the IWQOL or IWQOL-Lite Quality of Life score of less than 25 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences an improvement in IWQOL or IWQOL-Lite Quality of Life score of less than 20 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in IWQOL or IWQOL-Lite Quality of Life score of less than 18 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in IWQOL or IWQOL-Lite Quality of Life score of less than 16 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in IWQOL or IWQOL-Lite Quality of Life score of less than 14 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in IWQOL or IWQOL-Lite Quality of Life score of less than 12 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in IWQOL or IWQOL-Lite Quality of Life score of less than 10 points as compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences an improvement in IWQOL or IWQOL-Lite Quality of Life score of less than 9 points compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in IWQOL or IWQOL-Lite Quality of Life score of less than 8 points compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in IWQOL or IWQOL-Lite Quality of Life score of less than 7 points compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences an improvement in IWQOL or IWQOL-Lite Quality of Life score of less than 6 points compared to the subject's IWQOL or IWQOL-Lite Quality of Life score prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0298] In embodiments, the methods described herein result in a decrease in fasting in the subject (e.g., the subject's fasting prior to treatment, or a predetermined fasting, e.g., the average fasting of an obese human population of approximately the same age and sex as the subject, or a previous measurement, e.g., the subject's fasting at a previous visit) compared to a control. In embodiments, the methods described herein result in the disappearance of fasting in the subject.

[0299] In an embodiment, the fasting is in the range of 0 to 10 and is measured by a scale such as the Rickert fasting scale described herein. In an embodiment, the method described herein results in a decrease in the fasting score in a subject (e.g., the fasting level of the subject before treatment, or a predetermined fasting level, e.g., the average fasting level of an obese human population of approximately the same age and gender as the subject, or a previous measurement, e.g., the fasting level of the subject at a previous visit) compared to a control. In an embodiment, the method described herein results in a smaller score, e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 points smaller, on the Rickert fasting scale compared to a control (e.g., the fasting level of the subject before treatment, or a predetermined fasting level, e.g., the average fasting level of an obese human population of approximately the same age and gender as the subject, or a previous measurement, e.g., the fasting level of the subject at a previous visit). In an embodiment, the method described herein results in a score of 0 on the Rickert fasting scale after treatment.

[0300] In an embodiment, the decrease in fasting is measured / observed more than 1 to 2 weeks after treatment, more than 2 to 4 weeks after treatment, more than 4 to 8 weeks after treatment, or more than 8 to 16 weeks after treatment.

[0301] REE is an indicator of the subject's basal metabolic rate and can be measured using methods such as those described in Chen et al. J. Clin. Endocrinol. Metab. 100.4 (2015): 1639 - 45. In embodiments, REE can be measured by placing the subject in a whole - room indirect calorimeter (also called a metabolic chamber) after a predetermined period of treatment (e.g., after 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks or more). In embodiments, REE is measured over a 30 - minute measurement period, and in some cases, REE values from several 30 - minute periods are averaged to generate an average REE. In embodiments, REE can be measured after a 10 - to 12 - hour fasting period in the thermoneutral zone (e.g., about 25°C), where the subject is in a state of waking without psychological or physical stress. In embodiments, REE is measured in units of energy per unit time (e.g., kcal / h or kcal / day). In embodiments, REE is measured relative to the fat - free mass (kg) in the subject (e.g., REE / kg fat - free mass), as described, for example, in the examples.

[0302] In embodiments, the methods described herein do not result in a change or decrease in the metabolic rate, e.g., the resting energy expenditure (REE), in the subject over time (e.g., hourly, daily (e.g., 24 hours), weekly (e.g., 7 days), or monthly (e.g., 30 days)) when compared to a control REE (e.g., the REE in the subject before treatment, or a predetermined REE, e.g., the mean REE normalized to the weight of the subject of an obese human population of the same age and same sex, or a previous measurement, e.g., the subject's REE at a previous visit), measured, for example, 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks or more after treatment.

[0303] In an embodiment, the method described herein does not result in a detectable change or a detectable decrease in the metabolic rate, for example, the resting energy expenditure (REE) per kg of fat-free mass, in the subject over time (e.g., hourly, daily (e.g., 24 hours), weekly (e.g., 7 days), or monthly (e.g., 30 days)) as compared to a control REE (e.g., the REE in the subject before treatment, or a predetermined REE, such as the average REE of an obese human population of the same age and same gender, or a previous measurement, e.g., the REE of the subject at a previous visit), measured, for example, 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks or more after treatment.

[0304] In an embodiment, the method described herein results in an increase in the metabolic rate, for example, the resting energy expenditure (REE), in the subject over time (e.g., hourly, daily (e.g., 24 hours), weekly (e.g., 7 days), or monthly (e.g., 30 days)) as compared to a control REE (e.g., the REE in the subject before treatment, or a predetermined REE, such as the average REE of an obese human population of the same age and same gender normalized to the weight of the subject, or a previous measurement, e.g., the REE of the subject at a previous visit), measured, for example, 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks or more after treatment.

[0305] In an embodiment, the increase in the REE in the subject is at least 20 kcal / day (e.g., at least 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150 kcal / day or more) when measured, for example, 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks or more after treatment.

[0306] In an embodiment, the increase in the REE in the subject is at least 2% (e.g., at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or more) when measured, for example, 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks or more after treatment as compared to the REE in the subject before treatment.

[0307] In an embodiment, the REE in a subject (e.g., an adult subject) after treatment with an MC4R agonist (e.g., 3, 4, 5, 6, 7 days after treatment, or 1, 2, 3, 4 weeks or more after treatment) is, for example, at least 1800 kcal / day (e.g., 1800, 1825, 1850, 1875, 1900, 1925, 1950, 1975, 2000, 2025, 2050, 2100, 2150, 2200, 2250, 2300, 2400 kcal / day or more) for an adult subject. In an embodiment, the REE in a subject (e.g., a pediatric subject) after treatment with an MC4R agonist (e.g., 3, 4, 5, 6, 7 days after treatment, or 1, 2, 3, 4 weeks or more after treatment) is, for example, at least 200 kcal / day (e.g., at least 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500 kcal / day or more) for a pediatric patient.

[0308] In embodiments, the methods described herein result in a decrease in food intake by a subject as compared to a control (e.g., the food intake of the subject before treatment, e.g., a predetermined food intake amount, e.g., the food intake of an average human obesity population, or a previous measurement, e.g., the food intake of the subject at a previous visit), when food intake is measured, for example, as daily food intake, or over a period of 24 hours, or one week. In embodiments, the decrease is, for example, for an adult subject, at least 100 kilocalories, e.g., at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 1000 kilocalories or more, for daily food intake, or over a period of 24 hours, or one week, or 30 days, or a longer period of time. In embodiments, the average food intake can decrease from baseline to, for example, at least 100 kcal / kg / day to about 90, 80, 70, 60, 50, 40, 30, 20, or 10 kcal / kg / day or less in a pediatric subject of about 1 year of age after treatment with an MC4R agonist, e.g., setmelanotide. In embodiments, the average food intake can decrease from baseline to, for example, about 40 kcal / kg / day to about 35, 30, 20, or 10 kcal / kg / day or less in a pediatric subject in late adolescence after treatment with an MC4R agonist, e.g., setmelanotide.

[0309] Food intake can be measured by standard methods, such as those described in Rutishauser. Pub. Health Nutr. 8.7A(2005):1100-07.

[0310] In embodiments, the methods described herein result in a decrease in the abdominal circumference of a subject as compared to a control (e.g., the abdominal circumference of the subject before treatment, or a previous measurement, e.g., the abdominal circumference at a previous visit) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after the start of treatment.

[0311] In an embodiment, when measured at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after the start of treatment, the reduction in abdominal circumference is at least 2 cm (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 cm or more) in a subject (e.g., an adult subject) compared to a control (e.g., the abdominal circumference of the subject before treatment, or a predetermined abdominal circumference, e.g., the abdominal circumference of an average obese human population of the same age and same sex, or a previous measurement, e.g., the abdominal circumference of the subject at a previous visit).

[0312] In an embodiment, the abdominal circumference is measured using standard methods. In an embodiment, the abdominal circumference is the largest circumference around the central cross-section of the subject, e.g., around the abdomen of the subject. In other embodiments, the abdominal circumference is measured around the natural waist (e.g., between the lowest rib and the top of the hip bone), the umbilicus, or the narrowest part of the central cross-section.

[0313] The subject may experience a decrease in abdominal circumference upon administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). For example, the subject may experience a decrease in abdominal circumference of more than 1 cm compared to the subject's abdominal circumference before administration of the agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140) upon administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in abdominal circumference of more than 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10 cm or greater compared to the subject's abdominal circumference before administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in abdominal circumference of more than 1.5 cm compared to the subject's abdominal circumference before administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in abdominal circumference of more than 2 cm compared to the subject's abdominal circumference before administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in abdominal circumference of more than 2.5 cm compared to the subject's abdominal circumference before administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in abdominal circumference of more than 3 cm compared to the subject's abdominal circumference before administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in abdominal circumference of more than 4 cm compared to the subject's abdominal circumference before administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in abdominal circumference of more than 5 cm compared to the subject's abdominal circumference before administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a decrease in abdominal circumference of more than 6 cm compared to the subject's abdominal circumference before administration of the MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).In one embodiment, the subject experiences a reduction in abdominal circumference of more than 7 cm compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of more than 8 cm compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of more than 9 cm compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of more than 10 cm compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0314] In one embodiment, the subject experiences a reduction in abdominal circumference of more than 10” compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0315] In one embodiment, the subject experiences a reduction in abdominal circumference of about 1 to about 10 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 1 to about 9 cm, 1 to about 8 cm, 1 to about 7 cm, 1 to about 6 cm, 1 to about 5 cm, 1 to about 4 cm, 1 to about 3 cm, or 1 to about 2 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 1 to about 9 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 1 to about 8 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 1 to about 7 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 1 to about 6 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 1 to about 5 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 1 to about 4 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 1 to about 3 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 1 to about 2 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0316] In one embodiment, the subject experiences a reduction in abdominal circumference of about 2 to about 10 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 2 to about 9 cm, 2 to about 8 cm, 2 to about 7 cm, 2 to about 6 cm, 2 to about 5 cm, 2 to about 4 cm, or 2 to about 3 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 2 to about 9 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 2 to about 8 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 2 to about 7 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 2 to about 6 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 2 to about 5 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 2 to about 4 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 2 to about 3 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0317] In one embodiment, the subject experiences a reduction in abdominal circumference of about 3 to about 10 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 3 to about 9 cm, 3 to about 8 cm, 3 to about 7 cm, 3 to about 6 cm, 3 to about 5 cm, or 3 to about 4 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 3 to about 9 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 3 to about 8 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 3 to about 7 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 3 to about 6 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 3 to about 5 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 3 to about 4 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0318] In one embodiment, the subject experiences a reduction in abdominal circumference of about 4 to about 10 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 4 to about 9 cm, 4 to about 8 cm, 4 to about 7 cm, 4 to about 6 cm, or 4 to about 5 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 4 to about 9 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 4 to about 8 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 4 to about 7 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 4 to about 6 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 4 to about 5 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0319] In one embodiment, the subject experiences a reduction in abdominal circumference of about 5 to about 10 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 5 to about 9 cm, 5 to about 8 cm, 5 to about 7 cm, or 5 to about 6 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 5 to about 9 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 5 to about 8 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 5 to about 7 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 5 to about 6 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0320] In one embodiment, the subject experiences a reduction in abdominal circumference of about 6 to about 10 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 6 to about 9 cm, 6 to about 8 cm, or 6 to about 7 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 6 to about 9 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 6 to about 8 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 6 to about 7 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0321] In one embodiment, the subject experiences a reduction in abdominal circumference of about 7 to about 10 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 7 to about 9 cm or about 7 to about 8 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 7 to about 9 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 7 to about 8 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0322] In one embodiment, the subject experiences a reduction in abdominal circumference of about 8 to about 10 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a reduction in abdominal circumference of about 8 to about 9 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0323] In one embodiment, the subject experiences a reduction in abdominal circumference of about 9 to about 10 cm as compared to the abdominal circumference of the subject before administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140).

[0324] In one embodiment, the subject experiences a waist circumference reduction of less than 10” as compared to the subject's waist circumference prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a waist circumference reduction of less than 9, 8, 7, 6, 5, 4, 3, 2.5, 2, 1.5, 1 cm, or less than that and smaller as compared to the subject's waist circumference prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). In one embodiment, the subject experiences a waist circumference reduction of less than 9 cm as compared to the subject's waist circumference prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). The subject experiences a waist circumference reduction of less than 8 cm as compared to the subject's waist circumference prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). The subject experiences a waist circumference reduction of less than 7 cm as compared to the subject's waist circumference prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). The subject experiences a waist circumference reduction of less than 6 cm as compared to the subject's waist circumference prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). The subject experiences a waist circumference reduction of less than 5 cm as compared to the subject's waist circumference prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). The subject experiences a waist circumference reduction of less than 4 cm as compared to the subject's waist circumference prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). The subject experiences a waist circumference reduction of less than 3 cm as compared to the subject's waist circumference prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). The subject experiences a waist circumference reduction of less than 2.5 cm as compared to the subject's waist circumference prior to administration of an MC4R agonist (e.g., an MC4R agonist described herein, e.g., SEQ ID NO: 140). The subject experiences a waist circumference reduction of less than 2 cm as compared to the subject's waist circumference prior to administration of an MC4R agonist (e.g., an MC4R agonist described her...

Claims

1. A method for treating hypothalamic obesity in a subject, comprising administering a melanocortin-4 receptor (MC4R) agonist to the subject, wherein the subject: (i) has hypothalamic obesity or is identified as having hypothalamic obesity; (ii) has brain tissue damage or is recognized as having brain tissue damage; (iii) has a proliferative brain disease or is identified as having a proliferative brain disease, thereby treating hypothalamic obesity in the subject, said method.

2. The method according to claim 1, comprising (i).

3. The method according to claim 1, comprising (ii).

4. The method according to claim 1, comprising (iii).

5. The method according to claim 1, wherein the hypothalamic obesity is caused by abnormal neurodevelopment or brain malformation.

6. The method according to claim 1, wherein the brain tissue damage is present in the hypothalamus.

7. The method according to claim 6, wherein the brain tissue damage is present in the paraventricular nucleus of the hypothalamus, the ventromedial nucleus of the hypothalamus, or the arcuate nucleus of the hypothalamus.

8. The method according to claim 7, wherein the brain injury or trauma occurs in the ventromedial nucleus.

9. The method according to claim 1, wherein the subject has hypothalamic obesity.

10. The method according to claim 1, wherein the proliferative brain disease includes a benign tumor, a benign lesion, or a malignant tumor (e.g., cancer).

11. The method according to claim 10, wherein the proliferative brain disease is present in the hypothalamus.

12. The method according to claim 10, wherein the proliferative brain disease is present in the paraventricular nucleus of the hypothalamus, the ventromedial nucleus of the hypothalamus, or the arcuate nucleus of the hypothalamus.

13. The method according to claim 10, wherein the proliferative brain disease includes a craniopharyngioma or an astrocytoma.

14. The method according to claim 1, wherein the subject has undergone surgery (e.g., tumor removal or bariatric surgery) or received radiation.

15. The method according to claim 1, wherein the subject is obese, e.g., severely obese.

16. The method according to claim 1, wherein the subject has bulimia nervosa.

17. wherein the subject has a body mass index (BMI) of more than 35 kg / m ２ (e.g., ≧ 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m ２ or more) before administration of the MC4R agonist, for example when the MC4R agonist is prescribed or at the first administration, according to the method of claim 1.

18. wherein the subject has a body mass index (BMI) of more than 40 kg / m ２ (e.g., ≧ 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m ２ or more) prior to administration of the MC4R agonist, e.g., when the MC4R agonist is prescribed or at the time of the first administration, according to the method of claim 1.

19. The method according to claim 1, wherein the subject has failed one or more previous treatment methods, e.g., exercise, diet, or behavioral therapy, before administration of the MC4R agonist, e.g., when the MC4R agonist is prescribed or at the first administration.

20. The method according to claim 1, wherein the subject has a lower body weight after administration of the MC4R agonist than before administration of the MC4R agonist. **Claim 21** The method according to claim 1, wherein the MC4R agonist has the following formula (I): (R ２ R ３ ) - A １ - c(A ２ - A ３ - A ４ - A ５ - A ６ - A ７ - A ８ - A ９ ) - A １０ - R １ （ I) [Wherein, A １ is Acc, HN-(CH ２ ) ｍ -C(O), an L- or D-amino acid, or is absent; A ２ is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu; A ３ is Gly, Ala, β-Ala, GABA, Aib, a D-amino acid, or is deleted; A ４ is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X １ , X ２ , X ３ , X ４ , X ５ ) Phe; A ５ is D-Phe, Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X １ , X ２ , X ３ , X ４ , X ５ ), Phe, or D-(Et)Tyr; A ６ is Arg, hArg, Dab, Dap, Lys, Orn, or HN—CH((CH ２ )) ｎ —N(R ４ R ５ ))—C(O); A ７ is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-2-Nal, D-Bal, or D-Bip; A ８ is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, Ahx, Aha, HN-(CH ２ ) ｓ -C(O) or is deleted; A ９ is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys; A １０ is Acc, HN-(CH ２ ) ｔ -C(O), an L- or D-amino acid, or is deleted; R １ is OH or NH ２ ; and R ２ and R ３ each, with respect to each occurrence, independently, is H, (C １ -C ３０ ), alkyl, (C １ -C ３０ ), heteroalkyl, (C １ -C ３０ ), acyl, (C ２ -C ３０ ), alkenyl, (C ２ -C ３０ ), alkynyl, aryl(C １ -C ３０ ), alkyl, aryl(C １ -C ３０ ), acyl, substituted (C １ -C ３０ ), alkyl, substituted (C １ -C ３０ ), heteroalkyl, substituted (C １ -C ３０ ), acyl, substituted (C ２ -C ３０ ), alkenyl, substituted (C ２ -C ３０ ), alkynyl, substituted aryl(C １ -C ３０ ), alkyl, and substituted aryl(C １ -C ３０ ) acyl and is selected from the group consisting of; R ４ and R ５ each, for each occurrence independently, is H, (C １ -C ４０ alkyl, (C １ -C ４０ heteroalkyl, (C １ -C ４０ acyl, (C ２ -C ４０ alkenyl, (C ２ -C ４０ alkynyl, aryl(C １ -C ４０ alkyl, aryl(C １ -C ４０ acyl, substituted (C １ -C ４０ alkyl, substituted (C １ -C ４０ heteroalkyl, substituted (C １ -C ４０ acyl, substituted (C ２ -C ４０ alkenyl, substituted (C ２ -C ４０ alkynyl, substituted aryl(C １ -C ４０ alkyl, substituted aryl(C １ -C ４０ acyl, (C １ -C ４０ alkylsulfonyl, or -C(NH)-NH ２ and; m is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; n is, independently for each occurrence, 1, 2, 3, 4, or 5; s is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; t is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; X １ 、 X ２ 、 X ３ 、 X ４ 、 and X ５ are each, independently for each occurrence, H, F, Cl, Br, I, (C １ -C １０ )alkyl, substituted (C １ -C １０ )alkyl, (C ２ -C １０ )alkenyl, substituted (C ２ -C １０ )alkenyl, (C ２ -C １０ )alkynyl, substituted (C ２ -C １０ )alkynyl, aryl, substituted aryl, OH, NH ２ , NO ２ , or CN]. **Claim 22** A １ The method according to claim 21, wherein A is selected from Lys, D-Lys, Arg, and D-Arg. **Claim 23** A ２ and A ９ The method according to claim 21, wherein each of them is independently selected from Cys, hCys, and Pen. **Claim 24** A ３ The method according to claim 21, wherein A is selected from Ala or D-Ala. **Claim 25** A ４ The method according to claim 21, wherein A is selected from His and D-His. **Claim 26** A ５ The method according to claim 21, wherein A is selected from Phe, D-Phe, D-1-Nal, and D-2-Nal. **Claim 27** A ６ The method according to claim 21, wherein A is Arg. **Claim 28** A ７ The method according to claim 21, wherein A is Trp. **Claim 29** A ８ and / or A １０ The method according to claim 21, wherein A and / or A is missing. **Claim 30** R １ is NH ２ The method according to claim 21, wherein **Claim 31** R ２ and R ３ one of which is independently hydrogen, and R ２ and R ３ the other of which is independently (C １ -C ３０ ) acyl (e.g., acetyl), the method according to claim 21. **Claim 32** The MC4R agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH ２ (SEQ ID NO: 140), the method according to claim 1. **Claim 33** The method according to claim 1, wherein the MC4R agonist has the structure of formula (II) or a pharmaceutically acceptable salt thereof: 【Chemical 31】 [Wherein, XXX is Asn, Gln, Ser, or Thr, A １ is H or Ac, A ２ is OH or NH ２ and Yyy is Lys, Arg, D-Lys, or D-Arg]. **Claim 34** The method according to claim 33, wherein the MC4R agonist is selected from the following: Sequence number 629) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 630) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 631) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 632) Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 633) Ac-Arg-c(Glu-Gln-D-Phe-Arg-Trp-Dpr)-NH ２ ; (SEQ ID NO: 634) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 635) H-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 636) H-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 637) Ac-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 638) H-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 639) Ac-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 640) H-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 641) Ac-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 642) Ac-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 643) H-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 644) H-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 645) Ac-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 646) H-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 647) Ac-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 648) H-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 649) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 650) H-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 651) H-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 652) Ac-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 653) H-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 654) Ac-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 655) H-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 656) Ac-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 657) Ac-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 658) H-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 659) H-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 660) Ac-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 661) H-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 662) Ac-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 663) H-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 664) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 665) H-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 666) H-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 667) Ac-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 668) H-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 669) Ac-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 670) H-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 671) Ac-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 672) Ac-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 673) H-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 674) H-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 675) Ac-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 676) H-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 677) Ac-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 678) H-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 679) Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 680) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 681) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 682) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 683) H-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 684) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 685) H-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 686) Ac-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 687) Ac-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 688) H-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 689) H-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 690) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 691) H-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 692) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; and (SEQ ID NO: 693) H-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ , or pharmaceutically acceptable salts thereof.

35. The method according to claim 1, wherein the MC4R agonist is formulated as a pharmaceutical composition.

36. The method according to claim 35, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

37. The method according to claim 35, wherein the pharmaceutical composition comprises polyethylene glycol (e.g., modified polyethylene glycol, e.g., mPEG-DSPE, e.g., mPEG-2,000-DSPE).

38. The method according to claim 1, comprising administering the MC4R agonist to the subject in a unit dose suitable for injection, e.g., subcutaneous injection.

39. The method according to claim 38, wherein the unit dosage form is disposed within a delivery device, e.g., a syringe (e.g., a prefilled syringe), an implantable device, a needleless subcutaneous injection device, an infusion pump (e.g., an implantable infusion pump), or an osmotic delivery system.

40. The method according to claim 39, wherein the MC4R agonist is administered subcutaneously, e.g., by subcutaneous injection.

41. The method according to claim 1, wherein the subject is a human.

42. The method according to claim 1, wherein the subject is an adult (e.g., 18 years of age or older).

43. The method according to claim 1, wherein the subject is a pediatric subject, e.g., a child (e.g., less than 18, 16, 14, 12, 10, 8, 6, or 4 years old).

44. The method according to claim 1, wherein the subject has previously received treatment for obesity, e.g., non-genetic obesity, e.g., hypothalamic obesity, prior to administration of the MC4R agonist.

45. The method according to claim 1, wherein the subject exhibits a decrease in BMI after the first administration of the MC4R agonist (e.g., at least 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 4 months, 5 months, 6 months, 8 months, 10 months, 1 year, or more later).

46. The method according to claim 45, wherein the decrease in the subject's BMI is, e.g., 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20% or more compared to a reference standard (e.g., the BMI before administration of the MC4R agonist).

47. The method according to claim 45, wherein the decrease in the BMI of the subject exceeds 0.5%, for example, as compared to a reference standard (for example, the BMI before administration of the MC4R agonist).

48. The method according to claim 45, wherein the decrease in the BMI of the subject exceeds 5%, for example, as compared to a reference standard (for example, the BMI before administration of the MC4R agonist).

49. The method according to claim 45, wherein the decrease in the BMI of the subject exceeds 10%, for example, as compared to a reference standard (for example, the BMI before administration of the MC4R agonist).

50. The method according to claim 45, wherein the decrease in the BMI of the subject is 1% to 10% (for example, 1 to 5%, or 5 to 10%), for example, as compared to a reference standard (for example, the BMI before administration of the MC4R agonist).

51. The method according to claim 45, wherein the decrease in the BMI of the subject occurs 8 weeks to 6 months after administration of the MC4R agonist.

52. The method according to claim 1, wherein an additional agent (for example, an additional therapeutic agent) is administered to the subject.

53. The method according to claim 1, wherein the MC4R agonist is a compound of formula (I-a): H-A １ -c(A ２ -A ３ -A ４ -A ５ -A ６ -A ７ -A ８ -A ９ )-A １０ -NH ２ (I-a) or a pharmaceutically acceptable salt thereof, wherein A １ is Phe, D-Phe, or Nle; A ２ is Cys; A ３ is missing; A ４ is His; A ５ is D-Phe or D-(Et)Tyr; A ６ is Arg or hArg; A ７ is Trp or Bip; A ８ is Ala, β-Ala, GABA, or Apn; A ９ is D-Cys; A １０ The method wherein is Thr or is deleted.

54. The method according to claim 53, wherein the MC4R agonist of formula (I-a) is selected from: (SEQ ID NO:4) D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH ２ ; (SEQ ID NO:5) D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH ２ ; (SEQ ID NO:6) D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH ２ ; (SEQ ID NO:79) D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH ２ ; (SEQ ID NO: 80) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH ２ ; (SEQ ID NO:81) D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH ２ ; (SEQ ID NO: 82) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH ２ ; (SEQ ID NO: 83) D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH ２ ; (SEQ ID NO: 84) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH ２ ; (SEQ ID NO:85) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH ２ ; and (SEQ ID NO: 105) Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH ２ 。

55. The method according to claim 1, wherein the MC4R agonist is a compound of formula (I-b): Ac - A １ -c(A ２ -A ３ -A ４ -A ５ -A ６ -A ７ -A ８ -A ９ ) - A １０ -NH ２ (I - b) or a pharmaceutically acceptable salt thereof, wherein A １ is Nle, A6c, D-2-Nal, Cha, Oic, Chg, hCha, D-Cha, D-hCha, Nip, hPro, hLeu, Phe, D-Phe, D-Chg, hPhe, β-hMet, GABA, Leu, Ile, Val, 2-Nal, Arg or D-Arg; A ２ is Asp, Cys, D-Cys, or Pen; A ３ is missing D-Ala, β-Ala, GABA, Aib, Gly, Ala, D-Glu, D-Abu, D-Val, D-Ile, D-Leu, D-Tle, D-Cha; A ４ is His or 3-Pal; A ５ is Phe, D-Phe, or D-2-Nal; A ６ is Arg; A ７ is Trp, 1-Nal, 2-Nal, Bal, or D-Trp; A ８ is β-Ala, A6c, Ahx, Apn, Gaba, Ala, Aha, D-Ala, or is deleted; A ９ is Lys, Cys, D-Cys, or Pen; A １０ is missing, A ２ and A ９ which are selected in pairs to form a disulfide or lactam bridge, said method.

56. The method according to claim 55, wherein the MC4R agonist of formula (I-b) is selected from: (SEQ ID NO:1) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH ２ ; (SEQ ID NO:2) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH ２ ; (SEQ ID NO: 3) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH ２ ; (SEQ ID NO:7) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH ２ ; (SEQ ID NO:8) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH ２ ; (SEQ ID NO:9) Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO:10) Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO: 11) Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO:12) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO: 13) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO:14) Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO:15) Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO:16) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO:17) Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO:18) Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO:19) Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO: 20) Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO: 21) Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO: 22) Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO: 23) Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO: 24) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH ２ ; (SEQ ID NO:25) Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH ２ ; (SEQ ID NO: 26) Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH ２ ; (SEQ ID NO:27) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH ２ ; (SEQ ID NO:28) Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH ２ ; (SEQ ID NO:29) Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH ２ ; (SEQ ID NO: 30) Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH ２ ; (SEQ ID NO: 31) Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH ２ ; (SEQ ID NO: 32) Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH ２ ; (SEQ ID NO: 33) Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH ２ ; (SEQ ID NO: 34) Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO: 35) Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO: 36) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO:37) Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO: 38) Ac-D-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO:39) Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO: 40) Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO: 41) Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO: 42) Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO: 43) Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO:44) Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO:47) Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO:48) Ac-β-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO:49) Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO:50) Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH ２ ; (SEQ ID NO: 51) Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH ２ ; (SEQ ID NO:52) Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH ２ ; (SEQ ID NO:53) Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH ２ ; (SEQ ID NO:54) Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH ２ ; (SEQ ID NO:55) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH ２ ; (SEQ ID NO: 56) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH ２ ; (SEQ ID NO:57) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO:58) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH ２ ; (SEQ ID NO:59) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH ２ ; (SEQ ID NO: 60) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH ２ ; (SEQ ID NO: 61) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH ２ ; (SEQ ID NO: 62) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH ２ ; (SEQ ID NO: 63) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH ２ ; (SEQ ID NO: 64) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH ２ ; (SEQ ID NO: 65) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO: 66) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH ２ ; (SEQ ID NO: 67) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH ２ ; (SEQ ID NO: 70) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH ２ ; (SEQ ID NO:71) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-1-Nal-Cys)-NH ２ ; (SEQ ID NO: 72) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH ２ ; (SEQ ID NO:73) Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO:74) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH ２ ; (SEQ ID NO: 75) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH ２ ; (SEQ ID NO:76) Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO:77) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO:78) Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 86) Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH ２ ; (SEQ ID NO:87) Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH ２ ; (SEQ ID NO:89) Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO: 90) Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO: 91) Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO: 92) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO: 93) Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO: 94) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO: 95) Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH ２ ; (SEQ ID NO: 96) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH ２ ; (SEQ ID NO: 97) Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH ２ ; (SEQ ID NO:98) Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH ２ ; (SEQ ID NO:99) Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH ２ ; (SEQ ID NO: 100) Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH ２ ; (SEQ ID NO: 101) Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH ２ ; (SEQ ID NO: 102) Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH ２ ; (SEQ ID NO: 103) Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH ２ ; (SEQ ID NO: 106) Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH ２ ; (SEQ ID NO: 108) Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH ２ ; (SEQ ID NO: 109) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH ２ ; (SEQ ID NO: 110) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH ２ ; (SEQ ID NO: 111) Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH ２ ; (SEQ ID NO: 112) Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH ２ ; (SEQ ID NO: 113) Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO: 114) Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH ２ ; (SEQ ID NO: 139) Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO: 140) Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO: 141) Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH ２ ; (SEQ ID NO: 142) Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 143) Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH ２ ; (SEQ ID NO: 144) Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH ２ ; (SEQ ID NO: 145) Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 146) Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH ２ ; and (SEQ ID NO: 147) Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH ２ 。

57. The method according to claim 1, wherein the MC4R agonist is a compound of formula (XII-a): H - Yyy - c(Aaa - Xxx - D - Phe - Arg - Trp - Bbb) - NH ２ (XII - a) or a pharmaceutically acceptable salt thereof, wherein Aaa and Bbb are Cys, hCys, Pen which can form a disulfide bridge; or selected from Glu, Asp, Lys, Orn, Dpr, Dbu which can form a lactam bridge; Xxx is Asn, Gln, Ser, Thr; Yyy is Lys, Arg, D-Lys, D-Arg, the method.

58. The method according to claim 57, wherein the MC4R agonist of formula (XII-a) is selected from: (SEQ ID NO: 635) H-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 643) H-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 646) H-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 650) H-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 653) H-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 658) H-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 661) H-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 665) H-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 668) H-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 673) H-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 676) H-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 680) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 683) H-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 688) H-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 691) H-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; and (SEQ ID NO: 693) H-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ 。

59. The method according to claim 1, wherein the MC4R agonist is a compound of formula (XII-b): Ac - Yyy - c(Aaa - Xxx - D - Phe - Arg - Trp - Bbb) - NH ２ (XII - b) or a pharmaceutically acceptable salt thereof, wherein Aaa and Bbb are selected from Cys, hCys, Pen which can form a disulfide bridge; or Glu, Asp, Lys, Orn, Dpr, Dbu which can form a lactam bridge; Xxx is Asn, Gln, Ser, or Thr; Yyy is Lys, Arg, D-Lys, or D-Arg, the said method.

60. The method according to claim 59, wherein the MC4R agonist of formula (XII-b) is selected from: (SEQ ID NO: 629) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 630) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 631) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 632) Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 633) Ac-Arg-c(Glu-Gln-D-Phe-Arg-Trp-Apr)-NH ２ ; (SEQ ID NO: 637) Ac-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 641) Ac-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 645) Ac-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 652) Ac-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 656) Ac-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 660) Ac-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 667) Ac-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 671) Ac-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 675) Ac-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 682) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 686) Ac-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 690) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; and (SEQ ID NO: 692) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ 。

61. The method according to claim 1, wherein the MC4R agonist is a compound of formula (XII-c): A １ -Yyy-c(Aaa-Xxx-D-Phe-Arg-Trp-Bbb)-A ２ (XII-c) or a pharmaceutically acceptable salt thereof, wherein A １ is H or Ac; A ２ is OH or NH ２ ; Yyy is L-Arg or D-Arg; Aaa and Bbb are selected from Cys, hCys, and Pen which can form a disulfide bridge; or Glu, Asp, Lys, Orn, Dpr, and Dbu which can form a lactam bridge; Xxx is Asn, Gln, Ser, or Thr, the said method.

62. The method according to claim 61, wherein the MC4R agonist of formula (XII-c) is selected from: (SEQ ID NO: 629) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 630) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 631) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 632) Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 633)Ac-Arg-c(Glu-Gln-D-Phe-Arg-Trp-Apr)-NH ２ ; (SEQ ID NO: 634) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 635) H-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 636) H-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 637) Ac-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 638) H-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 639) Ac-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 640) H-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 649) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 650) H-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 651) H-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 652) Ac-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 653) H-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 654) Ac-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 655) H-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 664) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 665) H-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 666) H-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 667) Ac-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 668) H-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 669)Ac-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 670)H-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 679)Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 680) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 681)H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 682) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 683) H-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH ２ ; (SEQ ID NO: 684)Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; and (SEQ ID NO: 685)H-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH.

63. The method according to claim 1, wherein after administration of the MC4R agonist, the subject experiences a decrease in BMI of 5 to 10, for example, 16 weeks after administration, compared to the baseline BMI, for example, the BMI of the subject before administration of the MC4R agonist.

64. The method according to claim 63, wherein the subject is a pediatric subject aged 6 to 18 years.

65. The method according to claim 1, wherein after administration of the MC4R agonist, the subject experiences a decrease in body weight of about 5 kg to about 15 kg, for example, 16 weeks after administration, compared to the baseline body weight, for example, the body weight of the subject before administration of the MC4R agonist.

66. The method according to claim 65, wherein the subject is a pediatric subject aged 6 to 18 years.

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