Anorexia-sensitizing agents

Abstract

Provided herein are agents that increase a subject's sensitivity to anti-obesity and / or anorectic agents, allowing, for example, for decreased dosage or enhanced efficacy of treatment of obesity or related disorders. In particular, inhibitors of melanocortin 3 receptor (MC3R) expression or activity and / or activators of MC4R expression or activity are provided as anorexia-sensitizing agents for co-administration with anti-obesity and / or anorectic agents.

Description

[0001]Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 ANOREXIA-SENSITIZING AGENTS CROSS-REFERENCE TO RELATED APPLICATIONS The present invention claims the priority benefit of U.S. Provisional Patent Application 63 / 250,425, filed August 18, 2023, which is incorporated by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with government support under DK101357 and DK126715 awarded by the National Institutes of Health. The government has certain rights in the invention. SEQUENCE LISTING The text of the computer readable sequence listing filed herewith, titled “UM_42157_601_SequenceListing.xml”, created August 16, 2024, having a file size of 204,800 bytes, is hereby incorporated by reference in its entirety. FIELD Provided herein are agents that increase a subject’s sensitivity to anti-obesity and / or anorectic agents, allowing, for example, for decreased dosage or enhanced efficacy of treatment of obesity or related disorders. In particular, inhibitors of melanocortin 3 receptor (MC3R) expression or activity and / or activators of MC4R expression or activity are provided as anorexia- sensitizing agents for co-administration with anti-obesity and / or anorectic agents. BACKGROUND The central melanocortin system plays a fundamental role in regulating feeding behavior and maintaining body weight. Mutations in the melanocortin-4 receptor (MC4R) or genetic deletion of Mc4r results in hyperphagia, followed by hyperinsulinemia and obesity. In contrast, Mc3r deletion does not produce hyperphagia or hyperinsulinemia. However, MC3R disruption causes a shift in energy balance when exposed to external metabolic challenges such as fasting. In fact, MC3R is essential in promoting normal compensatory re-feeding in response to a Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 negative energy state. Moreover, MC3R is requisite for normal functional activation of the hypothalamic-pituitary axis and loss of MC3R function leads to late onset of pubertal activation in mice and humans. MC3R has also been demonstrated to be a negative regulator of MC4R neurons by virtue of presynaptic activity on GABAergic AgRP projections to these cells. SUMMARY Provided herein are agents that increase a subject’s sensitivity to anti-obesity and / or anorectic agents, allowing, for example, for decreased dosage or enhanced efficacy of treatment of obesity or related disorders. In particular, inhibitors of melanocortin 3 receptor (MC3R) expression or activity and / or activators of MC4R expression or activity are provided as anorexia- sensitizing agents for co-administration with anti-obesity and / or anorectic agents. Furthermore, subthreshold doses of an MC4R agonist, doses that in the absence of a co-administered anti- obesity agent have no effect on food intake or weight loss, can act as anorexia-sensitizing agents for co-administration with anti-obesity and / or anorectic agents, enhancing or potentiating the effect of the anti-obesity and / or anorectic agents. In some embodiments, provided herein are methods of treating or preventing obesity in a subject comprising administering an anti-obesity agent to the subject, wherein MC3R activity or expression has been inhibited in the subject. In some embodiments, provided herein are methods of treating or preventing obesity in a subject comprising co-administering an anti-obesity agent and an MC3R inhibitor to the subject. In some embodiments, provided herein are pharmaceutical compositions comprising: (a) an anti-obesity agent; and (b) an MC3R inhibitor. In some embodiments, the anti-obesity agent is selected from a GLP-1 agonist, a MC4R agonist, an anorectic, a pro-satiety agent, and a lipase inhibitor. In some embodiments, provided herein are methods of treating or preventing obesity in a subject comprising administering an anti-obesity agent to the subject, wherein MC4R activity or expression has been enhanced in the subject. In some embodiments, provided herein are methods of treating or preventing obesity in a subject comprising co-administering an anti-obesity agent and an MC4R activator to the subject. In some embodiments, provided herein are pharmaceutical compositions comprising: (a) an anti-obesity agent; and (b) an MC4R activator. In some Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 embodiments, the anti-obesity agent is selected from a GLP-1 agonist, an anorectic, a pro-satiety agent, and a lipase inhibitor. In some embodiments, an anti-obesity agent is a GLP-1 agonist. In some embodiments, the GLP-1 agonist is selected from exendin-4, albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, taspoglutide, tirzepatide, retatrutide, CNTO736, CNT03649, HM11260C (LAPS-Exendin), NN9926 (OG9S7GT), TT401 and ZYOG1. In some embodiments, an anti-obesity agent is a MC4R agonist. In some embodiments, the MC4R agonist is setmelanotide. In some embodiments, an anti-obesity agent is an anorectic. In some embodiments, the anorectic is selected from amphetamine, dexamphetamine, amfepramone, clobenzorex, mazindol, phentermine, phentermine and topiramate, and lorcaserin. In some embodiments, an anti-obesity agent is a pro-satiety agent. In some embodiments, the pro-satiety agent is selected from neurotrophic factor, amylin, calcitonin, cholecystokinin (CCK), leptin, metreleptin oxyntomodulin, pancreatic polypeptide (PP), peptide YY (PYY), and neuropeptide Y (NPY). In some embodiments, the anti-obesity agent is a lipase inhibitor. In some embodiments, the lipase inhibitor is selected from caulerpenyne, cetilistat, ebelactone A and B, esterastin, lipstatin, orlistat, percyquinin, panclicin A-E, valilactone and vibralactone. In some embodiments, an anti-obesity agent is administered at a sub-therapeutic dose. In some embodiments, an anti-obesity agent is administered at a sub-standard dose. In some embodiments, the MC3R inhibitor is an inhibitor of MC3R activity. In some embodiments, the inhibitor of MC3R activity is a small molecule or peptide MC3R antagonist or partial agonist. In some embodiments, the peptide MC3R antagonist or partial agonist is selected from a peptide of SEQ ID NOS 1-26. In some embodiments, the MC3R inhibitor is an inhibitor of MC3R expression. In some embodiments, the inhibitor of MC3R expression is a siRNA, a shRNA, a miRNA, a morpholino, a ribozyme, an antisense nucleic acid molecule, or a CRISPR -based construct. In some embodiments, the MC3R inhibitor is administered at a sub-therapeutic dose. In some embodiments, the MC3R inhibitor is administered at a sub-standard dose. Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 In some embodiments, the MC4R activator is an enhancer of MC4R activity. In some embodiments, the enhancer of MC4R activity is a small molecule or peptide MC4R agonist. In some embodiments, the peptide MC4R agonist is selected from a peptide of SEQ ID NOS 27- 115. In some embodiments, the MC4R activator is an enhancer of MC4R expression. In some embodiments, the MC4R agonist is administered at a sub-therapeutic dose. In some embodiments, the MC4R agonist is administered at a sub-standard dose. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1A-P. Genetic deletion and pharmacological inhibition of MC3R results in increased response to the anorectic and weight loss effects of GLP1-analogs. Liraglutide (0.05mg / kg – 0.4mg / kg) administration results in greater inhibition of (A) food intake and weight loss (B) in Mc3r- / -male mice compared to Mc3r+ / +mice in a dose dependent manner after 24-hours (N = 7–8 / group). Liraglutide-induced feeding (C) and body weight changes (D) of Mc3r+ / +and Mc3r- / -female mice (n = 7–8 / group; 0.05mg / kg – 0.4mg / kg). 24-hour semaglutide – induced feeding (E) and body weight changes (F) in Mc3r+ / +and Mc3r- / -male mice (n = 8 / group; 1nmol / kg – 100nmol / kg). 8, 12, and 24-hour feeding and 24-hour body weight changes (G-J) of pharmacological inhibition of MC3R using compound 11 (1nmol) and liraglutide (0.2mg / kg) in Mc3r+ / +and Mc3r- / -male mice (C11, n = 6, all other groups n = 7). Tirzepatide (1nmol / kg – 4nmol / kg) and coadministration of tirzepatide and C11- induced feeding responses and body weight changes (K-L) of wildtype male mice (vehicle, n = 10, all other groups n = 8) and wildtype female mice (M-N) at 24-hours post injection. 24-hour feeding (O) and body weight change (P) after chronic injections of tirzepatide (2nmol / kg), C11 (0.5nmol), tirzepatide and C11, and vehicle. Data is expressed as mean ± SEM, statistical tests were two-way ANOVA with Tukey’s test for posthoc analysis for (G-J). For all the dose-response curve data, a repeated measures of two-way ANOVA corrected for multiple comparisons using Tukey–Kramer method for each time point and data were fitted with four parameters nonlinear fit, *p < 0.05, *p <0.01, ***p <0.001. Figure 2A-L. Mc3r deletion has no effect on the incretin activity or malaise associated with liraglutide. (A–F) Glucose levels and AUC before and after oral administration of glucose (1 g / kg) after liraglutide (lira) (0.01–0.2 mg / kg) or vehicle Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 (veh) treatment in Mc3r+ / + and Mc3r– / – male mice (n = 6–7 / group). CTA test day 1 (G) and test day 2 (H) after liraglutide administration in Mc3r+ / + and Mc3r– / – male mice. (I) Representative images from the AP showing Fos IHC after saline or liraglutide injection from Mc3r+ / + and Mc3r– / – male mice. CC, central canal. Scale bars: 100 μm. (J) Quantification of cells expressing Fos after saline or liraglutide injection in Mc3r+ / + and Mc3r– / – male mice. (K) Representative images from the hypothalamus showing Fos IHC after liraglutide treatment in Mc3r+ / + and Mc3r– / – mice. Scale bars: 100 μm. (L) Quantification of cells expressing Fos in the ARH, VMH, and DMH after liraglutide treatment. Statistical analysis was done by 2-tailed Student’s t test, *P < 0.05, and ****P < 0.0001 (J, G, H, and L). Figure 3A-F. Deletion of Mc3r results in generalized enhanced sensitivity to anorectic hormones. Nocturnal feeding in response to leptin (0.1–1 mg / kg) 12 hours after injection (vehicle, n = 11, n = 6 / group) in Mc3r+ / + and Mc3r– / – (A) male and (D) female mice. Acute dark-phase feeding after administration of PYY3–36 (n = 7 / group) in Mc3r+ / + and Mc3r– / – (B ) male and (E) female mice. Acute dark-phase feeding after administration of CCK (n = 7–8 / group) in Mc3r+ / + and Mc3r– / – (C ) male and (F) female mice. Data represent the mean ± SEM. Statistical analysis was done by 2-way, repeated-mea- sures ANOVA with Tukey’s post hoc test (A–F). Figure 4A-L. Mc3r deletion enhances the ability of an MC4R agonist to increase sensitivity to liraglutide. (A, C, E, and G) Twenty-four-hour food intake and (B, D, F, and H) body weight changes in response to CTX 1211 or setmelanotide (2 mg / kg, i.p., n = 8 / group) or to liraglutide alone (0.05–0.4 mg / kg, s.c., n = 8), as indicated in male and female mice. (I and K) Twenty-four-hour food intake and (J and L) body weight changes in response to CTX 1211 (1.5 mg / kg, i.p., n = 5–6) or setmelanotide (1.5 mg / kg, i.p., n = 9) alone, liraglutide alone (0.2 mg / kg, s.c.), liraglutide plus CTX 21 or setmelanotide, and vehicle in Mc3r+ / + and Mc3r– / – mice. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-way, repeated-measures ANOVA. Figure 5A-F. Subthreshold doses of MC4R agonist CTX 1211 increases the sensitivity of liraglutide. (A and C). Twenty-four-hour food intake and (B and D) body weight changes in response to vehicle (n = 10 / group), liraglutide (0.1 mg / kg, n = Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 10 / group), CTX 1211 (1 mg / kg, n = 10 / group), and the combination of liraglutide plus CTX 1211 in male (A and B) and female(C and D) mice. (E and F) Same experiment repeated in male mice (n=9-10) using 0.5mg / kg of CTX 1211, showing effects on food intake (E) and body weight (F). Data represent the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA. Figure 6A-D. Subthreshold doses of MC4R agonist setmelanotide increases the sensitivity of liraglutide. Twenty-four-hour food intake (A and C) and body weight (B and D) changes in response to vehicle (n = 7-8 / group), setmelanotide (0.5 mg / kg, n = 7- 8 / group), and the combination of liraglutide plus setmelanotide in male (A and B) and female (C and D) mice. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA. DEFINITIONS Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments described herein, some preferred methods, compositions, devices, and materials are described herein. However, before the present materials and methods are described, it is to be understood that this invention is not limited to the particular molecules, compositions, methodologies, or protocols herein described, as these may vary in accordance with routine experimentation and optimization. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the embodiments described herein. 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. However, in case of conflict, the present specification, including definitions, will control. Accordingly, in the context of the embodiments described herein, the following definitions apply. As used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “an agonist peptide” is a reference to one or more agonist peptides and equivalents thereof known to those skilled in the art, and so forth. Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 As used herein, the term “comprise” and linguistic variations thereof denote the presence of recited feature(s), element(s), method step(s), etc. without the exclusion of the presence of additional feature(s), element(s), method step(s), etc. Conversely, the term “consisting of” and linguistic variations thereof, denotes the presence of recited feature(s), element(s), method step(s), etc. and excludes any unrecited feature(s), element(s), method step(s), etc., except for ordinarily-associated impurities. The phrase “consisting essentially of” denotes the recited feature(s), element(s), method step(s), etc. and any additional feature(s), element(s), method step(s), etc. that do not materially affect the basic nature of the composition, system, or method. Many embodiments herein are described using open “comprising” language. Such embodiments encompass multiple closed “consisting of” and / or “consisting essentially of” embodiments, which may alternatively be claimed or described using such language. As used herein, the term “MC3R antagonist” refers to an agent (e.g., peptide, etc.) that binds to MC3R and inhibits MC3R from producing its biological activity. In some embodiments, an MC3R antagonist binds to MC3R in the same location as a natural MC3R ligand (e.g., melanocyte-stimulating hormone and adrenocorticotropic hormone). As used herein, the term “MC3R partial agonist” refers to an agent (e.g., peptide, etc.) that binds to MC3R and promotes MC3R to produce its biological activity to a lesser extent than a full agonist (e.g., a natural agonist of MC3R (e.g., melanocyte-stimulating hormone and adrenocorticotropic hormone)). In some embodiments, an MC3R partial agonist binds to MC3R in the same location as a natural MC3R ligand (e.g., melanocyte-stimulating hormone and adrenocorticotropic hormone). As used herein, the term “MC4R agonist” refers to an agent (e.g., peptide, etc.) that binds to MC4R and promotes MC4R to produce its biological activity to at least the same degree as a natural ligand for MC4R (e.g., α-melanocyte stimulating hormone (α-MSH) or adrenocorticotropic hormone). In some embodiments, an MC4R agonist binds to MC4R in the same location as a natural MC4R ligand. As used herein, the term “subject” broadly refers to any animal, including but not limited to, human and non-human animals (e.g., dogs, cats, cows, horses, sheep, poultry, fish, crustaceans, etc.). As used herein, the term “patient” typically refers to a subject that is being treated for a disease or condition. Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 As used herein, the term “obesity” refers to a medical condition with excess body fat accumulation and people are generally defined to be obese when their body mass index (BMI; a value of body mass (kg) over body height squared (m)) is 30 or higher. Obesity is most commonly caused by energy imbalance due to excessive food intake compared to energy consumption over a long period of time (“positive energy balance”). Obesity, being a metabolic disease that affects the entire body, increases the possibility of developing of diabetes and hyperlipidemia, increases the risk of the incidence of sexual dysfunction, arthritis, and cardiovascular disease, and is associated with cancer development in some cases. As used herein, the term “obesity related condition” refers to the range of medical conditions that result from, exacerbate, and / or have a common cause with obesity. Examples of obesity related conditions include type 2 diabetes, gallbladder disease, hypertension, coronary heart disease, etc. As used herein, the term “subject at risk for a disease,” for example, “a subject at risk for diabetes” or “a subject at risk for hypertension” refers to a subject with one or more risk factors (e.g., obesity, overeating, etc.) for developing the disease. Depending upon the specific disease, risk factors may include, but are not limited to, gender, age, genetic predisposition, environmental exposures, and previous incidents of diseases, lifestyle, etc. As used herein the term “anorexia” refers to decreased appetite in a subject. As sued herein, the term “anorectic” refers to an agent that induces anorexia in a subject. As used herein, the terms “administration” and “administering” refer to the act of giving a drug, prodrug, or other agent, or therapeutic treatment to a subject or in vivo, in vitro, or ex vivo cells, tissues, and organs. Exemplary routes of administration to the human body can be through space under the arachnoid membrane of the brain or spinal cord (intrathecal), the eyes (ophthalmic), mouth (oral), skin (topical or transdermal), nose (nasal), lungs (inhalant), oral mucosa (buccal), ear, rectal, vaginal, by injection (e.g., intravenously, subcutaneously, intratumorally, intraperitoneally, etc.) and the like. As used herein, the terms “co-administration” and “co-administering” refer to the administration of at least two agent(s) (e.g., an MC3R antagonist and one or more additional therapeutics) or therapies to a subject. In some embodiments, the co-administration of two or more agents or therapies is concurrent (e.g., in a single formulation / composition or in separate Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 formulations / compositions). In other embodiments, a first agent / therapy is administered prior to a second agent / therapy. Those of skill in the art understand that the formulations and / or routes of administration of the various agents or therapies used may vary. The appropriate dosage for co- administration can be readily determined by one skilled in the art. In some embodiments, when agents or therapies are co-administered, the respective agents or therapies are administered at lower dosages than appropriate for their administration alone. Thus, co-administration is especially desirable in embodiments where the co-administration of the agents or therapies lowers the requisite dosage of a potentially harmful (e.g., toxic) agent(s), and / or when co- administration of two or more agents results in sensitization of a subject to beneficial effects of one of the agents via co-administration of the other agent. As used herein, the term “therapeutically effective dose” refers to the amount of a pharmaceutical agent sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “standard dose” refers to the amount of a pharmaceutical agent that is provided to a subject for the treatment / prevention of a particular condition under standard medical practice and / or regulatory guidelines. The standard dose may be defined by a range of doses and may be somewhat variable depending on patient-specific and / or condition-specific factors. For example, the standard dose may be higher for a subject with an extreme condition or with a higher body weight. As used herein, the term “sub-therapeutic dose,” refers to a dose of an agent which, when used in a standard protocol, would elicit little or no positive effect in the intended treatment, for example, a dose having a negligible or statistically insignificant anorectic effect. As used herein, the term “sub-standard dose,” refers to a dose of an agent which is less than the standard, accepted, or recommended dose for a given subject for a given condition. As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo. As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers including, but not limited to, phosphate buffered saline solution, Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents, any and all solvents, dispersion media, coatings, sodium lauryl sulfate, isotonic and absorption delaying agents, disintigrants (e.g., potato starch or sodium starch glycolate), and the like. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. (1975), incorporated herein by reference in its entirety. As used herein, the term “instructions for administering said compound to a subject,” and grammatical equivalents thereof, includes instructions for using the compositions contained in a kit for the treatment of conditions (e.g., providing dosing, route of administration, decision trees for treating physicians for correlating patient-specific characteristics with therapeutic courses of action). DETAILED DESCRIPTION Provided herein are agents that increase a subject’s sensitivity to anti-obesity and / or anorectic agents, allowing, for example, for decreased dosage or enhanced efficacy of treatment of obesity or related disorders. In particular, inhibitors of melanocortin 3 receptor (MC3R) expression or activity and / or activators of MC4R expression or activity are provided as anorexia- sensitizing agents for co-administration with anti-obesity and / or anorectic agents. In certain embodiments, administration of an inhibitor of MC3R and / or an activator of MC4R, even at a sub-therapeutic or sub-standard dose (e.g., below a dose capable of producing a statistically significant reduction in food intake, body weight, etc.), sensitizes a subject to anti-obesity and / or anorectic agents, such that co-administration of a (1) MC3R inhibitor or a MC4R activator with (2) an anti-obesity and / or anorectic agent enhances the efficacy of the anti-obesity and / or anorectic agent, allowing for greater benefit and / or reduced dose (e.g., with reduced side effects) from the anti-obesity and / or anorectic agent. Experiments conducted during development of embodiments herein revealed several important findings, including: (1) the absence or blockade of MC3R, or the activation of MC4R, increases the sensitivity to multiple GLP1R agonists and promotes weight loss and anorexia; (2) the hypersensitivity anorectic effects of MC3R inhibition are independent of the incretin properties and the malaise associated with GLP1R agonists, in line with findings that the MC3R Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 is not essential for regulating peripheral systems governing metabolism; (3) central systems regulating malaise or nausea, the hypersensitivity anorectic effect elicited by the deletion or inhibition of MC3R, can be generalized to other anorexigenic agents such as leptin, CCK, and PYY336; (4) deletion or inhibition of the MC3R potentiates the effects of MC4R agonists, demonstrating that MC3R is a negative regulator of MC4R, and (5) subthreshold doses of an MC4R agonist, doses that in the absence of a co-administered anti-obesity agent have no effect on food intake or weight loss, act as anorexia-sensitizing agents for co-administration with anti- obesity and / or anorectic agents. These findings demonstrate that inhibition or deletion of MC3R, or activation of the MC4R, promotes generalized hypersensitivity to anorexigenic agents. MC3Rs are expressed in hypothalamic and other central nuclei that influence energy homeostasis. Endogenous agonist alpha-melanocyte-stimulating (α-MSH) hormone shows strong affinity to MC3Rs. Loss of MC3Rs produces diverse phenotypes. MC3R is requisite for normal functional activation of the hypothalamic-pituitary axis and loss of MC3R function leads to late onset of pubertal activation in mice and humans. MC3R deficient mice exhibit anxiety in multiple forms including social isolation, restraint stress, and novelty suppressed feeding. MC3Rs are virtually expressed in both the orexigenic neurons expressing agouti-related protein (AgRP) and the opposing anorexigenic neurons expressing proopiomelanocortin (POMC) which also produce the endogenous ligand (α-MSH) for MC3R. Given the important and well- established role of POMC and AgRP neurons in regulating energy homeostasis, studying the bidirectional effect of MC3R in appetite control and weight loss is imperative. Deletion of MC3R promotes the anorectic effects and weight loss of glucagon-like peptide-1 receptor (GLP1R) agonist, liraglutide. Numerous GLP1R agonists have been developed and are in clinical use for the treatment of type 2 diabetes and obesity. To understand the combinational effect of GLP1Rs and the loss of MC3R on food intake and weight loss, Mc3r- / -and wildtype mice were systemically treated with liraglutide and semaglutide, two potent and selective GLP1R agonists, in a dose-dependent manner. It was found in both males and females that the loss of MC3R not only potentiated the effect of GLP1R agonists but sensitized the anorectic and weight loss effect of GLP1R agonists. This effect is seen for genetic deletion of MC3R and pharmacologic inhibition or MC3R. Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 It has been reported that the anorectic effects of liraglutide is exclusively due to central mechanism of action and central inhibition of GLP1R increases food intake and not the incretin effects of GLP1Rs. Experiments conducted during development of embodiments herein demonstrate that the hypersensitive anorectic effects of liraglutide in Mc3r- / -was independent of its glucose lowering effects. Acute administration of liraglutide causes visceral malaise. Experiments conducted during development of embodiments herein demonstrated that the increased anorectic effects in Mc3r- / -was not due to malaise, which was reflected by no changes in conditioned taste aversion assay and FOS reactivity in the area postrema – where GLP1R agonist-mediated nausea behaviors are seen, between genotypes. Both MC3R and GLP1R are distributed across several brain regions The anorectic effects of GLP1R have been heavily implicated in the nucleus solitary tract and hypothalamic nuclei. Expression of MC3Rs and the GLP1R-expressing brain regions either express the cell bodies of MC3R or MC3R terminals, indicating a crosstalk between the two receptors. The significance of the increased responsiveness of the GLP1R agonist in the Mc3r- / -mice lead to assessing of the generalizability of the hypersensitivity anorectic effect. Mice were treated with various well-studied anorexigenic hormones and compounds including CCK, PYY, leptin, and setmelanotide. Interestingly, we found that^Mc3r- / -mice were also hypersensitive to all the treatments. While these compounds provoke similar effects in the Mc3r- / -mice, the endogenous synthesis and release of , for example, CCK which is synthesized and released by enteroendocrine cells in the mucosal linings of the small intestine and initiates action through the vagal afferents nerve fibers vs. leptin which is synthesized by white adipose tissue and primarily acts on neurons of the medio-basal regions of the hypothalamus may have alternate pathways of controlling food intake. Therefore, it is highly likely there exists multiple mechanisms by which MC3R controls food intake and body weight throughout the brain. MC3R acts presynaptically to regulate GABA release from these cells onto secondary MC3R and MC4R sites. Furthermore, MC3R is highly expressed in POMC neurons (~82%) where they are thought to function as auto-receptors. The effects of MC4R agonists were tested in mice with loss or blockade of MC3R. Mc3r- / -mice showed an increased response to setmelanotide and the combination with the GLP1R agonist, liraglutide exacerbated this Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 hypersensitivity to setmelanotide. This finding indicates that there may be multiple anorexigenic neuronal populations that are perhaps increased in their activation. Since the highest region where MC3R is expressed is hypothalamic brain regions, c-Fos was analyzed as a surrogate marker of neural activity in hypothalamic tissue. ^ Experiments conducted during development of embodiments herein indicate that the loss of MC3R or pharmacological inhibition of MC3R results in hypersensitivity to GLP1R agonists without promoting malaise or peripheral incretin effects. Loss of MC3R promotes generalized hypersensitivity to multiple anorexigenic agents and can also in tandem promote the synergism of multiple compounds such as in the case of MC4R and GLP1R agonists. I. MC3R inhibition and / or MC4R activation In some embodiments, compositions are provided herein comprising an inhibitor of MC3R (e.g., provided with and / or co-formulated with an anti-obesity agent). In some embodiments, compositions are provided herein comprising an activator of MC4R (e.g., provided with and / or co-formulated with an anti-obesity agent). In some embodiments, methods are provided comprising administering an inhibitor of MC3R and / or activator of MC4R (e.g., co- administered with an anti-obesity agent). In some embodiments, an inhibitor of MC3R is an inhibitor of MC3R activity. In some embodiments, an MC3R inhibitor is a small molecule, peptide, antibody, antibody fragment, a genome editing agent, etc. that upon administration to a subject, cell, etc. reduces the activity of MC3R, for example, systemically, within a specific tissue, organ, or body system, within a specific cell population, etc. In some embodiments, an activator of MC4R is an activator of MC4R activity. In some embodiments, an MC4R activator is a small molecule, peptide, antibody, antibody fragment, a genome editing agent, etc. that upon administration to a subject, cell, etc. reduces the activity of MC4R, for example, systemically, within a specific tissue, organ, or body system, within a specific cell population, etc. Exemplary inhibitors of MC3R activity include MC3R antagonists or partial agonists of MC3R (partial agonists inhibit MC3R by binding to MC3R and activating it to a lesser extent than an endogenous substrate). In some embodiments, an MC3R inhibitor is a peptide. Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 Exemplary MC3R antagonist or partial agonist peptides are provided in WO 2023 / 028538; incorporated by reference in its entirety. In particular, the exemplary peptides of Table 1 exhibit MC3R antagonism or partial agonism and find use in embodiments herein. Table 1. MC3R cAMP IC50s and % maximal inhibition for exemplary MC3R antagonists or partial agonists Peptide N-term. Sequence SEQ C-term. MC3R code Mod. ID Mod. cAMP Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 CTX- Ac Arg-Nle-cyclo(Cys- 9 NH2 9.0 nM 1230 Arg-D-Phe(4-Br)- (57.2%) Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 CTX- Ac Ac-Arg-cyclo-(Cys- 22 NH2 1669 D-Ala-His-D-Fpm- 10.4nM Other antagonists of MC3R include Agouti related protein (AGRP). In some embodiments, a MC3R antagonist or partial agonist inhibits the activity of MC3R selectively over one or more other melanocortin receptors (e.g., MC1R, MC2R, MC4R, MC5R). In some embodiments, a MC3R antagonist or partial agonist and inhibits the activity of MC3R at least 2- fold greater (e.g., 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 20x, 30x, 40x, 50x, 60x, 70x, 80x, 90x, 100x, 200x, 500x, 1000x, 2000x, 5000x, or more) than one or more other melanocortin receptors (e.g., MC1R, MC2R, MC4R, MC5R). In some embodiments, a MC3R antagonist or partial agonist and inhibits the activity of MC3R selectively over MC4R. In some embodiments, a peptide herein is a MC3R antagonist or partial agonist and inhibits the activity of MC3R at least 2-fold greater (e.g., 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 20x, 30x, 40x, 50x, 60x, 70x, 80x, 90x, 100x, 200x, 500x, 1000x, 2000x, 5000x, or more) than MC4R. Exemplary activators of MC4R activity include MC4R agonists. In some embodiments, an MC4R activator is a peptide. Exemplary MC4R agonist peptides are provided in WO 2023 / 028538; incorporated by reference in its entirety. In particular, the exemplary peptides of Table 2 exhibit MC4R agonism and find use in embodiments herein. Table 2. MC4R cAMP (EC50) and % maximal activation for exemplary MC4R agonists. Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 Peptid N- Sequence SEQ C- MC4R e code term. ID term. cAMP ) Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 CTX- Ac Arg-cyclo(Cys-D- 38 NH2 6.5 nM 1263 Ala-Arg-D-Phe-Arg- (93%) ) ) Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 CTX- Ac Arg-cyclo(Cys-Aib- 52 NH2 0.6 nM 1289 Cit-D-Phe-Arg-Trp- (93%) Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 CTX- Ac Arg-cyclo(Cys-Aib- 66 NH2 1,524 nM 1604 Pal(2')-D-Phe-Arg- 96%) Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 CTX- Ac Arg-Nle-cyclo(Cys- 80 NH2 41 nM 1622 Arg-D-Phe-Arg- (101%) Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 CTX- Ac cyclo(Cys-Aib-Cit- 94 NH2 791 nM 1636 D-Phe-Arg-Phe- (102%) Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 CTX- Chloro Thioether- 108 NH2 >10,000 1652 acetyl cyclo(Aib-Cit-D- nM In some embodiments, a MC3R inhibitor is an antibody or antibody fragment. In some embodiments, a MC3R inhibitor is an antibody or antibody fragment that binds to MC3R and reduces MC3R activity. In some embodiments, an inhibitor of MC3R is an inhibitor of MC3R expression. In some embodiments, an inhibitor is a small molecule, peptide, antibody, antibody fragment, a genome editing agent, etc. In particular embodiments, a MC3R inhibitor is a nucleic acid-based inhibitor. In some embodiments, the inhibitor is a small molecule, an aptamer, a siRNA, a shRNA, a miRNA, a morpholino, a ribozyme, an antisense nucleic acid molecule, a CRISPR- Cas9-based construct, a CRISPR-Cpf1-based construct, a meganuclease, a zinc finger nuclease, a transcription activator-like (TAL) effector (TALE) nuclease, etc. In some embodiments, the MC3R inhibitor is a small interfering RNA (siRNA), also known as short interfering RNA or silencing RNA. In some embodiments, an siRNA is an 18 to Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 30 nucleotide, preferably 19 to 25 nucleotide, most preferred 21 to 23 nucleotide or even more preferably 21 nucleotide-long double-stranded RNA molecule. siRNA is involved in the RNA interference (RNAi) pathway where the siRNA interferes with the expression of a specific gene. siRNAs naturally found in nature have a well-defined structure: a short double-strand of RNA (dsRNA) with 2-nt 3' overhangs on either end. Each strand has a 5' phosphate group and a 3' hydroxyl (--OH) group. This structure is the result of processing by dicer, an enzyme that converts either long dsRNAs or small hairpin RNAs into siRNAs. siRNAs can also be exogenously (artificially) introduced into cells to bring about the specific knockdown of a gene of interest (e.g., Mc3r). Essentially any gene for which the sequence is known can thus be targeted based on sequence complementarity with an appropriately tailored siRNA. The double- stranded RNA molecule or a metabolic processing product thereof is capable of mediating target- specific nucleic acid modifications, particularly RNA interference and / or DNA methylation. Exogenously introduced siRNAs may be devoid of overhangs at their 3' and 5' ends, however, in some embodiments at least one RNA strand has a 5'- and / or 3'-overhang. Preferably, one end of the double-strand has a 3'-overhang from 1 to 5 nucleotides, more preferably from 1 to 3 nucleotides and most preferably 2 nucleotides. The other end may be blunt-ended or has up to 6 nucleotides 3'-overhang. In general, any RNA molecule suitable to act as siRNA and inhibit Mc3r is envisioned in the present invention. In some embodiments, siRNA duplexes are provided composed of 21-nt sense and 21-nt antisense strands, paired in a manner to have a 2-nt 3'-overhang. The sequence of the 2-nt 3' overhang makes a small contribution to the specificity of target recognition restricted to the unpaired nucleotide adjacent to the first base pair. 2'- deoxynucleotides in the 3' overhangs are as efficient as ribonucleotides, but are often cheaper to synthesize and probably more nuclease resistant. Delivery of siRNA may be accomplished using any of the methods known in the art, for example by combining the siRNA with saline and administering the combination intravenously or intranasally or by formulating siRNA in glucose (such as for example 5% glucose) or cationic lipids and polymers can be used for siRNA delivery in vivo through systemic routes either intravenously (IV) or intraperitoneally (IP). In some embodiments, provided herein are siRNA molecules that target and inhibit the expression (e.g., knock down) of Mc3r. Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 A short hairpin RNA (shRNA) is a sequence of RNA that makes a tight hairpin turn that can be used to silence gene expression (e.g., of Mc3r) via RNA interference. In some embodiments, shRNA uses a vector introduced into cells and utilizes the U6 promoter to ensure that the shRNA is always expressed. This vector is usually passed on to daughter cells, allowing the gene silencing to be inherited. The shRNA hairpin structure is cleaved by the cellular machinery into siRNA, which is then bound to the RNA-induced silencing complex (RISC). The RISC binds to and cleaves RNAs which match the siRNA that is bound to (e.g., comprising the sequence of the Mc3r). In some embodiments, si / shRNAs to be used in the present invention are chemically synthesized using appropriately protected ribonucleoside phosphoramidites and a conventional DNA / RNA synthesizer. In some embodiments, provided herein are shRNA molecules that target and inhibit the expression (e.g., knock down) of the Mc3r. Further molecules effecting RNAi (and useful herein for the inhibition of expression of the Mc3r) include, for example, microRNAs (miRNA). Said RNA species are single-stranded RNA molecules. Endogenously present miRNA molecules regulate gene expression by binding to a complementary mRNA transcript and triggering of the degradation of said mRNA transcript through a process similar to RNA interference. Accordingly, exogenous miRNA may be employed as an inhibitor of Mc3r after introduction into target cells. In some embodiments, provided herein are miRNA molecules that target and inhibit the expression (e.g., knock down) of Mc3r. Morpholinos (or morpholino oligonucleotides) are synthetic nucleic acid molecules having a length of about 20 to 30 nucleotides and, typically about 25 nucleotides. Morpholinos bind to complementary sequences of target transcripts (e.g., Mc3r) by standard nucleic acid base- pairing. They have standard nucleic acid bases which are bound to morpholine rings instead of deoxyribose rings and linked through phosphorodiamidate groups instead of phosphates. Due to replacement of anionic phosphates into the uncharged phosphorodiamidate groups, ionization in the usual physiological pH range is prevented, so that morpholinos in organisms or cells are uncharged molecules. The entire backbone of a morpholino is made from these modified subunits. Unlike inhibitory small RNA molecules, morpholinos do not degrade their target RNA molecules. Rather, they sterically block binding to a target sequence within a RNA and prevent access by molecules that might otherwise interact with the RNA. In some embodiments, Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 provided herein are morpholino oligonucleotides that target and inhibit the expression (e.g., knock down) of Mc3r. A ribozyme (ribonucleic acid enzyme, also called RNA enzyme or catalytic RNA) is an RNA molecule that catalyzes a chemical reaction. Many natural ribozymes catalyze either their own cleavage or the cleavage of other RNAs, but they have also been found to catalyze the aminotransferase activity of the ribosome. Non-limiting examples of well-characterized small self-cleaving RNAs are the hammerhead, hairpin, hepatitis delta virus, and in vitro-selected lead- dependent ribozymes, whereas the group I intron is an example for larger ribozymes. The principle of catalytic self-cleavage is well established. Since it was shown that hammerhead structures can be integrated into heterologous RNA sequences and that ribozyme activity can thereby be transferred to these molecules, catalytic antisense sequences can be engineered for almost any target sequence can be created, provided the target sequence contains a potential matching cleavage site. The basic principle of constructing hammerhead ribozymes is as follows: A region of interest of the RNA (e.g., a portion of Mc3r), which contains the GUC (or CUC) triplet, is selected. Two oligonucleotide strands, each usually with 6 to 8 nucleotides, are taken and the catalytic hammerhead sequence is inserted between them. In some embodiments, provided herein are ribozyme inhibitors oligonucleotides of Mc3r. In some embodiments, activity of expression of MC3R is inhibited by modifying the Mc3r sequence in target cells. In some embodiments, the alteration of Mc3r is carried out using one or more DNA-binding nucleic acids, such as alteration via an RNA-guided endonuclease (RGEN). For example, the alteration can be carried out using clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) proteins. In general, "CRISPR system" refers collectively to transcripts and other elements involved in the expression of or directing the activity of CRISPR-associated ("Cas") genes, including sequences encoding a Cas gene, a tracr (trans-activating CRISPR) sequence (e.g. tracrRNA or an active partial tracrRNA), a tracr-mate sequence (encompassing a "direct repeat" and a tracrRNA-processed partial direct repeat in the context of an endogenous CRISPR system), a guide sequence (also referred to as a "spacer" in the context of an endogenous CRISPR system), and / or other sequences and transcripts from a CRISPR locus. The CRISPR / Cas nuclease or CRISPR / Cas nuclease system can include a non-coding RNA molecule (guide) RNA, which sequence- Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 specifically binds to DNA, and a Cas protein (e.g., Cas9), with nuclease functionality (e.g., two nuclease domains). One or more elements of a CRISPR system can derive from a type I, type II, or type III CRISPR system, e.g., derived from a particular organism comprising an endogenous CRISPR system, such as Streptococcus pyogenes. In some aspects, a Cas nuclease and gRNA (including a fusion of crRNA specific for the target sequence (e.g., a sequence within Mc3r) and fixed tracrRNA) are introduced into the cell. In general, target sites at the 5' end of the gRNA target the Cas nuclease to the target site, e.g., Mc3r, using complementary base pairing. The target site may be selected based on its location immediately 5' of a protospacer adjacent motif (PAM) sequence, such as typically NGG, or NAG. In this respect, the gRNA is targeted to the desired sequence by modifying the first 20, 19, 18, 17, 16, 15, 14, 14, 12, 11, or 10 nucleotides of the guide RNA to correspond to the target DNA sequence (e.g., sequence within Mc3r). In general, a CRISPR system is characterized by elements that promote the formation of a CRISPR complex at the site of a target sequence. Typically, "target sequence" generally refers to a sequence to which a guide sequence is designed to have complementarity, where hybridization between the target sequence and a guide sequence promotes the formation of a CRISPR complex. Full complementarity is not necessarily required, provided there is sufficient complementarity to cause hybridization and promote formation of a CRISPR complex. The CRISPR system can induce double stranded breaks (DSBs) at the SRC-3 target site, followed by disruptions or alterations as discussed herein. In other embodiments, Cas9 variants, deemed "nickases," are used to nick a single strand at the target site (e.g., within Mc3r). Paired nickases can be used, e.g., to improve specificity, each directed by a pair of different gRNAs targeting sequences such that upon introduction of the nicks simultaneously, a 5' overhang is introduced. In other embodiments, catalytically inactive Cas9 is fused to a heterologous effector domain such as a transcriptional repressor or activator, to affect gene expression (e.g., to inhibit expression of Mc3r). In some embodiments, the CRISPR system is used to alter Mc3r, inhibit expression from Mc3r , and / or to inactivate the expression product of Mc3r. The term "antisense nucleic acid molecule" or “antisense oligonucleotide” as used herein, refers to a nucleic acid which is complementary to a target nucleic acid. An antisense molecule in accordance with the invention is capable of interacting with the target nucleic acid, more specifically it is capable of hybridizing with the target nucleic acid. Due to the formation of the Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 hybrid, transcription of the target gene(s) and / or translation of the target mRNA is reduced or blocked. Standard methods relating to antisense technology have been described (see, e.g., Melani et al., Cancer Res. (1991) 51:2897-2901). In some embodiments, provided herein are antisense oligonucleotides capable of inhibiting expression from Mc3r when administered to cell or subject. In some embodiments, the antisense oligonucleotides are antisense DNA- and / or RNA-oligonucleotides. In some embodiments, provided herein are modified antisense oligonucleotides, such as, antisense 2'-O-methyl oligo-ribonucleotides, antisense oligonucleotides containing phosphorothiaote linkages, antisense oligonucleotides containing Locked Nucleic Acid LNA(R) bases, morpholino antisense oligonucleotides, PPAR-gamma agonists, antagomirs. In some embodiments, ASOs comprise Locked Nucleic Acid (LNA) or 2’- methoxyethyl (MOE) modifications (internucleotide linkages are phosphorothioates interspersed with phosphodiesters, and all cytosine residues are 5’-methylcytosines). II. Anti-obesity agents In some embodiments, MC3R inhibition (and / or MC4R activation) is induced concomitantly (e.g., co-administration with a MC3R inhibitor) with one or more anti-obesity agents. In some embodiments, the anti-obesity agent exhibits one or more anti-obesity effects when administered alone; in such embodiments, co-administration of the anti-obesity agent with MC3R inhibition (and / or MC4R activation) results in enhanced efficacy of the anti-obesity agent and / or anti-obesity effects at a sub-standard and / or sub-therapeutic dose. In some embodiments, the anti-obesity agent for use in embodiments herein does not exhibit anti-obesity effects when administered alone (or when administered at a tolerable dose alone); in such embodiments, co- administration of the anti-obesity agent with MC3R inhibition (and / or MC4R activation) results in enhanced efficacy of the anti-obesity agent and / or anti-obesity effects at a tolerable dose. In some embodiments, an anti-obesity agent is a GLP-1 agonist. Suitable GLP-1 agonists for use in the compositions and methods herein include, but are not limited to, exendin-4, albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, taspoglutide, tirzepatide, retatrutide, CNTO736, CNT03649, HM11260C (LAPS-Exendin), NN9926 (OG9S7GT), TT401 and ZYOG1. In some embodiments, a GLP-1 agonist (e.g., liraglutide) is co-administered with an inhibitor of MC3R expression or activity. Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 In some embodiments, an anti-obesity agent is a MC4R agonist. Suitable MC4R agonists for use in the compositions and methods herein include, but are not limited to, setmelanotide and the peptides described in WO 2023 / 028538 (incorporated by reference in its entirety). In some embodiments, a MC4R agonist (e.g., setmelanotide) is co-administered with an inhibitor of MC3R expression or activity. In some embodiments, an anti-obesity agent is an anorectic. Suitable anorectics for use in the compositions and methods herein include, but are not limited to, amphetamine, dexamphetamine, amfepramone, clobenzorex, mazindol, phentermine (with or without topiramate) and lorcaserin. In some embodiments, an anorectic (e.g., phentermine) is co- administered with an inhibitor of MC3R expression or activity. In some embodiments, an anti-obesity agent is a pro-satiety agent. Suitable pro-satiety agents for use in the compositions and methods herein include, but are not limited to, neurotrophic factor (e.g., axokine) and longer-acting analogs of amylin, calcitonin, cholecystokinin (CCK), leptin, metreleptin oxyntomodulin, pancreatic polypeptide (PP), peptide YY (PYY), neuropeptide Y (NPY), and variants thereof (e.g., PYY3-36). In some embodiments, a pro-satiety agent (e.g., CCK) is co-administered with an inhibitor of MC3R expression or activity. In some embodiments, an anti-obesity agent is a lipase inhibitor. Suitable lipase inhibitors for use in the compositions and methods herein include, but are not limited to, caulerpenyne, cetilistat, ebelactone A and B, esterastin, lipstatin, orlistat, percyquinin, panclicin A-E, valilactone and vibralactone. In some embodiments, a lipase inhibitor (e.g., lipstatin) is co- administered with an inhibitor of MC3R expression or activity. In some embodiments, an anti-obesity agent is a leptin receptor agonist. Suitable leptin agonists include, but are not limited to leptin, metraleptin, and leptin receptor agonist antibodies. In some embodiments, an inhibitor of MC3R expression or activity is administered as a leptin-sensitizer (e.g., with a leptin receptor agonist). In some embodiments, an inhibitor of MC3R expression or activity is administered to a subject suffering from lipodystrophy or leptin deficiency. III. Co-administration and / or formulation Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 In some embodiments, inhibition of MC3R (and / or MC4R activation) hypersensitizes a subject to the effects (e.g., anorectic effects) of a co-administered anti-obesity agent. In some embodiments, the hypersensitization results in enhanced efficacy of the co-administered anti- obesity agent, thereby increasing the effect (e.g., beyond the therapeutic effect of the MC3R inhibition (and / or MC4R activation) alone, beyond the therapeutic effect of the anti-obesity agent alone, beyond the additive therapeutic effect of the MC3R inhibition (and / or MC4R activation) and anti-obesity agent), and increasing the effectiveness of the therapy. In some embodiments, the hypersensitization results in a reduction in the therapeutically effective dose when compared to the therapeutically effective dose for the administration of the anti-obesity agent administered alone. In some embodiments, when co-administered with MC3R inhibition (and / or MC4R activation), an anti-obesity agent is administered at a sub-therapeutic dose. In some embodiments, when co-administered with MC3R inhibition (and / or MC4R activation), an anti-obesity agent is administered at a sub-standard dose. In some embodiments, administering an anti-obesity agent at a sub-therapeutic and / or sub-standard dose (e.g., co-administering with MC3R inhibition (and / or MC4R activation)) results in a reduction in side effects associated with the treatment when compared to the side effects associated with the therapeutically effective dose and / or standard dose for administration of the anti-obesity agent alone. In some embodiments, standard doses for various therapeutics (e.g., anti-obesity agents) are well understood in the field. In some embodiments, methods are provided comprising inhibiting MC3R expression or activity (and / or MC4R activation) and administering an anti- obesity agent at a sub-standard dose (e.g., co-administering with MC3R inhibition (and / or MC4R activation)). In some embodiments, methods are provided comprising co-administering an inhibitor of MC3R expression or activity (e.g., an MC3R antagonist) (and / or activator of MC4R expression or activity) and a sub-standard dose of an anti-obesity agent. In some embodiments, pharmaceutical compositions are provided comprising a sub-standard dose of an anti-obesity agent. In some embodiments, pharmaceutical compositions are provided comprising an MC3R inhibitor (e.g., antagonist) (and / or activator of MC4R) and a sub-standard dose of an anti-obesity agent. The standard dose for subcutaneous administration of liraglutide is 3 mg per week. In some embodiments, methods are provided comprising inhibiting MC3R expression or activity Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 (and / or enhancing MC3R expression or activity) and administering liraglutide at a sub-standard dose (e.g., co-administering with MC3R inhibition and / or MC4R activation). In some embodiments, methods are provided comprising co-administering an inhibitor of MC3R expression or activity (e.g., an MC3R antagonist) (and / or an activator of MC4R expression or activity (e.g., an MC4R antagonist)) and a sub-standard dose of liraglutide. In some embodiments, pharmaceutical compositions are provided comprising a sub-standard dose of liraglutide. In some embodiments, pharmaceutical compositions are provided comprising an MC3R inhibitor (e.g., antagonist) (and / or MC4R activator (e.g., agonist)) and a sub-standard dose of liraglutide. In some embodiments, a dose of less than 3 mg of liraglutide is administered and / or provided in a pharmaceutical formulation (e.g., 2.5 mg, 2 mg, 1.5 mg, 1 mg, 0.5 mg, 0.1 mg, or less, or ranges therebetween). The standard dose for subcutaneous administration of metreleptin is 2.5-10 mg per day. In some embodiments, methods are provided comprising inhibiting MC3R expression or activity (and / or enhancing MC3R expression or activity) and administering metreleptin at a sub-standard dose (e.g., co-administering with MC3R inhibition and / or MC4R activation). In some embodiments, methods are provided comprising co-administering an inhibitor of MC3R expression or activity (e.g., an MC3R antagonist) (and / or an activator of MC4R expression or activity (e.g., an MC4R antagonist))and a sub-standard dose of metreleptin. In some embodiments, pharmaceutical compositions are provided comprising a sub-standard dose of metreleptin. In some embodiments, pharmaceutical compositions are provided comprising an MC3R inhibitor (e.g., antagonist) (and / or MC4R activator (e.g., agonist)) and a sub-standard dose of metreleptin. In some embodiments, a dose of less than 2.5-10 mg of metreleptin is administered and / or provided in a pharmaceutical formulation (e.g., 7.5 mg, 5.0 mg, 2.5 mg , 2 mg, 1.5 mg, 1 mg, 0.5 mg, 0.1 mg, or less, or ranges therebetween). The standard dose for oral administration of orlistat is 60 mg (over-the-counter dose) or 120 mg (prescription dose) with each meal. In some embodiments, methods are provided comprising inhibiting MC3R expression or activity (and / or enhancing MC3R expression or activity) and administering orlistat at a sub-standard dose (e.g., co-administering with MC3R inhibition and / or MC4R activation). In some embodiments, methods are provided comprising co- administering an inhibitor of MC3R expression or activity (e.g., an MC3R antagonist) (and / or an Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 activator of MC4R expression or activity (e.g., an MC4R antagonist))and a sub-standard dose of orlistat. In some embodiments, pharmaceutical compositions are provided comprising a sub- standard dose of orlistat. In some embodiments, pharmaceutical compositions are provided comprising an MC3R inhibitor (e.g., antagonist) (and / or MC4R activator (e.g., agonist)) and a sub-standard dose of orlistat. In some embodiments, a dose of less than 60 mg of orlistat is administered and / or provided in a pharmaceutical formulation (e.g., 50 mg, 40 mg, 30 mg , 20 mg, 10 mg, 5 mg, 2 mg, 1 mg, or less, or ranges therebetween). The standard dose for oral administration of phentermine and topiramate co- administration is 3.75-15 mg of phentermine (e.g., 3.75 mg, 7.5 mg, 11.25 mg, 15 mg, etc.) and 23-92 mg of topiramate (e.g., 23 mg, 46 mg, 69 mg, 92 mg, etc.) per day. In some embodiments, methods are provided comprising inhibiting MC3R expression or activity (and / or enhancing MC3R expression or activity) and administering phentermine and topiramate at a sub-standard dose (e.g., co-administering with MC3R inhibition and / or MC4R activation). In some embodiments, methods are provided comprising co-administering an inhibitor of MC3R expression or activity (e.g., an MC3R antagonist) (and / or an activator of MC4R expression or activity (e.g., an MC4R antagonist)) and a sub-standard dose of phentermine and topiramate. In some embodiments, pharmaceutical compositions are provided comprising a sub-standard dose of phentermine and topiramate. In some embodiments, pharmaceutical compositions are provided comprising an MC3R inhibitor (e.g., antagonist) (and / or MC4R activator (e.g., agonist)) and a sub-standard dose of phentermine and topiramate. In some embodiments, a dose of less than 3.75-15 mg of phentermine (e.g., 10 mg, 7.5 mg, 5 mg , 4 mg, 3 mg, 2 mg, 1 mg, 0.5 mg, or less, or ranges therebetween) and / or less than 23-92 mg of topiramate (e.g., 80 mg, 60 mg, 40 mg , 20 mg, 10 mg, 5 mg, 2 mg, 1 mg, or less, or ranges therebetween) is administered and / or provided in a pharmaceutical formulation. The standard dose for oral administration of naltrexone / bupropion is 90-360 mg per day. In some embodiments, methods are provided comprising inhibiting MC3R expression or activity (and / or enhancing MC3R expression or activity) and administering naltrexone / bupropion at a sub-standard dose (e.g., co-administering with MC3R inhibition and / or MC4R activation). In some embodiments, methods are provided comprising co-administering an inhibitor of MC3R expression or activity (e.g., an MC3R antagonist) (and / or an activator of MC4R expression or Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 activity (e.g., an MC4R antagonist)) and a sub-standard dose of naltrexone / bupropion. In some embodiments, pharmaceutical compositions are provided comprising a sub-standard dose of naltrexone / bupropion. In some embodiments, pharmaceutical compositions are provided comprising an MC3R inhibitor (e.g., antagonist) (and / or MC4R activator (e.g., agonist)) and a sub-standard dose of naltrexone / bupropion. In some embodiments, a dose of less than 90-360 mg of naltrexone / bupropion is administered and / or provided in a pharmaceutical formulation (e.g., 300 mg, 250 mg, 200 mg , 150 mg, 100 mg, 75 mg, 50 mg, 25 mg, 10 mg, or less, or ranges therebetween). The standard dose for subcutaneous administration of semaglutide for the treatment of obesity is 0.25-2.0 mg per week. In some embodiments, methods are provided comprising inhibiting MC3R expression or activity (and / or enhancing MC3R expression or activity) and administering semaglutide at a sub-standard dose (e.g., co-administering with MC3R inhibition and / or MC4R activation). In some embodiments, methods are provided comprising co- administering an inhibitor of MC3R expression or activity (e.g., an MC3R antagonist) (and / or an activator of MC4R expression or activity (e.g., an MC4R antagonist)) and a sub-standard dose of semaglutide. In some embodiments, pharmaceutical compositions are provided comprising a sub-standard dose of semaglutide. In some embodiments, pharmaceutical compositions are provided comprising an MC3R inhibitor (e.g., antagonist) (and / or MC4R activator (e.g., agonist)) and a sub-standard dose of semaglutide. In some embodiments, a dose of less than 0.25-2.0 mg of semaglutide is administered and / or provided in a pharmaceutical formulation (e.g., 1.5 mg, 1.0 mg, 0.5 mg 0.2 mg, 0.15 mg, 0.1 mg , 0.05 mg, or less, or ranges therebetween). The standard dose for subcutaneous administration of setmelanotide for the treatment of obesity is 1-3 mg per week. In some embodiments, methods are provided comprising inhibiting MC3R expression or activity (and / or enhancing MC3R expression or activity) and administering setmelanotide at a sub-standard dose (e.g., co-administering with MC3R inhibition and / or MC4R activation). In some embodiments, methods are provided comprising co-administering an inhibitor of MC3R expression or activity (e.g., an MC3R antagonist) (and / or an activator of MC4R expression or activity (e.g., an MC4R antagonist)) and a sub-standard dose of setmelanotide. In some embodiments, pharmaceutical compositions are provided comprising a Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 sub-standard dose of setmelanotide. In some embodiments, pharmaceutical compositions are provided comprising an MC3R inhibitor (e.g., antagonist) (and / or MC4R activator (e.g., agonist)) and a sub-standard dose of setmelanotide. In some embodiments, a dose of less than 1- 3 mg of setmelanotide is administered and / or provided in a pharmaceutical formulation (e.g., 2.5 mg, 2 mg, 1.5 mg , 1 mg, 0.5 mg, 0.3 mg, 0.2 mg, 0.1 mg, or less, or ranges therebetween). The standard dose for subcutaneous administration of tirzepatide for the treatment of obesity is 2.5-15 mg per week. In some embodiments, methods are provided comprising inhibiting MC3R expression or activity (and / or enhancing MC3R expression or activity) and administering tirzepatide at a sub-standard dose (e.g., co-administering with MC3R inhibition and / or MC4R activation). In some embodiments, methods are provided comprising co- administering an inhibitor of MC3R expression or activity (e.g., an MC3R antagonist) (and / or an activator of MC4R expression or activity (e.g., an MC4R antagonist)) and a sub-standard dose of tirzepatide. In some embodiments, pharmaceutical compositions are provided comprising a sub- standard dose of tirzepatide. In some embodiments, pharmaceutical compositions are provided comprising an MC3R inhibitor (e.g., antagonist) (and / or MC4R activator (e.g., agonist)) and a sub-standard dose of tirzepatide. In some embodiments, a dose of less than 2.5-15 mg of tirzepatide is administered and / or provided in a pharmaceutical formulation (e.g., 10 mg, 7.5 mg, 5 mg , 2.5 mg, 2 mg, 1.5 mg, 1 mg, 0.5 mg, or less, or ranges therebetween). The standard dose for subcutaneous administration of leptin for the treatment of obesity is 2.5-10 mg per day. In some embodiments, methods are provided comprising inhibiting MC3R expression or activity (and / or enhancing MC3R expression or activity) and administering leptin at a sub-standard dose (e.g., co-administering with MC3R inhibition and / or MC4R activation). In some embodiments, methods are provided comprising co-administering an inhibitor of MC3R expression or activity (e.g., an MC3R antagonist) (and / or an activator of MC4R expression or activity (e.g., an MC4R antagonist)) and a sub-standard dose of leptin. In some embodiments, pharmaceutical compositions are provided comprising a sub-standard dose of leptin. In some embodiments, pharmaceutical compositions are provided comprising an MC3R inhibitor (e.g., antagonist) (and / or MC4R activator (e.g., agonist)) and a sub-standard dose of leptin. In some embodiments, a dose of less than 2.5-15 mg of leptin is administered and / or provided in a Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 pharmaceutical formulation (e.g., 7.5 mg, 5 mg , 2.5 mg, 2 mg, 1.5 mg, 1 mg, 0.5 mg, or less, or ranges therebetween). The standard dose for subcutaneous administration of exendin-4 or exenatide for the treatment of obesity is 2 mg per week. In some embodiments, methods are provided comprising inhibiting MC3R expression or activity (and / or enhancing MC3R expression or activity) and administering exendin-4 or exenatide at a sub-standard dose (e.g., co-administering with MC3R inhibition and / or MC4R activation). In some embodiments, methods are provided comprising co- administering an inhibitor of MC3R expression or activity (e.g., an MC3R antagonist) (and / or an activator of MC4R expression or activity (e.g., an MC4R antagonist)) and a sub-standard dose of exendin-4 or exenatide. In some embodiments, pharmaceutical compositions are provided comprising a sub-standard dose of exendin-4 or exenatide. In some embodiments, pharmaceutical compositions are provided comprising an MC3R inhibitor (e.g., antagonist) (and / or MC4R activator (e.g., agonist)) and a sub-standard dose of exendin-4 or exenatide. In some embodiments, a dose of less than 2 mg of exendin-4 or exenatide is administered and / or provided in a pharmaceutical formulation (e.g., 1.5 mg, 1 mg, 0.5 mg, 0.1 mg, or less, or ranges therebetween). The standard dose for subcutaneous administration of albiglutide for the treatment of obesity is 30 mg per week. In some embodiments, methods are provided comprising inhibiting MC3R expression or activity (and / or enhancing MC3R expression or activity) and administering albiglutide at a sub-standard dose (e.g., co-administering with MC3R inhibition and / or MC4R activation). In some embodiments, methods are provided comprising co-administering an inhibitor of MC3R expression or activity (e.g., an MC3R antagonist) (and / or an activator of MC4R expression or activity (e.g., an MC4R antagonist)) and a sub-standard dose of albiglutide. In some embodiments, pharmaceutical compositions are provided comprising a sub-standard dose of albiglutide. In some embodiments, pharmaceutical compositions are provided comprising an MC3R inhibitor (e.g., antagonist) (and / or MC4R activator (e.g., agonist)) and a sub-standard dose of albiglutide. In some embodiments, a dose of less than 30 mg of albiglutide is administered and / or provided in a pharmaceutical formulation (e.g., 25 mg, 20 mg , 15 mg, 10 mg, 5 mg, 1 mg, 0.5 mg, or less, or ranges therebetween). Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 The standard dose for subcutaneous administration of dulaglutide for the treatment of obesity is 0.75-4.5 mg per week. In some embodiments, methods are provided comprising inhibiting MC3R expression or activity (and / or enhancing MC3R expression or activity) and administering dulaglutide at a sub-standard dose (e.g., co-administering with MC3R inhibition and / or MC4R activation). In some embodiments, methods are provided comprising co- administering an inhibitor of MC3R expression or activity (e.g., an MC3R antagonist) (and / or an activator of MC4R expression or activity (e.g., an MC4R antagonist)) and a sub-standard dose of dulaglutide. In some embodiments, pharmaceutical compositions are provided comprising a sub- standard dose of dulaglutide. In some embodiments, pharmaceutical compositions are provided comprising an MC3R inhibitor (e.g., antagonist) (and / or MC4R activator (e.g., agonist)) and a sub-standard dose of dulaglutide. In some embodiments, a dose of less than 0.75-4.5 mg of dulaglutide is administered and / or provided in a pharmaceutical formulation (e.g., 4 mg, 2 mg , 1 mg, 0.5 mg, 0.2 mg, 0.1 mg, or less, or ranges therebetween). The standard dose for subcutaneous administration of lixisenatide for the treatment of obesity is 10-20 µg per day. In some embodiments, methods are provided comprising inhibiting MC3R expression or activity (and / or enhancing MC3R expression or activity) and administering lixisenatide at a sub-standard dose (e.g., co-administering with MC3R inhibition and / or MC4R activation). In some embodiments, methods are provided comprising co-administering an inhibitor of MC3R expression or activity (e.g., an MC3R antagonist) (and / or an activator of MC4R expression or activity (e.g., an MC4R antagonist)) and a sub-standard dose of lixisenatide. In some embodiments, pharmaceutical compositions are provided comprising a sub- standard dose of lixisenatide. In some embodiments, pharmaceutical compositions are provided comprising an MC3R inhibitor (e.g., antagonist) (and / or MC4R activator (e.g., agonist)) and a sub-standard dose of lixisenatide. In some embodiments, a dose of less than 10-20 mg of lixisenatide is administered and / or provided in a pharmaceutical formulation (e.g., 15 mg, 10 mg, 5 mg, 1 mg, 0.5 mg, or less, or ranges therebetween). The standard dose for subcutaneous administration of taspoglutide is 10-20 µg per day. In some embodiments, methods are provided comprising inhibiting MC3R expression or activity (and / or enhancing MC3R expression or activity) and administering taspoglutide at a sub- standard dose (e.g., co-administering with MC3R inhibition and / or MC4R activation). In some Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 embodiments, methods are provided comprising co-administering an inhibitor of MC3R expression or activity (e.g., an MC3R antagonist) (and / or an activator of MC4R expression or activity (e.g., an MC4R antagonist)) and a sub-standard dose of taspoglutide. In some embodiments, pharmaceutical compositions are provided comprising a sub-standard dose of taspoglutide. In some embodiments, pharmaceutical compositions are provided comprising an MC3R inhibitor (e.g., antagonist) (and / or MC4R activator (e.g., agonist)) and a sub-standard dose of taspoglutide. In some embodiments, a dose of less than 10-20 mg of taspoglutide is administered and / or provided in a pharmaceutical formulation (e.g., 15 mg, 10 mg, 5 mg, 1 mg, 0.5 mg, or less, or ranges therebetween). In some embodiments, a sub-standard dose is less than 10-90% of the standard dose (e.g., <10%, <20%, <30%, <40%, <50%, <60%, <70%, <80%, <90%, etc.). In some embodiments, the therapies provided herein (e.g., MC3R inhibition and anti- obesity agent) are co-administered with psychotherapy. The term "psychotherapy" refers to use of non-pharmacological therapies a clinician or therapist uses any of a variety of techniques that involve verbal and other interactions with a patient to affect a positive therapeutic outcome. Such techniques include, but are not limited to, behavior therapy, cognitive therapy, psychodynamic therapy, psychoanalytic therapy, group therapy, family counseling, art therapy, music therapy, vocational therapy, humanistic therapy, existential therapy, transpersonal therapy, client-centered therapy (also called person-centered therapy), Gestalt therapy, biofeedback therapy, rational emotive behavioral therapy, reality therapy, response based therapy, Sandplay therapy, status dynamics therapy, hypnosis and validation therapy. Any suitable psychotherapy techniques, including those listed above, may be co-administered with a MC3R antagonist or partial agonist peptide for the treatment / prevention of appropriate conditions / diseases (e.g., overeating, obesity, diabetes, heart disease, hypertension, sleep apnea, depression, kidney disease, arthritis, etc.). In some embodiments, the therapies provided herein (e.g., MC3R inhibition and anti- obesity agent) are co-administered with an antidepressant agent. Suitable antidepressants for co- administration may include serotonin and noradrenaline reuptake inhibitors (e.g., duloxetine (Cymbalta), venlafaxine (Effexor), desvenlafaxine (Pristiq), etc.), selective serotonin reuptake inhibitors (e.g., italopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), etc.), tricyclic Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 antidepressants (e.g., amitriptyline (Elavil), amoxapine- clomipramine (Anafranil), desipramine (Norpramin), doxepin (Sinequan), imipramine (Tofranil), nortriptyline (Pamelor), protriptyline (Vivactil), trimipramine (Surmontil), etc.), monoamine oxidase inhibitors (e.g., phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan), selegiline (EMSAM, Eldepryl), etc.), noradrenaline and specific serotoninergic antidepressants (e.g., Mianserin (Tolvon), Mirtazapine (Remeron, Avanza, Zispin, etc.), etc. In some embodiments, the therapies provided herein (e.g., MC3R inhibition and anti- obesity agent) are co-administered with an antianxiety agent. Suitable antianxiety medications for co-administration may include selective serotonin reuptake inhibitors, serotonin- norepinephrine reuptake inhibitors, tricyclics, benzodiazepines (e.g., alprazolam (Xanax), chlordiazepoxide (Librium), diazepam (Valium), lorazepam (Ativan) etc.), beta-blockers (e.g., atenolol (Tenormin), propranolol (Inderal), etc.), buspirone (BuSpar), monoamine oxidase inhibitors, etc. In some embodiments, the therapies provided herein (e.g., MC3R inhibition and anti- obesity agent) are co-administered with a mood stabilizer. Suitable mood stabilizers for co- administration may include lithium, anticonvulsants (e.g., valproate, lamotrigine, carbamazepine, etc.), etc. In some embodiments, any suitable routes and / or modes of administering the agents herein (e.g., MC3R inhibitor (e.g., MC3R antagonist or partial agonist), anti-obesity agent, etc.) find use in embodiments herein. In some embodiments, the compositions and methods described herein act upon the central nervous system (CNS) and therefore routes and / or modes of administration that facilitate entry of the agents into the CNS are utilized. In some embodiments, the compositions and methods described herein act upon the brain of a subject and therefore routes and / or modes of administration that facilitate entry of the agents into the brain (e.g., allow agents to cross the blood-brain barrier) are utilized. In some embodiments, the compositions and methods described herein act upon the hypothalamus of a subject and therefore routes and / or modes of administration that facilitate delivery of the agents to the hypothalamus are utilized. In some embodiments, the compositions and methods described herein act upon the arcuate nucleus of the hypothalamus of a subject and therefore routes and / or modes of administration that facilitate delivery of the agents to the arcuate nucleus are utilized. In some embodiments, Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 the compositions and methods described herein act upon the AgRP neurons of a subject and therefore routes and / or modes of administration that facilitate delivery of the agents to AgRP neurons are utilized. In some embodiments, the compositions and methods described herein act upon the POMC neurons of a subject and therefore routes and / or modes of administration that facilitate delivery of the agents to POMC neurons are utilized. In some embodiments, routes of administration, formulation of the desired agent, and the pharmaceutical composition are selected to provide efficient and effective delivery. In some embodiments, the therapeutic agents herein (e.g., MC3R inhibitor (e.g., MC3R antagonist or partial agonist), anti-obesity agent, etc.) are provided in pharmaceutical formulations for administration to a subject by a suitable route. The pharmaceutical formulations described herein can be administered to a subject by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. Moreover, the pharmaceutical compositions described herein (e.g., MC3R inhibitor (e.g., MC3R antagonist or partial agonist), anti-obesity agent, etc.) are formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, and capsules. One may administer the compounds and / or compositions in a local rather than systemic manner, for example, via injection of the compound directly into an organ or tissue, often in a depot preparation or sustained release formulation. Such long-acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. In addition, the drug may be provided in the form of a rapid release formulation, in the form of an extended-release formulation, or in the form of an intermediate release formulation. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with the therapeutic agent (e.g., MC3R inhibitor (e.g., MC3R antagonist or partial agonist), anti-obesity agent, etc.) with any suitable substituents and functional groups disclosed Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets, pills, or capsules. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. In some embodiments, agents are delivered by inhalation. For administration by inhalation, the agents described herein (e.g., MC3R inhibitor (e.g., MC3R antagonist or partial agonist), anti-obesity agent, etc.) may be in a form as an aerosol, a mist or a powder. In some embodiments, pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Buccal formulations that include the agents described herein (e.g., MC3R inhibitor (e.g., MC3R antagonist or partial agonist), anti-obesity agent, etc.) may be administered using a variety of formulations which include, but are not limited to, U.S. Pat. Nos.4,229,447, 4,596,795, 4,755,386, and 5,739,136. In some embodiments, the agents described herein (e.g., MC3R inhibitor (e.g., MC3R antagonist or partial agonist), anti-obesity agent, etc.) are delivered transdermally. Transdermal formulations described herein may be administered using a variety of devices including but not limited to, U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and 6,946,144; incorporated by reference in their entireties. In some embodiments, the agents described herein (e.g., MC3R inhibitor (e.g., MC3R antagonist or partial agonist), anti-obesity agent, etc.) are delivered by parenteral administration Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 (e.g., intramuscular, subcutaneous, intravenous, epidural, intracerebral, intracerebroventricular, etc.). Formulations suitable for parenteral administration may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Agents described herein (e.g., MC3R inhibitor (e.g., MC3R antagonist or partial agonist), anti-obesity agent, etc.) may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally recognized in the field. For other parenteral injections, appropriate formulations may include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally recognized in the field. In certain embodiments, delivery systems for pharmaceutical agents (e.g., MC3R inhibitor (e.g., MC3R antagonist or partial agonist), anti-obesity agent, etc.) may be employed, such as, for example, liposomes and emulsions. In certain embodiments, compositions provided herein also include an mucoadhesive polymer, selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate and dextran. Determination of effective amounts of the agents herein (e.g., MC3R inhibitor (e.g., MC3R antagonist or partial agonist), anti-obesity agent, etc.) for administration or co- administration may involve in vitro assays in which varying doses of agent are administered to cells in culture and the concentration of agent effective for ameliorating some or all symptoms is determined in order to calculate the concentration required in vivo. Effective amounts may also be based in in vivo animal studies. Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 Pharmaceutical compositions may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more agents (e.g., MC4R agonist (and / or MC3R antagonist or partial agonist) peptide, a co-administered agent, etc.). Dosing and administration regimes are tailored by the clinician, or others skilled in the pharmacological arts, based upon well-known pharmacological and therapeutic considerations including, but not limited to, the desired level of therapeutic effect, and the practical level of therapeutic effect obtainable. In some embodiments, and upon the clinician’s discretion, the administration of the compounds may be administered for an extended period of time, including throughout the duration of the patient’s life in order to treat the disorder or ameliorate or otherwise control or limit the symptoms of the patient’s disease. In a case wherein the patient’s status does improve, upon the clinician’s discretion the administration of the agents (e.g., MC3R inhibitor (e.g., MC3R antagonist or partial agonist), anti-obesity agent, etc.) may be given continuously; alternatively, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). The length of the drug holiday can vary between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday may be from about 10% to about 100%, including, by way of example only, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. In some embodiments, once improvement of the patient's symptoms / disorder / condition has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 In some embodiments, the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 – about 1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day. As discussed above, provided in certain embodiments herein are combination therapies in which a MC3R inhibitor (e.g., MC3R antagonist or partial agonist) is co-administered with an additional agent for the treatment or prevention of obesity. Co-administered agents do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes. Co- administered agents may be administered concurrently (in the same or separate formulations / compositions) or at separate times (separated by minutes, hours, days, etc.) The co- administered agents may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the disease, disorder, or condition, the condition of the patient, and the actual choice of agent used. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the clinician after evaluation of the disease being treated and the condition of the patient. Therapeutically-effective dosages can vary when the drugs are used in treatment combinations. Methods for experimentally determining therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens are described in the literature. For example, the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects, has been described extensively in the literature. Combination Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient. For combination therapies described herein, dosages of the co-administered agents will of course vary depending on the type of co-drug employed, on the specific drug employed, on the disease being treated and so forth. In addition, when co-administered with one or more biologically active agents, the compound provided herein may be administered either simultaneously with the biologically active agent(s), or sequentially. In some embodiments, provided herein is the co-administration of (1) a sensitizing agent (e.g., MC3R antagonist / inhibitor or MC4R agonist / activator) and a (2) an anti-obesity and / or anorectic agent. In some embodiments, the co-administration allows for enhanced benefit (e.g., greater weight loss, greater reduction in food intake, etc.) and / or reduced dosing (e.g., reduced side effects) of the anti-obesity and / or anorectic agent when compared to administration of the anti-obesity and / or anorectic agent alone. In some embodiments, the enhanced benefit is produced with a sub-therapeutic or sub-standard dose of the sensitizing agent (e.g., MC3R antagonist / inhibitor or MC4R agonist / activator). Therefore, embodiments herein include: • co-administration of a sub-therapeutic or sub-standard dose of a sensitizing agent (e.g., MC3R antagonist / inhibitor or MC4R agonist / activator) with an anti-obesity and / or anorectic agent (e.g., to produce an enhanced therapeutic benefit); • co-administration of a sensitizing agent (e.g., MC3R antagonist / inhibitor or MC4R agonist / activator) with a sub-therapeutic or sub-standard dose of an anti-obesity and / or anorectic agent (e.g., to allow for reduced side effects); • co-administration of a sub-therapeutic or sub-standard dose of a sensitizing agent (e.g., MC3R antagonist / inhibitor or MC4R agonist / activator) with a sub-therapeutic or sub- standard dose of an anti-obesity and / or anorectic agent; and • co-administration of a sensitizing agent (e.g., MC3R antagonist / inhibitor or MC4R agonist / activator) with an anti-obesity and / or anorectic agent. EXPERIMENTAL Methods Animals models Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 All procedures involving animals were approved by the Institutional Animal Care and Use Committee of University of Michigan following the American Veterinary Medical Association guidelines. Experiments were performed in C57BL / 6J (wild-type, wt) purchased from The Jackson Laboratory, transgenic Mc3r wild-type (Mc3r+ / +) and knockout (Mc3r- / -) (bred in-house), mice expressing enhanced green fluorescent protein (EGFP) under control of the proopiomelanocortin (Pomc-EGFP), and neural-specific POMC knockout (nPOMCKO). Pomc- EGFP and nPOMCKO mice were generously provided by Dr. Malcom Low (University of Michigan School of Medicine). Mice were maintained on a reverse 12-h:12-h light-dark schedule and given ad libitum access to chow and water, unless otherwise specified. Both sexes were used in these experiments and are shown as such in the results. Peptides and drugs Liraglutide (0.05 – 0.4 mg / kg, sc, Tocris), semaglutide (1 – 100 nmol / kg, sc, Caymen Chemicals), CCK octapeptide (sulfated) (2 and 4 µg / kg, i.p., Tocris) and PYY3-36 were dissolved in a USP Grade sterile phosphate-buffered saline solution (PBS), and working concentrations were made from stock on the day of experiment. Leptin (0.1 – 1 mg / kg, ip, Golden West BioSolutions) was dissolved in sterile isotonic saline and working concentrations were made on the day of the experiment. Tirzepatide hydrochloride (1-5nmol / kg, s.c., MedChem Express) was dissolved in DMSO to create stock solutions and working concentration were made in PBS. Setmelanotide (1.5mg / kg, ip, Rhythm Pharmaceuticals), was dissolved in saline and working concentrations were made on the day of the experiment. Compound 11 (Singh et al., 2013) (1nmol, icv.) was dissolved in DMSO. Compound 1211 (2 mg / kg or 1mg / kg, i.p.) was generously provided by Courage Therapeutics Inc., and dissolved in saline and fresh concentrations were made on the day of the experiment. Acute and chronic nighttime feeding All mice (9-14 weeks old) were single housed in individual cages and were acclimated to injection and handled daily for 5-7 days before experimentation. Mice were randomly assigned to groups on the first day of the experiment. The number of mice used in each experiment is explained in the figure legends. For the dose-response experiments, the same mice were used for Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 each experiment in a crossover manner. There were at least 4 days between each dosage. All compounds were administered 20-30 mins before the onset of the dark, active cycle. Food was manually weighted according to experimental time points. For chronic experiments, mice received vehicle injection for at least 4 days before the start of the experiment. Compounds / peptides were injected in a volume between 150-200μl / injection. For the CCK and PYY3-336 experiments, preweighed pellets of chow were measured before and after the acute feeding test. Surgery and cannula placement C57BL / 6J mice (7-8 weeks) were housed in groups of 3 with ad libitum access to standard chow and water prior to surgery. On the day of surgery, mice were anesthetized with 3- 4% (v / v) isoflurane before being placed in a stereotaxic surgical frame (Kopf) and then maintained at 1.5-2% (v / v) isoflurane for the rest of the surgery. Cannulae were implanted as previously described (Sweeney et al., 2021). Guide Cannulae (Plastics One, Roanoke, VA) targeted the right lateral ventricle using the following flat skull coordinates (-0.460 mm posterior to Bregma, 1.00 lateral to midline, -2.20 M / L, and -2.20 ventral to the surface of the skull). The cannula was secured to the skull with dental cement. Following recovery, mice received intracerebroventricular injection (icv) of 20 ng angiotensin II (Sigma-Aldridge) to confirm cannula placement by angiotensin-water intake. Cannula placement was also confirmed postmortem under a microscope. Saccharin conditioned taste aversion Age-matched Mc3r+ / +and Mc3r- / -were handled and individually housed for 1 week with ad libitum access to standard chow and water. A 2-bottle test was used to administer the saccharin solution and water to mice. For the bottles, custom-made bottles (25 mL serological pipette) were fitted with rubber stopper on one end and fabricated sipper tube with a hole diameter of 3.175 mm (about 0.12 in) on the other end. A silicone tubing was used to seal the sipper tube and the bottle. To acclimate the mice to the 2-bottle choice and the timing of presentation, the bottles were provided to the mice in their home cage for 2 days between 4-6 hours after the dark cycle for two hours while also injecting mice with intraperitoneal (ip) Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 injection of sterile saline. Bottles were measured to ensure mice were equally drinking from the two bottles. Following acclimation, mice were conditioned for 2 days where water was removed from mice. On conditioning days, one group of mice received 1^mL of intraoral application of 0.1% saccharin made in water (conditioned stimulus, CS), and then immediately paired with injections (ip) of either 150^mM LiCl to cause gastric malaise (unconditioned stimulus, US), 0.05 mg / kg liraglutide, or 150^mM NaCl (saline) as a control solution. Mice were then given access to the saccharin solution and water in the 2-bottle tests for an additional 90 mins. On the two testing days, mice were given access to the 2-bottle test during the typical 90-min access, one bottle had water and the bottle had saccharin solution. The bottles (left vs right) were switched at the 45- minute mark to account for potential sidedness. An empty cage with 2-bottles test was set up to account for potential spillage and was thus subtracted from each intake. Fluid intake was recorded at the end of the 90-min test. Immunofluorescence staining were handled and injected to minimize background neuronal activation (fos) due to stress. Immunofluorescence experiments were done to mimic the first 90 minutes of the acute experiments; thus, mice were injected with the compounds at the onset of the dark cycle to simulate the anorectic effects of the drugs. Mice received sc injection of 0.2mg / kg liraglutide, 2nmol / kg Tirzepatide, 2nmol / kg Tirzepatide plus 1nmol C11, 1μl icv C11 alone, or vehicle (PBS for liraglutide experiments and 1μl icv injection of DMSO and saline for the tirzepatide experiments). After 90 mins, mice were given a lethal dose of anesthesia and transcardially l perfused with 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.4). Brains were removed and postfixed in the same fixative overnight. Tissues were rinsed in PBS and cryoprotected in 30% sucrose in PBS until the tissue sank. Brains were embedded in OCT (Tissue-Tek), frozen in dry ice ethanol bath, and stored in -80 °C. Hypothalamic and brainstem sections were cut on a cryostat at 50 μm thick. The tissues were immediately washed with PBS, rocking slowly at room temperature (RT) to warm. Free-floating sections were blocked for 1 h with 0.5% triton, 5% normal serum in PBS. Primary cfos antibody (1:2000; synaptic systems 226 004) was diluted in the blocking buffer. Sections were incubated with the primary antibody Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 overnight, rocking at RT, rinsed 3 times in PBS, incubated with secondary antibody in blocking buffer (Alexa conjugated antibodies, Thermo Fisher Scientific, 1:500) for 2 h at RT. Sections were rinsed 3 times with PBS, and counterstained with Hoechst 33342 (Thermo Fisher Scientific, 1 / 2000 in PBS-0.05% Tween 20), rinsed 2 times with PBS. Sections were moved, slides and coverslips were mounted with Fluoromount G (Southern Biotechnology). Glucose or insulin tolerance tests and hormone analyses: Mc3r+ / +and Mc3r- / -mice were fasted at the onset of the light-cycle for 6 hours and randomly received either treatment (0.2mg / kg liraglutide) or vehicle (PBS). Repeated OGTT occurred 2 weeks apart to ensure proper washout and recovery. A baseline blood was collected from the tail, followed by oral administration of 0.5 - 2g / kg glucose bolus in water. Blood glucose was administered over 2 h. For an insulin tolerance test, a similar procedure was followed except mice received 0.75 IU insulin / kg and blood glucose levels were measured over 2 h. All mice received saline injections to account for fluid loss at the end of experiment and food was returned to mice. Separate mice were used for hormone assays. 0.15-0.2 mL of whole blood was collected via submandibular vein in mice with food removed for 1 h. Blood was mixed with a chilled solution consisting of EDTA, dipeptidyl peptidase IV (DPP-IV) inhibitor, and aprotinin. Plasma was separated and stored at -80 °C. Total GLP-1 was assessed using Multi Species GLP-1 Total ELISA (Thermo Fisher Scientific, EZGLP1T-36K) as well as insulin (ultrasensitive Mouse Insulin ELISA; Crystal Chem) according to the manufactures’ protocol. Results Concomitant effect of weight loss and anorexia by GLP-1 analogs and MC3R Deletion of MC3R (Mc3r- / -) in males and females results in an increased responses to the glucagon-like peptide-1 receptor agonist (GLP1R), liraglutide. Experiments were conducted during development of embodiments herein to test the effect of various concentrations of liraglutide in mice lacking MC3R and their wildtype counterpart mice. In this testing paradigm, concentrations of 0.05 mg / kg – 0.4 mg / kg of liraglutide were administered at least 30 mins before the onset of the dark cycle. 24-hr food intake (spillage included) and body weight change was manually measured in both male and female mice. Liraglutide reduced food intake and body weight in both male and female mice in a concentration-dependent manner in wildtype mice (Fig Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 1A-D). This effect was clearer in the higher concentrations of liraglutide. In the Mc3r- / -, liraglutide resulted in hypersensitivity in both food intake and promoted profound loss following 24hr administration of liraglutide. Unlike the wild type mice, deletion of MC3R had a significant effect on food intake and weight loss in low concentrations of liraglutide; 0.05mg / kg, indicating a synergistic hypersensitivity and not a mere additive effect. Experiments were then conducted during development of embodiments herein to test the extent of MC3R deletion leading to sensitizing other GLP1R agonists. The effect of semaglutide, a secondary GLP-1 drug that has been shown to have longer half-life than liraglutide, thereby increasing both the incretin and anorectic effect of the drug, was tested on male mice, and it was found that, like liraglutide, deletion of MC3R leads to increased responsiveness of semaglutide. Mc3r- / -mice responded more to both the anorectic effects and weight loss of semaglutide than the wildtype mice, demonstrating that the hypersensitivity is not specific to liraglutide (Fig 1E-F). Compound 11 (C11) reliably inhibits the activity of the MC3R and co-administration of C11 and liraglutide can lower the body weight of wildtype mice further than liraglutide alone. The same experiment was repeated and Mc3r- / -mice were used to illustrate the specificity of C11. Pharmacological inhibition of MC3R with C11 (1nmol, intracerebroventricularly, icv), when administered with liraglutide, resulted in profound weight loss and decreased food intake over 8-hr, 12hr, and 24-hr period (Fig 1G-1J), but no effect was seen in mice with MC3R deletion, indicating that there is a pharmacological utility of compounds targeting MC3R in lowering body weight and decreasing food intake (Fig 1G-1J). The weight loss and anorectic effects of MC3R pharmacological inhibition and tirzepatide, a drug that is under development for the treatment of diabetes that acts as a dual agonist for GLP1R and the glucose-dependent insulinotropic polypeptide (GIP), was examined. Administration of tirzepatide (1nmol / kg - 5nmol / kg, sc) in wildtype mice decreased food intake and promoted weight loss in both male and female mice; however, clearer in the male mice (Fig 1K-1N). Furthermore, co-administration of C11 (1nmol, icv) and varying dosages of tirzepatide profoundly decreased 24-hour food intake and decreased 24-hour body weight after a single injection of both compounds. To determine if chronic administration of tirzepatide and C11 further promotes their hypersensitivity effects, 24-hour food intake and body weight of male mice administered with C11 (0.5nmol, icv), tirzepatide (2nmol / kg, sc), C11 and tirzepatide, and Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 vehicle (DMSO, icv and saline, sc) was measured. The vehicle was initially administered for 4 days, followed by treatment for 3 days, and recovery effects were recorded for an additional 3 days. Administration of C11 and tirzepatide alone showed comparable effects on weight loss and decreased food intake compared to vehicle treated groups. However, the administration of both compounds had significant weight loss and anorectic effects compared to either compounds alone or the additive effects of both compounds, demonstrating that higher efficacy of tirzepatide is achieved with MC3R antagonism (Fig 1O-1P)). Deletion of MC3R is associated with the normal incretin effects and malaise by GLP1 drugs Glucagon-like peptide 1 (GLP-1) analogs have been historically associated with their incretin effects by stimulating insulin secretion in and suppressing glucagon secretion in hyperglycemic or euglycemic states. Currently, all the GLP1R analogs approved by the FDA are reliably used to treat Type II diabetes and participate in the regulation of glucose homeostasis. Experiments were conducted during development of embodiments herein to test whether the liraglutide-induced hypersensitivity anorectic effects in the Mc3r- / -mice were independent of the incretin effects of GLP1-analogs. Oral glucose (GTT) and insulin (ITT) tolerance tests were conducted, and insulin and GLP1 levels were measured in Mc3r+ / +and Mc3r- / -mice. Mice were fasted and injected with liraglutide (0.2mg / kg, sc) or vehicle (PBS, sc) for 6 hours and glucose responses were measured after 0.5g / kg, 1g / kg, and 2g / kg of oral glucose bolus. It was found that liraglutide consistently produced a significantly better glucose disposal than mice injected with vehicle (Fig 2A-2F). However, Mc3r+ / +and Mc3r- / -mice responded similarly to the oral GTT. The most frequently reported adverse effects of GLP1R agonists are gastrointestinal in nature; patients report increase in emetic responses. To test whether the observed hypersensitivity anorectic responses to GLP1-analogs were due to physiological responses to food intake or alternatively to increased malaise, it was tested whether liraglutide triggered increased malaise in Mc3r- / -mice. Using conditioned taste aversion assay (CTA), a low concentration of liraglutide that resulted in decreased food intake and promoted weight loss (0.05mg / kg) was paired with the non- nutritive sweetener saccharin made in water (0.1%). A second group of mice received saccharin paired with lithium chloride (150mM) to induce gastric malaise. A third group received saccharin Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 paired with saline (150mM NaCl). Mice underwent training for two days, conditioning for two days, and testing for two days. It was found that genetic deletion of MC3R did not contribute to increase in malaise-induced administration of GLP1 drugs (Fig 2G-H). Mc3r+ / +and Mc3r- / -mice had low avoidance for saccharin when paired with saline and high avoidance when paired with either the liraglutide or LiCl. GLP1 agonists are also known to activate neurons in the area postrema (AP) at doses that induce conditioned taste aversion (CTA) (27). Deletion of the MC3R was not observed to increase activation of AP neurons in response to 0.1 mg / kg liraglutide (Figure 2, I and J). In contrast, a profound increase in neuronal activation following liraglutide treatment was seen in hypothalamic feeding circuits in the ventromedial hypothalamus (VMH), dorsomedial hypothalamus (DMH), and arcuate nucleus of the hypothalamus (ARH) of the Mc3r– / – mice relative to WT mice (Figure 2, K and L). Collectively, these data suggest that the observed anorectic hypersensitization of GLP1 analogs in Mc3r– / – mice was independent of emetic responses. Hypersensitization of MC3R promotes generalized satiation to various anorectic stimuli Experiments were conducted during development of embodiments herein to examine the generalizability of the increased anorectic response in the Mc3r- / -mouse by testing other anorectic compounds. The effect of the long-term adipostatic hormone leptin, a hormone produced by the adi- pose tissue in proportion to fat stores, was tested. Given that Mc3r– / – mice display late-onset weight gain and hyperleptinemia, these mice should theoretically exhibit leptin resistance. In contrast, Mc3r– / – mice also exhibited increased anorectic sensitivity to leptin; low doses of leptin, which otherwise did not affect food intake in WT mice, showed robust anorectic activity in male Mc3r– / – mice (Figure 3A). The effect was not observed in female mice (Figure 3D), although the estrous cycle, an important determinant of daily food intake and leptin levels (29, 30), was not synchronized in this study. Gut hormones, known to act acutely as satiety factors, including a form of the peptide YY (PYY3–36) and cholecystokinin (CCK), both secreted by enteroendocrine cells in the small intestine, were next tested. It was found that male and female Mc3r– / – mice had increased responses to PYY3–36 in a dose-dependent Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 manner over a 2-hour nocturnal feeding period (Figure 3, B and E). Similarly, administration of CCK produced an increased anorectic response in male and female Mc3r– / – mice compared with the WT mice in a dose-dependent manner (Figure 3, C and F). GLP-1 analogs increase the responsiveness of MC4R agonist in an MC3R-dependent manner MC3R presynaptically releases GABA and synapses onto downstream MC4R neurons, highlighting that MC3R is a negative regulator of melanocortin-4 receptor-expressing (MC4R) neurons. Co-administration of liraglutide and setmelanotide, an MC4R agonist, have an additive effect on weight loss. Hence, it was tested whether the administration of MC4R agonists might also increase sensitivity to liraglutide-induced inhibition of food intake and weight loss (Figure 4, A–H). Peripheral administration of the MC4R peptide agonist CTX-1211 also increased the sensitivity to liraglutide-induced inhibition of food intake and weight loss in WT male mice 24 hours after treatment (Figure 4, A and B). Sensitization of feeding behavior was less evident in female mice (Figure 4C), but liraglutide-induced weight loss was clearly sensitized by CTX- 1211 (Figure 4D). Setmelanotide (Imcivree), an MC4R agonist marketed to treat certain forms of genetic obesity, resulted in similar responses with the combination of liraglutide (Figure 4, E–H), illustrating that multiple MC4R agonists can increase the effect of liraglutide in inhibiting food intake and weight loss. Next, it was tested whether MC3R deletion would further enhance sensitization of liraglutide action by CTX 1211 and setmelanotide. Vehicle, setmelanotide, or CTX 1211 (1.5 mg / kg, i.p.), liraglutide (0.1 mg / kg, i.p.), or both an MC4R agonist and liraglutide were administered to WT and Mc3r– / – mice, and 24-hour food intake and changes in body weight were measured (Figure 4, I–L). MC4R agonists and liraglutide decreased food intake and promoted weight loss in WT mice, the magnitude of which was increased for both agents in Mc3r– / – mice. Notably, the anorectic and weight loss responses to the coadministration of MC4R agonists and liraglutide were yet further increased in Mc3r– / – mice compared with WT mice (Figure 4, I–L). Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 MC4R agonist effects on liraglutide action are synergistic and can be elicited with subthreshold doses Experiments were conducted during development of embodiments herein to determine whether the heightened responsiveness observed with concurrent administration of the MC4R agonist and liraglutide was additive or synergistic. To test this, WT mice were treated with a low dose of CTX 1211 (1 mg / kg), a concentration known not to affect food intake or body weight, in combination with an optimal dose of liraglutide (0.1 mg / kg). Both male and female mice that received the cotreatment of liraglutide and CTX 1211 exhibited significant reductions in food intake and weight loss compared with those receiving liraglutide alone (Figure 5A–D). WT mice were treated with an even lower dose of CTX 1211 (0.5 mg / kg), in combination with an optimal dose of liraglutide (0.1 mg / kg) also exhibited significant reductions in food intake and weight loss compared with those receiving liraglutide alone (Figure 5E-F). These experiments were repeated with a sub-therapeutic dose of setmelanotide, which also enhanced the food intake reduction and weight loss benefit of liraglutide without producing benefit on its own (Figure 6A- D). REFERENCES The following reference are herein incorporated by reference in their entireties. Dahir et al. Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice. J Clin Invest. 2024 Jul 15;134(14):e178250. Huszar, D., et al., Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell, 1997. 88(1): p. 131-41. Lam, B.Y.H., et al., MC3R links nutritional state to childhood growth and the timing of puberty. Nature, 2021. 599(7885): p. 436-441. Vaisse, C., et al., A frameshift mutation in human is associated with a dominant form of obesity. Nature Genetics, 1998. 20(2): p. 113-114. Butler, A.A., et al., A unique metabolic syndrome causes obesity in the melanocortin-3 receptor- deficient mouse. Endocrinology, 2000. 141(9): p. 3518-21. Chen, A.S., et al., Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet, 2000. 26(1): p. 97-102. Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 Marks, D. and R.D. Cone, The role of the melanocortin-3 receptor in cachexia. Ann N Y Acad Sci, 2003. 994: p. 258-66. Renquist, B.J., et al., Melanocortin-3 receptor regulates the normal fasting response. Proc Natl Acad Sci U S A, 2012. 109(23): p. E1489-98. Lippert, R.N., K.L. Ellacott, and R.D. Cone, Gender-specific roles for the melanocortin-3 receptor in the regulation of the mesolimbic dopamine system in mice. Endocrinology, 2014. 155(5): p. 1718-27. Ghamari-Langroudi, M., et al., Regulation of energy rheostasis by the melanocortin-3 receptor. Sci Adv, 2018. 4(8): p. eaat0866. Sweeney, P., et al., The melanocortin-3 receptor is a pharmacological target for the regulation of anorexia. Sci Transl Med, 2021. 13(590). Bedenbaugh, M.N., et al., Organization of neural systems expressing melanocortin-3 receptors in the mouse brain: Evidence for sexual dimorphism. J Comp Neurol, 2022. 530(16): p. 2835-2851. Cowley, M.A., et al., Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature, 2001. 411(6836): p. 480-4. Gui, Y., et al., Melanocortin-3 receptor expression in AgRP neurons is required for normal activation of the neurons in response to energy deficiency. Cell Rep, 2023. 42(10): p. 113188. Rubino, D., et al., Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA, 2021. 325(14): p. 1414-1425. Singh, A., et al., Structure-activity relationships of peptides incorporating a bioactive reverse- turn heterocycle at the melanocortin receptors: identification of a 5800-fold mouse melanocortin-3 receptor (mMC3R) selective antagonist / partial agonist versus the mouse melanocortin-4 receptor (mMC4R). J Med Chem, 2013. 56(7): p. 2747-63. Coskun, T., et al., LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol Metab, 2018. 18: p. 3-14. Jastreboff, A.M., et al., Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med, 2022. 387(3): p. 205-216. El, K., et al., The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets. Nat Metab, 2023. 5(6): p. 945-954. Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 Muller, T.D., et al., Glucagon-like peptide 1 (GLP-1). Mol Metab, 2019. 30: p. 72-130. Anderson, J., The Pharmacokinetic Properties of Glucagon-like Peptide-1 Receptor Agonists and Their Mode and Mechanism of Action in Patients with Type 2 Diabetes. . The Journal of family practice, 2018. 67. Astrup, A., et al., Safety, tolerability and sustained weight loss over 2 years with the once- daily human GLP-1 analog, liraglutide. Int J Obes (Lond), 2012. 36(6): p. 843-54. Buse, J.B., et al., Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26- week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet, 2009. 374(9683): p. 39-47. Kanoski, S.E., et al., The role of nausea in food intake and body weight suppression by peripheral GLP-1 receptor agonists, exendin-4 and liraglutide. Neuropharmacology, 2012. 62(5-6): p. 1916-27. Borner, T., et al., Glucagon-like peptide-1 in diabetes care: Can glycaemic control be achieved without nausea and vomiting? Br J Pharmacol, 2022. 179(4): p. 542-556. Young, C.F., M. Moussa, and J.H. Shubrook, Diabetic Gastroparesis: A Review. Diabetes Spectr, 2020. 33(3): p. 290-297. Halatchev, I.G. and R.D. Cone, Peripheral administration of PYY(3-36) produces conditioned taste aversion in mice. Cell Metab, 2005. 1(3): p. 159-68. Yamamoto, H., et al., Glucagon-like peptide-1-responsive catecholamine neurons in the area postrema link peripheral glucagon-like peptide-1 with central autonomic control sites. J Neurosci, 2003. 23(7): p. 2939-46. Myers, M.G., Jr., et al., Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol Metab, 2010. 21(11): p. 643-51. Clemmensen, C., et al., Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice. EMBO Mol Med, 2015. 7(3): p. 288-98. He, Z., et al., Direct and indirect effects of liraglutide on hypothalamic POMC and NPY / AgRP neurons - Implications for energy balance and glucose control. Mol Metab, 2019. 28: p. 120-134. Wang, D., et al., Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons. Front Neuroanat, 2015. 9: p. 40. Jais, A. and J.C. Bruning, Arcuate Nucleus-Dependent Regulation of Metabolism- Pathways to Obesity and Diabetes Mellitus. Endocr Rev, 2022. 43(2): p. 314-328. Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 Cone, R.D., Anatomy and regulation of the central melanocortin system. Nat Neurosci, 2005. 8(5): p. 571-8. Rau, A.R. and S.T. Hentges, GABAergic Inputs to POMC Neurons Originating from the Dorsomedial Hypothalamus Are Regulated by Energy State. J Neurosci, 2019. 39(33): p. 6449-6459. Garfield, A.S., et al., Dynamic GABAergic afferent modulation of AgRP neurons. Nat Neurosci, 2016. 19(12): p. 1628-1635. Berrios, J., et al., Food cue regulation of AGRP hunger neurons guides learning. Nature, 2021. 595(7869): p. 695-700. Palmiter, R.D., The Parabrachial Nucleus: CGRP Neurons Function as a General Alarm. Trends Neurosci, 2018. 41(5): p. 280-293. Chen, Y., et al., Hunger neurons drive feeding through a sustained, positive reinforcement signal. Elife, 2016. 5. Li, H.E., et al., Hypothalamic-Extended Amygdala Circuit Regulates Temporal Discounting. J Neurosci, 2021. 41(9): p. 1928-1940. Rupp, A.C., et al., Suppression of food intake by Glp1r / Lepr-coexpressing neurons prevents obesity in mouse models. J Clin Invest, 2023. 133(19). Bumaschny, V.F., et al., Obesity-programmed mice are rescued by early genetic intervention. J Clin Invest, 2012. 122(11): p. 4203-12. Matikainen-Ankney, B.A., et al., An open-source device for measuring food intake and operant behavior in rodent home-cages. Elife, 2021. 10.

Claims

Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 CLAIMS 1. A method of treating or preventing obesity in a subject comprising administering an anti- obesity agent to the subject, wherein MC3R activity or expression has been inhibited in the subject.

2. The method of claim 1, wherein the anti-obesity agent is selected from a GLP-1 agonist, a MC4R agonist, an anorectic, a pro-satiety agent, and a lipase inhibitor.

3. A method of treating or preventing obesity in a subject comprising administering an anti- obesity agent to the subject, wherein MC4R activity or expression has been enhanced in the subject.

4. The method of claim 3, wherein the anti-obesity agent is selected from a GLP-1 agonist, an anorectic, a pro-satiety agent, and a lipase inhibitor.

5. The method of claim 2 or 4, wherein the anti-obesity agent is a GLP-1 agonist.

6. The method of claim 5, wherein the GLP-1 agonist is selected from exendin-4, albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, taspoglutide, tirzepatide, retatrutide, CNTO736, CNT03649, HM11260C (LAPS-Exendin), NN9926 (OG9S7GT), TT401 and ZYOG1.

7. The method of claim 2, wherein the anti-obesity agent is a MC4R agonist.

8. The method of claim 5, wherein the MC4R agonist is setmelanotide.

9. The method of claim 2 or 4, wherein the anti-obesity agent is an anorectic.Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 10. The method of claim 9, wherein the anorectic is selected from amphetamine, dexamphetamine, amfepramone, clobenzorex, mazindol, phentermine, phentermine and topiramate, and lorcaserin 11. The method of claim 2 or 4, wherein the anti-obesity agent is a pro-satiety agent.

12. The method of claim 11, wherein the pro-satiety agent is selected from neurotrophic factor, amylin, calcitonin, cholecystokinin (CCK), leptin, metreleptin oxyntomodulin, pancreatic polypeptide (PP), peptide YY (PYY), and neuropeptide Y (NPY).

13. The method of claim 2 or 4, wherein the anti-obesity agent is a lipase inhibitor.

14. The method of claim 13, wherein the lipase inhibitor is selected from caulerpenyne, cetilistat, ebelactone A and B, esterastin, lipstatin, orlistat, percyquinin, panclicin A-E, valilactone and vibralactone.

15. The method of claim 1 or 3, wherein the anti-obesity agent is administered at a sub- therapeutic dose.

16. The method of claim 1 or 3, wherein the anti-obesity agent is administered at a sub- standard dose.

17. A method of treating or preventing obesity in a subject comprising co-administering an anti-obesity agent and an MC3R inhibitor to the subject.

18. The method of claim 17, wherein the anti-obesity agent is selected from a GLP-1 agonist, a MC4R agonist, an anorectic, a pro-satiety agent, and a lipase inhibitor.

19. A method of treating or preventing obesity in a subject comprising co-administering an anti-obesity agent and an MC4R activator to the subject.Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 20. The method of claim 19, wherein the anti-obesity agent is selected from a GLP-1 agonist, an anorectic, a pro-satiety agent, and a lipase inhibitor.

21. The method of claim 18 or 20, wherein the anti-obesity agent is a GLP-1 agonist.

22. The method of claim 19, wherein the GLP-1 agonist is selected from exendin-4, albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, taspoglutide, tirzepatide, retatrutide, CNTO736, CNT03649, HM11260C (LAPS-Exendin), NN9926 (OG9S7GT), TT401 and ZYOG1.

23. The method of claim 20, wherein the anti-obesity agent is a MC4R agonist.

24. The method of claim 23, wherein the MC4R agonist is setmelanotide.

25. The method of claim 18 or 20, wherein the anti-obesity agent is an anorectic.

26. The method of claim 25, wherein the anorectic is selected from amphetamine, dexamphetamine, amfepramone, clobenzorex, mazindol, phentermine, phentermine and topiramate, and lorcaserin 27. The method of claim 18 or 20, wherein the anti-obesity agent is a pro-satiety agent.

28. The method of claim 27, wherein the pro-satiety agent is selected from neurotrophic factor, amylin, calcitonin, cholecystokinin (CCK), leptin, metreleptin oxyntomodulin, pancreatic polypeptide (PP), peptide YY (PYY), and neuropeptide Y (NPY).

29. The method of claim 18 or 20, wherein the anti-obesity agent is a lipase inhibitor.Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 30. The method of claim 29, wherein the lipase inhibitor is selected from caulerpenyne, cetilistat, ebelactone A and B, esterastin, lipstatin, orlistat, percyquinin, panclicin A-E, valilactone and vibralactone.

31. The method of claim 17 or 19, wherein the anti-obesity agent is administered at a sub- therapeutic dose.

32. The method of claim 17 or 19, wherein the anti-obesity agent is administered at a sub- standard dose.

33. The method of claim 17, wherein the MC3R inhibitor is an inhibitor of MC3R activity.

34. The method of claim 33, wherein the inhibitor of MC3R activity is a small molecule or peptide MC3R antagonist or partial agonist.

35. The method of claim 34, wherein the peptide MC3R antagonist or partial agonist is a peptide selected from one of SEQ ID NOS 1-26.

36. The method of claim 17, wherein the MC3R inhibitor is an inhibitor of MC3R expression.

37. The method of claim 36, wherein the inhibitor of MC3R expression is a siRNA, a shRNA, a miRNA, a morpholino, a ribozyme, an antisense nucleic acid molecule, or a CRISPR - based construct.

38. The method of one of claims 33-37, wherein the MC3R inhibitor is administered at a sub- therapeutic dose.

39. The method of one of claims 33-37, wherein the MC3R inhibitor is administered at a sub- standard dose.Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 40. The method of claim 19, wherein the MC4R activator is an enhancer of MC4R activity.

41. The method of claim 40, wherein the enhancer of MC4R activity is a small molecule or peptide MC4R agonist.

42. The method of claim 41, wherein the peptide MC4R agonist is selected from a peptide selected from one of SEQ ID NOS 27-115.

43. The method of claim 19, wherein the MC4R activator is an enhancer of MC4R expression.

44. The method of one of claims 40-43, wherein the MC4R activator is administered at a sub- therapeutic dose.

45. The method of one of claims 40-43, wherein the MC4R activator is administered at a sub- standard dose.

46. A pharmaceutical composition comprising: (a) an anti-obesity agent; and (b) an MC3R inhibitor.

47. The pharmaceutical composition of claim 46, wherein the anti-obesity agent is selected from a GLP-1 agonist, a MC4R agonist, an anorectic, a pro-satiety agent, and a lipase inhibitor.

48. A pharmaceutical composition comprising: (a) an anti-obesity agent; and (b) an MC4R activator.Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 49. The pharmaceutical composition of claim 48, wherein the anti-obesity agent is selected from a GLP-1 agonist, an anorectic, a pro-satiety agent, and a lipase inhibitor.

50. The pharmaceutical composition of claim 47 or 49, wherein the anti-obesity agent is a GLP-1 agonist.

51. The pharmaceutical composition of claim 50, wherein the GLP-1 agonist is selected from exendin-4, albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, taspoglutide, tirzepatide, retatrutide, CNTO736, CNT03649, HM11260C (LAPS-Exendin), NN9926 (OG9S7GT), TT401 and ZYOG1.

52. The pharmaceutical composition of claim 47, wherein the anti-obesity agent is a MC4R agonist.

52. The pharmaceutical composition of claim 52, wherein the MC4R agonist is setmelanotide.

54. The pharmaceutical composition of claim 47 or 49, wherein the anti-obesity agent is an anorectic.

55. The pharmaceutical composition of claim 54, wherein the anorectic is selected from amphetamine, dexamphetamine, amfepramone, clobenzorex, mazindol, phentermine, phentermine and topiramate, and lorcaserin 56. The pharmaceutical composition of claim 47 or 49, wherein the anti-obesity agent is a pro-satiety agent.

57. The pharmaceutical composition of claim 56, wherein the pro-satiety agent is selected from neurotrophic factor, amylin, calcitonin, cholecystokinin (CCK), leptin, metreleptin oxyntomodulin, pancreatic polypeptide (PP), peptide YY (PYY), and neuropeptide Y (NPY).Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 58. The pharmaceutical composition of claim 47 or 49, wherein the anti-obesity agent is a lipase inhibitor.

59. The pharmaceutical composition of claim 58, wherein the lipase inhibitor is selected from caulerpenyne, cetilistat, ebelactone A and B, esterastin, lipstatin, orlistat, percyquinin, panclicin A-E, valilactone and vibralactone.

60. The pharmaceutical composition of claim 47 or 49, wherein the anti-obesity agent is present at a sub-therapeutic dose.

61. The pharmaceutical composition of claim 46 or 48, wherein the anti-obesity agent is present at a sub-standard dose.

62. The pharmaceutical composition of claim 46, wherein the MC3R inhibitor is an inhibitor of MC3R activity.

63. The pharmaceutical composition of claim 62, wherein the inhibitor of MC3R activity is a small molecule or peptide MC3R antagonist or partial agonist.

64. The pharmaceutical composition of claim 63, wherein the peptide MC3R antagonist or partial agonist is selected from a peptide of SEQ ID NOS 1-26.

65. The pharmaceutical composition of claim 46, wherein the MC3R inhibitor is an inhibitor of MC3R expression.

66. The pharmaceutical composition of claim 65, wherein the inhibitor of MC3R expression is a siRNA, a shRNA, a miRNA, a morpholino, a ribozyme, an antisense nucleic acid molecule, or a CRISPR-based construct.Attorney Docket No. UM-42157.601 Client Ref. No. OTT 2023-521 67. The method of one of claims 62-66, wherein the MC3R inhibitor is administered at a sub- therapeutic dose.

68. The method of one of claims 62-66, wherein the MC3R inhibitor is administered at a sub- standard dose.

69. The pharmaceutical composition of claim 48, wherein the MC4R activator is an enhancer of MC4R activity.

70. The pharmaceutical composition of claim 69, wherein the enhancer of MC4R activity is a small molecule or peptide MC4R agonist.

71. The pharmaceutical composition of claim 70, wherein the peptide MC4R partial agonist is selected from a peptide of SEQ ID NOS 27-115.

72. The pharmaceutical composition of claim 48, wherein the MC4R activator is an enhancer of MC4R expression.

73. The method of one of claims 69-72, wherein the MC4R activator is administered at a sub- therapeutic dose.

74. The method of one of claims 69-72, wherein the MC4R activator is administered at a sub- standard dose.

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