Methods for treating and preventing anorexia nervosa

Abstract

This application relates to methods of treating anorexia nervosa (AN), obsessive-compulsive disorder (OCD), and anxiety in a subject comprising administering an incretin analog (e.g., a glucagon-like peptide 1 (GLP-1) receptor agonist) to the subject, as well as a composition comprising an incretin analog (e.g., a GLP-1 receptor agonist) and a food and / or a beverage.

Description

Attorney Docket No: 251609.000157METHODS FOR TREATING AND PREVENTING ANOREXIA NERVOSACROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U. S. Provisional Patent Application No. 63 / 755,799, filed February 7, 2025, the disclosure of which is herein incorporated by reference in its entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on January 20, 2026, is named 251609„000157__SL.xml and is 6,113 bytes in size.FIELD OF THE INVENTION

[0003] This application relates to methods of treating anorexia nervosa (AN), obsessive- compulsive disorder (OCD), and anxiety in a subject comprising administering an incretin analog (e.g., a glucagon-like peptide 1 (GLP-1) receptor agonist) to the subject, as well as a composition comprising an incretin analog (e.g., a GLP-1 receptor agonist) and a food and / or a beverage.BACKGROUND

[0004] Anorexia nervosa (AN) is a serious neuro-psychiatric disease with neither an effective cure nor a clear etiological understanding. AN has the highest mortality rate among all psychiatric illnesses (Harris and Barraclough, 1998) and mainly affects females (roughly 92%) (Udo and Grilo, 2018). The first medical description of AN, anorexic hysterique, was in 1873 by Dr. William Gull. Gull studied phenotypic alterations in a patient before and after treatment for AN (Gull, 1873). According to the Diagnostic & Statistical Manual of Mental Disorders (Sth ed.), the criterion for AN include: a restriction of energy intake leading to significantly low body weight, an intense fear of gaining weight, and a disturbance in perception of body (American Psychiatric Association, 2013).

[0005] To study AN in comparative medicine, an Activity-Based Anorexia (ABA) Paradigm is used. Figure 1 compares anorexia, AN, and the ABA model. Note that AN differs from1325218025vlAttorney Docket No: 251609.000157anorexia, which is defined simply as the loss of appetite. AN patients willfully starve themselves due to the obsessive fear of weight gain and disturbance in body perception despite hunger. In addition to aberrant behaviors of food restriction, compulsive voluntary exercise is a common phenotypic development in AN. Excessive locomotion has been associated with greater obsessionality (Holden, 1990); in fact, AN is a frequent antecedent of obsessive-compulsive disorder (OCD) (Zribi et al., 1989). Even following weight restoration, a compulsive behavioral profile often persists, possibly because harm-avoidance behaviors may contribute to the pathogenesis of AN itself (Frangois and Zeltser, 2022; Kucukdereli et al., 2023). Many aspects of AN parallel OCD and both comorbidities are exacerbated and reinforced by progressive starvation (Mandel li et al., 2020).

[0006] Due to the complexity of AN, no one animal model captures all its clinical features and psychological idiosyncrasies. The ABA paradigm exhibited in a mouse model of activity-based AN is the best characterized and most used animal model for AN (Klenotich and Dulawa, 2012), modeling key aspects of the disease: restricted feeding, excessive exercise, and weight loss (Frangois and Zeltser, 2022). The mouse model of activity-based AN are lean and food restricted mice with access to a running wheel that replicate and model many of the key symptoms, i.e., phenotypes, of AN, e.g., starvation and compulsive exercise. Figure 2 shows the ABA 3-step protocol of acclimation, calorie restriction, and refeeding. Mice previously exposed to food restriction are driven to running, instead of eating, even when food access is resumed.

[0007] The mouse model of activity-based AN was validated in comparative medicine with the Minnesota starvation experiment. The Minnesota starvation experiment was the last human starvation experiment used to study post-wartime refeeding. The Minnesota starvation experiment had an almost identical protocol to ABA, i.e., the 3-step protocol of acclimation, calorie restriction, and refeeding. The protocol encompassed a control period of 12 weeks, semi¬ starvation period of 24 weeks, and rehabilitation period of 12 weeks. Participants of the Minnesota starvation experiment exhibited key symptoms of AN, including increased displacement behaviors (Keys et al., 1950).

[0008] AN is a cyclical disorder exacerbated and reinforced as the brain is deprived of nutrients. A displacement behavior, which is a defense mechanism that emerges with situations that cannot be faced nor avoided (Freud, 1936), serves to reduce tension (Maestripieri et al., 1992; Wiepkema, 1987). In the context of AN, not eating serves as a displacement behavior and2325218025vlAttorney Docket No: 251609.000157if hunger is not satisfied, energy originating from a different source will displace its normal expression (Kortmulder, 1998). Figure 3 shows the cycle of AN.

[0009] Current pharmacological interventions for AN include interventions that promote hunger / appetite (e.g., second generation antipsychotics, cannabis sativa, ghrelin agonists) and / or interventions that provide an anxiolytic effect (e.g., SSRIs, SRIs, mood stabilizers, non-selective opioid antagonists). Despite these efforts, current methods still result in high rates of relapse (-40%), chronicity, and death (Berends et al., 2016). SRIs are used as a first-line pharmacological intervention for OCD. However, most individuals with OCD benefit only partially or not at all from first-line intervention. Accordingly, there remains an unmet need in the art for effective treatments for AN, OCD, and anxiety.SUMMARY OF THE INVENTION

[0010] In one aspect, provided herein is a method of treating anorexia nervosa (AN) in a subject in need thereof, the method comprising: administering a therapeutically effective amount of an incretin analog to the subject.

[0011] In some embodiments, the incretin analog is a glucagon-like peptide 1 (GLP-1) receptor agonist.

[0012] In some embodiments, the incretin analog is selected from the group consisting of semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, CJC-1134-PC, taspoglutide, efpeglenatide, tirzepatide, and any combinations thereof.

[0013] In some embodiments, the incretin analog is administered parenterally, orally, or intranasally.

[0014] In some embodiments, the parenteral administration comprises subcutaneous injection, intramuscular injection, intraperitoneal injection, and / or intravenous injection.

[0015] In some embodiments, the oral administration comprises administration with a food product and / or a beverage, and optionally wherein the incretin analog is administered with sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC).

[0016] In some embodiments, the food product is a nutritional bar or an energy bar.

[0017] In some embodiments, the beverage is water, a nutritional beverage, an energy beverage, or a protein shake.3325218025vlAttorney Docket No: 251609.000157

[0018] In some embodiments, the intranasal administration comprises intranasal drops, intranasal sprays, and / or nebulized formulations.

[0019] In some embodiments, the incretin analog is administered in a dose of 0.04 to 0.32 mg / kg.

[0020] In some embodiments, the incretin analog is administered once per week for a first period of one week at a dose of 0.04 to 0.08 mg / kg.

[0021] In some embodiments, the incretin analog is administered once per week following the first period of one week at a dose of 0.04 to 0.08 mg / kg.

[0022] In some embodiments, the incretin analog is co-administered with leptin.

[0023] In some embodiments, the subject also receives counseling and / or therapy.

[0024] In some embodiments, the counseling is nutritional counseling.

[0025] In some embodiments, the therapy is cognitive behavioral therapy.

[0026] In some aspects, provided herein is a method of treating obsessive-compulsive disorder (OCD) in a subject in need thereof, the method comprising: administering a therapeutically effective amount of an incretin analog to the subject.

[0027] In some embodiments, the incretin analog is a glucagon-like peptide 1 (GLP-1 ) receptor agonist.

[0028] In some embodiments, the incretin analog is selected from the group consisting of semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, CJC-1134-PC, taspoglutide, efpeglenatide, tirzepatide, and any combinations thereof.

[0029] In some embodiments, the incretin analog is administered parenterally, orally, or intranasally.

[0030] In some embodiments, the parenteral administration comprises subcutaneous injection, intramuscular injection, intraperitoneal injection, and / or intravenous injection.

[0031] In some embodiments, the oral administration comprises capsules, tablets, caplets, pills, troches, lozenges, powders, and granules, and optionally wherein the incretin analog is administered with sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC).

[0032] In some embodiments, the intranasal administration comprises intranasal drops, intranasal sprays, and / or nebulized formulations.

[0033] In some embodiments, the incretin analog is administered in a dose of 0.04 to 0.32 mg / kg.4325218025vlAttorney Docket No: 251609.000157

[0034] In some embodiments, the incretin analog is administered once per week for a first period of one week at a dose of 0.04 to 0.08 mg / kg.

[0035] In some embodiments, the incretin analog is administered once per week following the first period of one week at a dose of 0.04 to 0.32 mg / kg.

[0036] In some embodiments, the subject also receives counseling and / or therapy.

[0037] In some embodiments, the counseling is behavioral counseling.

[0038] In some embodiments, the therapy is cognitive behavioral therapy and / or exposure and response prevention.

[0039] In some aspects, provided herein is a method of treating anxiety in a subject in need thereof, the method comprising: administering a therapeutically effective amount of an incretin analog to the subject.

[0040] In some embodiments, the incretin analog is a glucagon-like peptide 1 (GLP-1) receptor agonist.

[0041] In some embodiments, the incretin analog is selected from the group consisting of semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, CJC-1134-PC, taspoglutide, efpeglenatide, tirzepatide, and any combinations thereof.

[0042] In some embodiments, the incretin analog is administered parenterally, orally, or intranasally.

[0043] In some embodiments, the parenteral administration comprises subcutaneous injection, intramuscular injection, intraperitoneal injection, and / or intravenous injection.

[0044] In some embodiments, the oral administration comprises capsules, tablets, caplets, pills, troches, lozenges, powders, and granules, and optionally wherein the incretin analog is administered with sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC).

[0045] In some embodiments, the intranasal administration comprises intranasal drops, intranasal sprays, and / or nebulized formulations.

[0046] In some embodiments, the incretin analog is administered in a dose of 0.04 to 0.32 mg / kg.

[0047] In some embodiments, the incretin analog is administered once per week for a first period of one week at a dose of 0.04 to 0.08 mg / kg.

[0048] In some embodiments, the incretin analog is administered once per week following the first period of one week at a dose of 0.04 to 0.32 mg / kg.5325218025vlAttorney Docket No: 251609.000157

[0049] In some embodiments, the subject also receives counseling and / or therapy.

[0050] In some embodiments, the counseling is behavioral counseling.

[0051] In some embodiments, the therapy is pharmacotherapy, cognitive behavioral therapy, and / or exposure and response prevention.

[0052] In some aspects, provided herein is a composition comprising: a therapeutically effective amount of an incretin analog; and a food product and / or a beverage.

[0053] In some embodiments, the incretin analog is a glucagon-like peptide 1 (GLP-1) receptor agonist.

[0054] In some embodiments, the incretin analog is selected from the group consisting of semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, CJC-1134-PC, taspoglutide, efpeglenatide, tirzepatide, and any combinations thereof.

[0055] In some embodiments, the composition further comprises sodium N-(8-[2- hydroxybenzoyljamino) caprylate (SNAC).

[0056] In some embodiments, the food product is a nutritional bar or an energy bar.

[0057] In some embodiments, the beverage is water, a nutritional beverage, an energy beverage, or a protein shake.

[0058] In some embodiments, the incretin analog is present in an amount of 1-7 mg.BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 shows a Venn diagram comparing anorexia, anorexia nervosa (AN), and the activity-based anorexia (ABA) model.

[0060] Figure 2 shows the ABA 3-step protocol of acclimation, calorie restriction, and refeeding.

[0061] Figure 3 shows the cycle of AN.

[0062] Figure 4 shows projections in the brain from the AgRP and POMC neurons (Dietrich et al., 2015).

[0063] Figure 5 shows a graphic of the metabolic state shift from starvation to satiety with semaglutide treatment by promoting POMC activation and indirectly inhibiting AgRP neurons.

[0064] Figu re 6 shows the Promethion™ high-definition multiplexed respirometry cage for mice measurement collection.6325218025vlAttorney Docket No: 251609.000157

[0065] Figure 7 shows the protocol for mice treatment in the vehicle group (n - 17) and the semaglutide group (n - 18).

[0066] Figures 8A-8G show semaglutide does not reduce food intake or body weight in adolescent mice exposed to ABA paradigm, but does decrease fat mass and prevents development of excessive exercise phenotype during the same paradigm. Studies were conducted in peripubertal female C57BL / 6J mice (P36-P50); vehicle (left, n = 17) and semaglutide (right, n = 18). Results plotted denote p ± SEM; significance was determined using two-way ANOVA followed by Sfdak's multiple comparisons test. Figure 8A shows food intake changes during ABA. No statistical differences across groups were found. Figure 8B shows body weight changes during ABA. No statistical differences across groups were found. Figure 8C shows comparison of percent fat mass between controls and semaglutide cohorts; semaglutide animals experience a reduction in fat mass. Body composition was measured using magnetic resonance imaging and completed at the end of the refeeding period at P42. Plot represents the p ± SEM and significance was determined by a two-sided i-test; **p = 0.0024 (semaglutide versus control). Figure 8D shows the daily running wheel activity during acclimatization and calorie restriction, displaying the daily number of running wheel revolutions. Semaglutide decreased running activity on all days following injection, compared to controls. Error bars represent p ± SEM. P values represent Sidak's multiple comparisons test. A significant difference was observed the day following the first injection, *pday3“ 0.0312, and on all days of calorie restriction, *pdayg“ 0.0404, **Pday6" 0.0061, and *pday, ~ 0.0211. There was a decrease 48 hours after the first drug administration, though not significant, pday4= 0.0641. Figure 8E shows the same data as Figure 8D, but displayed as a heat map. Figure 8F shows the same data as Figure 8D and Figure 8G shows the same data as Figure 8E, but show the daily running wheel activity in distance traveled vs. the daily number of running wheel revolutions.

[0067] Figures 9A-9C show semaglutide decreases basal metabolic rate (BMR) and reduces respiratory quotient (RQ) for mice in an activity-based anorexia model. Figures 9A-9B shows changes in energy expenditure (kcal / hr) verses time in vehicle-treated mice vs. semaglutide - treated mice represented via bar graph (Figure 9A) and heat map (Figure 9B). Studies were conducted in peripubertal female C57BL / 6J mice ( P36-P50); vehicle (left, n = 17) and semaglutide (right, n = 18). Only data for female mice are shown, and results plotted denote p ± SEM. Energy expenditure was measured using the Weir equation: metabolic rate (kcal / day) =7325218025vlAttorney Docket No: 251609.000157(3.94 x VO2) + (1.1 x VCO2). VChis oxygen consumption and VCChis carbon dioxide production. VO2 and VCO2 are measured in L / min. Significance was determined using two-way ANOVA follow'ed by Sldak’s multiple comparisons test. The star symbol indicates a p value of statistical significance. Semaglutide decreased energy expenditure on days four and five of the ABA paradigm, ***pday4— 0.0010 and ***pdays— 0.0006, respectively. Although a decrease was noted on days six and seven, Pday6— 0.0656 and pday7— 0.0513, respectively, the results were not statistically significant. GraphPad Prism 10.0 was used to analyze data and plot figures. Figure 9C shows changes in the respiratory quotient (RQ) over time in vehicle -treated mice vs. semaglutide-treated mice. Semaglutide reduces respiratory quotient in mice subject to the ABA paradigm, compared to controls with same conditions. Error bars represent p ±SEM. Significance was determined using two-way ANOVA followed by Sidak’s multiple comparisons test. The star symbol indicates a p value of statistical significance. Semaglutide decreased RQ on all days following injection, compared to controls. P values equal *Pday3= 0.0439. ***pday4= 0.0007, *pday5= 0.0132, ***pday6= 0.0003, and *pday?= 0.0229. GraphPad Prism 10.0 was used to analyze data and plot figures. Illustrations were created with BioRender.

[0068] Figures 10A-10E show semaglutide promotes exploratory behavior in weight-restored mice exposed to ABA paradigm. Figure 10A shows the elevated zero maze (EZM) apparatus. Figures 10B-10C show data from an elevated zero maze test in vehicle-treated mice vs. semaglutide-treated mice. Studies were conducted in peripubertal female C57BL / 6J mice on postnatal day 42 (P42); cohorts consisted of vehicle (left, n = 17) and semaglutide (right, n = 18) groups. Only data for female mice are shown, and results plotted denote u ± SEM. Significance was determined by a two-sided / -test. Mice were placed in the apparatus and tracked using Any-Maze video tracking software for ten minutes. Figure 10B shows the time (s) spent in the open arms in the elevated zero maze. Semaglutide mice spent significantly more time in the open arm zone, *p = 0.0423. Figure 10C shows the latency (s) to first exit from the open arms zone, p = 0.07. Figures 10D-10E show a marble bury test in vehicle-treated mice vs. semaglutide-treated mice. Figure 10D shows a visual depiction of the marble-burying test. One animal is placed in a cage with 24 marbles arrayed on the surface of clean bedding. After 30 minutes, the number of marbles buried to at least 2 / 3 their depth with bedding were counted. Figure 10E shows a bar plot displaying the percentage of marbles buried after exposure to AB in mice with and without8325218025vlAttorney Docket No: 251609.000157semaglutide treatment. The bar represents the p + SEM; significance was determined by a two- sided / -test, *p = 0.0489. GraphPad Prism 10.0 was used to analyze data and plot figures.Illustrations were created with BioRender.

[0069] Figures 11A-11J show AgRP neurons are necessary for weight-loss and metabolic effects of semaglutide. Figure 11A shows a schematic illustration for generation of AgRPDIRmice. Figure 11B shows body weight of wild-type controls (n = 6) and mutant female animals across 14 days of treatment (control semaglutide, n - 7; AgRPUIR, n - 1). Figure 11C shows energy expenditure (kcal / h) of wild-type and mutant mice treated with semaglutide, measured through indirect calorimetry (control vehicle, n - 6; control semaglutide, n = 7; AgRPDTRvehicle, n = 4; AgRPDTRsemaglutide, n ~ 7). Figure 11D shows blood glucose and ketone bodies levels in wild-type and AgRP-ablated mice (control vehicle, n - 6; control semaglutide, n - 7; AgRPDTRvehicle, n - 4; AgRPDTRsemaglutide, n - 4). Figure HE shows Agrp and Npy expression in wild-type mice after 2- or 15-days injections (dpi) with semaglutide (vehicle, n = 3; semaglutide, n - 4). Figure HF show's a schematic illustration for generation of AgRP-Szr / 7 knockout mice. Figure 11G shows body weight of wild-type and transgenic female animals across 14 days of treatment (control vehicle, n - 6; control semaglutide, n - 6; AgRP-Szr / 7 KO semaglutide, n = 7). Figure 11H shows body composition analysis of control and transgenic mice after 2 or 15 days of treatment with semaglutide. Figure HI shows insulin and leptin levels in the blood of controls or transgenic mice treated for 15 days with semaglutide (control vehicle, n = 4; control semaglutide, n = 6; AgRP-Sirtl KO vehicle, n = 2; AeRP-Sirtl KO semaglutide, n - 2). Figure 11 J shows blood glucose and ketone bodies levels in controls and transgenic mice treated with semaglutide for 15 days (control vehicle, n - 4; control semaglutide, n - 6; AgRP-Sirtl KO vehicle, n = 2; AgRP-Szr / 7 KO semaglutide, n - 2). Values are mean ± s.d.; *P < 0.05, **P < 0.01, ***P < 0.001 vs. control vehicle; #P < 0.05; ##P < 0.01 vs. control semaglutide. Data were analyzed using two-way ANOVA folio wed by Tukey post-hoc.

[0070] Figures 12A-12J show AgRP neurons are necessary for the anxiolytic effects of semaglutide. Figure 12A shows time in the center of the apparatus measured in the two-phase open field test. Figure 12B shows number of investigations to the center of the apparatus.Figure 12C shows latency to the center of the apparatus (control vehicle, n = 6; control semaglutide, n ~ 6; AgRP-Szr / 7 KO vehicle, n ~ 4; AgRP-Szr / 7 KO semaglutide, n - 4). Figure 12D shows nest building in w'ild-type and AgRP-Szr / 7 KO mice after 2 days of injection with9325218025vlAttorney Docket No: 251609.000157semaglutide. Figure 12E shows nest building in wild-type and AgRP-Sirtl KO mice after 15 days of injection with semaglutide. Figure 12F shows number of marbles buried in wild-type and AgRP-Sirtl KO mice after 2 days of injection with semaglutide. Figure 12G shows spontaneous running activity in wild-type and AgRPDTRmice. Figure 12H shows time in the open arm in the Elevated Zero Maze test in animals treated with semaglutide submitted to the activity-based anorexia (ABA) paradigm. Figure 121 shows latency to the open arms zone of the Elevated Zero Maze apparatus in animals submitted to the ABA. Figure 12J shows number of marbles buried by animals treated with semaglutide and submitted to the ABA paradigm. Data are expressed as mean ± S. E. M. Statistical analysis was performed by using Two-way ANOVA followed by Sfdak's or Tukey’s multiple-comparisons tests, p<0.05 was considered as significant.

[0071] Figures 13A-13I show semaglutide prevents the development of activit -based anorexia in female mice through an AgRP-dependent mechanism. Figure 13A shows a schematic illustration for generation of AgRPDIRmice and the ABA paradigm. Animals started treatment with semaglutide on the second day of acclimatization. Figure 13B shows running activity (cumulative distance in meters) of control and AgRPD1Rmice treated with semaglutide. Figure 13C shows cumulative ambulatory activity of mice throughout the ABA paradigm. Figure 13D shows body weight (g) of animals through the seven days of ABA. Figure 13E shows food intake during the early dark cycle (7-10 PM). Figure 13F shows energy expenditure of mice during acclimatization and calorie restriction phases of the ABA, solid lines are the control and AgRPD1Rvehicle mice, while dotted lines are the control and AgRPDfRsemaglutide mice. Figure 13G shows blood glucose levels (mg / dL) of animals submitted to the ABA paradigm. Figure 13H shows blood ketone bodies levels (mg / dL) of animals submitted to the ABA paradigm. Figure 131 shows a representative heatmap of the respiratory exchange ratio (RER) of wild-type and AgRPDTRmice treated with semaglutide. Control vehicle, n=6; control semaglutide, ri-7; AgRPDTRvehicle, n=4; AgRPDTRsemaglutide, n=4. Data are expressed as mean ± S. E. M. Statistical analysis was performed by using Two-way ANOVA followed by Sidak's or Tukey’s multiple-comparisons tests, as appropriate. *P < 0.05; ** P < 0.01; ***P < 0.001 vs. vehicle control and # P < 0.05 and ## P < 0.01 vs. vehicle AgRPDTR.

[0072] Figures 14A-14B show loss of AgRP neurons does not affect weight loss promoted by semaglutide in male mice. Figure 14A shows male AgRPDTRor AgRP-Sirtl KO do not recover10325218025vlAttorney Docket No: 251609.000157weight after continuous treatment with semaglutide (control, n - 6; semaglutide AgRP-Sirtl KO, n = 13; Semaglutide AgRPDTR, n - 6). Figure 14B shows gene expression analysis reveals no difference in Agrp levels and increased Npy expression in male mice treated for 15 days with semaglutide (n = 3). Data expressed as mean ± s.d. Student’s t-test was used to compare gene expression between vehicle and semaglutide treated mice. *P < 0.05 vs. vehicle.

[0073] Figures 15A-15H show dose-response curve of semaglutide in the development of activity-based anorexia. Female mice during ABA paradigm were treated with semaglutide i.p. at concentrations of 0.04, 0.08, 0.16, and 0.32 mg / kg. Figure 15A shows body weight measurement of animals treated. Figure 15B shows food intake during early dark cycle (7-10PM). Figure 15C shows running activity (cumulative distance in meters). Figure 15D shows total wheel revolutions (meters) after calorie restriction (CR). Figure 15E shows continuous energy expenditure (kcal / h) throughout paradigm. Figure 15F shows average daily energy expenditure (kcal / h). Figure 15G shows continuous respiratory exchange ratio (RER) throughout paradigm. Figure 15H shows heatmap of RER of mice treated with semaglutide in the second day of acclimatization (line). Data is expressed as mean ± S. E. M. Statistical analysis was performed using Two-way ANOVA followed by Tukey test (n=6 for all groups). *P < 0.05; ** P<0.01; ***P<0.001; ****P<0.0001 vs. control.DETAILED DESCRIPTION

[0074] Energy homeostasis is regulated by the central nervous system and specifically, feeding behavior is regulated by the hypothalamus. AgRP neurons and POMC neurons are located within the arcuate nucleus (ARC) of the hypothalamus. AgRP neurons are orexigenic, promoting hunger and stereotypic behavioral responses like foraging. POMC neurons are anorexigenic & promote satiety. Figure 4 shows projections in the brain from the AgRP neurons and POMC neurons, in white and black, respectively (Dietrich et al., 2015).

[0075] Incretin analogs, such as the GLP-1 receptor agonist semaglutide, have emerged as breakthrough therapeutic strategies for people with type 2 diabetes and obesity, which predominantly stems from overeating. Since its approval by the U. S. Food and Drug Administration (FDA) for the treatment of type 2 diabetes and weight loss, semaglutide has been prescribed to over 5 million individuals in the United States alone (Toal, 2024). Incretin analogs operate through mechanisms that suppress appetite and promote satiety. Semaglutide promotes11325218025vlAttorney Docket No: 251609.000157weight loss with individual variability, and its continuous administration is critical for maintenance of a lower body weight. Semaglutide shifts the metabolic state from starvation to satiety by promoting POMC activation and indirectly inhibiting AgRP neurons (Dong et al., 2021) as shown in Figure 5.

[0076] There are several caveats of the clinical impact of incretin analogs at the individual and population level. For example, incretin analogs need to be continuously used even when targeted weigh loss is achieved (Hall, 2023). Targeted weight loss is not reached in a significant percentage of subjects regardless of dose used (Jastreboff, et al., 2022) and there is a population of subjects who do not respond to incretin analogs with significant weight loss (Tzoulis & Baldeweg, 2024). The precise mechanisms through which incretin analogs, including semaglutide, exert their long-term pleiotropic effects are not well defined. For example, cell populations in the hindbrain and hypothalamus have been suggested as main sites of action of semaglutide regarding satiety and weight loss of subjects with diet-induced obesity (Gabery, et al., 2020; Huang, et al., 2024).

[0077] On the other hand, subjects with AN purposefully starve themselves and frequently exercise compulsively to decrease body weight. Because cell starvation is highly stressful, incretin analogs may be sought after by subjects with AN to suppress appetite. It is assumed that such intervention would be detrimental as incretin analogs would seem counterintuitive as a therapeutic for subjects with AN. This potentially detrimental outcome in subjects with AN and OCD was studied as described herein since how semaglutide exerts its effects and whether exposure of lean subjects to semaglutide may impact other brain functions was ill-defined. The usage of semaglutide in lean and starving subjects had not previously been tested. Since semaglutide downregulates AgRP activity, it was studied whether it could also inhibit stereotypic displacement behaviors that arise in the absence of food, thereby stopping the AN cycle. Interest surrounded the potential therapeutic applications of semaglutide in metabolic and neuropsychiatric conditions such as anxiety (D ’Avila, et al., 2024).

[0078] Herein, ad libitum-fed lean female mice were given daily semaglutide injections and correspondingly exhibited lowered body weight within days, which, in turn, was maintained if daily semaglutide injections continued. Concomitant with its weight reducing effects, semaglutide injections also diminished anxiety of female mice. Strikingly, impairment of hypothalamic Agouti-related peptide (AgRP)-producing neurons, which are indirectly inhibited12325218025vlAttorney Docket No: 251609.000157by incretin analogs, blocked the sustained weight-loss promoted by semaglutide, and mitigated the anxiolytic effects of semaglutide. Weight loss of lean subjects and the role of AgRP neurons have also been implicated in AN.

[0079] Accordingly, a mouse model of activity-based AN was used (Routtenberg and Kuznesof, 1967) to determine if GLP-1 mimetic semaglutide impacts phenotypic development. Tn this paradigm, peri-pubertal mice given semaglutide displayed key differences compared to vehicle controls. Semaglutide diminished phenotype development of mice in an activity-based anorexia model. Peri-pubertal female mice given semaglutide displayed reduced wheel running activity, reduced basal metabolic rate / energy expenditure, elevated lipid metabolism, decreased blood ketone levels, and decreased anxiety compared to the values of their vehicle controls. Tn addition, one week after returning to ad libitum feeding without wheel access, mice that received semaglutide showed reduced stereotypic behaviors and anxiety compared to control mice.However, ablation of AgRP neurons diminished the observed beneficial effects of semaglutide on these AN phenotypes.

[0080] The study herein unmasked a critical role for hypothalamic AgRP neurons in the maintenance of lower body weight and anxiety promoted by chronic administration of semaglutide in female mice, and revealed that semaglutide has beneficial effects in animal models of AN dependent on the integrity of the AgRP neuronal circuitry. While counterintuitive, the data as described herein show that semaglutide diminishes many of the negative attributes and consequences of AN in an animal model. Surprisingly, semaglutide benefited the mice subjects and prevented serious side effects of AN, including long term psychological impairment. Semaglutide could be a novel approach to treat AN. Semaglutide treatment may be used in conjunction with nutritional counseling and cognitive behavioral therapy. Semaglutide treatment may be administered in a dose-dependent manner, proportional to illness severity. Definitions

[0081] To facilitate an understanding of the principles and features of the various embodiments of the invention, various illustrative embodiments are explained below. Although exemplary embodiments of the invention are explained in detail, it is to be understood that other embodiments are contemplated. Accordingly, it is not intended that the invention is limited in its scope to the details of construction and arrangement of components set forth in the following description or examples. The invention is capable of other embodiments and of being practiced13325218025vlAttorney Docket No: 251609.000157or carried out in various ways. Also, in describing the exemplary embodiments, specific terminology will be resorted to for the sake of clarity.

[0082] As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to “a method” includes one or more methods, and / or steps of the type described herein and / or which will become apparent to those persons skilled in the art upon reading this disclosure.

[0083] The terms “treat”, “treating”, or “treatment” of a state, disorder or condition include: (1 ) preventing, delaying, or reducing the incidence and / or likelihood of the appearance of at least one clinical or sub-clinical symptom of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; or (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or sub-clinical symptom thereof; or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or sub-clinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.

[0084] As used herein the term “effective” applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a subject in need thereof. Note that when a combination of active ingredients is administered, the effective amount of the combination may or may not include amounts of each ingredient that would have been effective if administered individually. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition being treated, the particular drug or drugs employed, the mode of administration, and the like.

[0085] In the context of the field of medicine, the term “prevent” encompasses any activity which reduces the burden of mortality or morbidity from disease. Prevention can occur at primary, secondary and tertiary prevention levels. While primary prevention avoids the development of a disease, secondary and tertiary levels of prevention encompass activities aimed at preventing the progression of a disease and the emergence of symptoms as well as reducing14325218025vlAttorney Docket No: 251609.000157the negative impact of an already established disease by restoring function and reducing disease- related complications.

[0086] The terms “patient”, “individual”, “subject”, and “animal” are used interchangeably herein and refer to mammals, including, without limitation, human and veterinary animals (e.g., cats, dogs, cows, horses, goats, sheep, pigs, etc.) and experimental animal models. In a preferred embodiment, the subject is a human.

[0087] The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions fire preferably employed as carriers, particularly for injectable solutions. Alternatively, the carrier can be a solid dosage form carrier, including but not limited to one or more of a binder (for compressed pills), a glidant, an encapsulating agent, a flavorant, and a colorant. Suitable pharmaceutical carriers are described in “Remington’s Pharmaceutical Sciences” by E. W. Martin, incorporated by reference in its entirety for all purposes.

[0088] The term “about” or “approximately” means within a statistically meaningful range of a value. Such a range can be within an order of magnitude, preferably within 50%, more preferably within 20%, still more preferably within 10%, and even more preferably within 5% of a given value or range. The allowable variation encompassed by the term “about” or “approximately” depends on the particular system under study, and can be readily appreciated by one of ordinary skill in the art.

[0089] By “comprising” or “containing” or “including” is meant that at least the named compound or method step is present in the composition or method, but does not exclude the presence of other compounds or method steps, even if the other such compounds or method steps have the same function as what is named.

[0090] “Glucagon-like peptide 1 (GLP-1) receptor” is known as GLP-1R. GLP-1R is a fundamental component of the G protein-coupled receptor (GPCR) family. GLP-1R is located within the human body predominantly on cell surfaces of various cell types. GLP-1R explicitly interacts with GLP-1, which is an important hormone released from the gut after eating. Thus, GLP-1 serves an integral role in regulating lipid metabolism, blood glucose levels, and numerous15325218025vlAttorney Docket No: 251609.000157other critical biological functions. GLP-1R agonists activate GLP-1R by mimicking the hormone GLP-1.

[0091] “Semaglutide” is a GLP-1R agonist. Semaglutide has been commonly used as a treatment for type 2 diabetes and obesity. It is also known as brand names Ozempic®, Rybelsus®, and Wegovy®. Semaglutide is a 31 -amino acid peptide with a similar structure to GLP-1 (amino acids 7-37) with amino acid substitutions at positions 8 and 34. a-aminoisobutyric acid (Aib) replaces alanine at position 8 and arginine replaces lysine at position 34. Further, the lysine at position 26 is acylated with stearic diacid, which increases the half-life of semaglutide by increasing albumin binding and thereby improving resistance to metabolic degradation.

[0092] It is also to be understood that the mention of one or more method steps does not preclude the presence of additional method steps or intervening method steps between those steps expressly identified. Similarly, it is also to be understood that the mention of one or more components in a device or system does not preclude the presence of additional components or intervening components between those components expressly identified.

[0093] Also, in describing the exemplary embodiments, terminology will be resorted to for the sake of clarity. It is intended that each term contemplates its broadest meaning as understood by those skilled in the art and includes all technical equivalents which operate in a similar manner to accomplish a similar purpose.Method of treating anorexia nervosa (AN)

[0094] In one aspect, provided herein is a method of treating anorexia nervosa (AN) in a subject in need thereof, the method comprising: administering a therapeutically effective amount of an incretin analog to the subject.

[0095] Anorexia nervosa is an eating disorder wherein people with anorexia have a strong fear of gaining weight. They often limit the amount of food they eat and may exercise excessively. Anorexia nervosa is a condition in which hunger is present, but there is a pathological psychological suppression to act on that hunger drive.

[0096] In some embodiments, the incretin analog is a glucagon-like peptide 1 (GLP-1) receptor agonist. GLP-1 analogs, fusion proteins, and GLP-1 receptor agonists are disclosed, for example, in US7452966, US8389689, US8497240, US8557769, US8883447, US8895694, US9409966, US20160194371, US20140024586, US20140073563, US20120148586, US20170114115, US20170112904, US20160361390, US20150313908, US20150259416, WO2017074715,16325218025vlAttorney Docket No: 251609.000157WO2016127887, W02015021871, WO2014113357, EP3034514, EP2470198, and EP2373681, all of which are incorporated herein in their entireties.

[0097] In some embodiments, the incretin analog is selected from the group consisting of semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, CJC-1134-PC, taspoglutide, efpeglenatide, tirzepatide, and any combinations thereof.

[0098] Semaglutide is also known as Ozempic®, Rybelsus®, and Wegovy®. Dulaglutide is also known as Trulicity®, liraglutide is also known as Victoza® or Saxenda®, exenatide is also known as Byetta® or Bydureon®, lixisenatide is also known as Lyxumia® and Adlyxin®, albiglutide is also known as Eperzan® or Tanzeum®, CJC-1134-PC is also known as exendin-4, and tirzepatide is also known as Zepbound®.

[0099] The incretin analog of this invention can be administered by a variety of routes including oral, rectal, intraocular, transderm al, subcutaneous, intravenous, intramuscular, intraperitoneal, intradermal, directly into cerebrospinal fluid, intratracheal, and intranasal.Depending on the intended route of delivery, the compounds of this invention are preferably formulated as injectable compositions. Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. The active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.

[0100] In some embodiments, the incretin analog is administered parenterally, orally, or intranasally.

[0101] In some embodiments, the parenteral administration comprises subcutaneous injection, intramuscular injection, intraperitoneal injection, and / or intravenous injection.

[0102] In some embodiments, the oral administration comprises administration with a food product and / or a beverage, and optionally the incretin analog is administered with sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC).

[0103] In some embodiments, the food product is a nutritional bar or an energy bar.

[0104] In some embodiments, the beverage is water, a nutritional beverage, an energy beverage, or a protein shake.

[0105] In some embodiments, the intranasal administration comprises intranasal drops, intranasal sprays, and / or nebulized formulations.17325218025vlAttorney Docket No: 251609.000157

[0106] The active compound can be effective over a wide dosage range and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0107] In some embodiments, the incretin analog is administered in a dose of 0.04 to 0.32 mg / kg.

[0108] In some embodiments, the incretin analog is administered in a dose of about 0.04 mg / kg to about 0.32 mg / kg. In some embodiments, the incretin analog is administered in a dose of about 0.04 mg / kg to about 0.32 mg / kg, for example in a dose of about 0.04 mg / kg to about 0.08 mg / kg, about 0.04 mg / kg to about 0.16 mg / kg, about 0.08 mg / kg to about 0.16 mg / kg, about 0.08 mg / kg to about 0.24 mg / kg, about 0.16 mg / kg to about 0.24 mg / kg, about 0.16 mg / kg to about 0.32 mg / kg, or about 0.24 mg / kg to about 0.32 mg / kg. In some embodiments, the incretin analog is administered in a dose of about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.10 mg / kg, about 0.11 mg / kg, about 0.12 mg / kg, about 0.13 mg / kg, about 0.14 mg / kg, about 0.15 mg / kg, about 0.16 mg / kg, about 0.17 mg / kg, about 0.18 mg / kg, about 0.19 mg / kg, about 0.20 mg / kg, about 0.21 mg / kg, about 0.22 mg / kg, about 0.23 mg / kg, about 0.24 mg / kg, about 0.25 mg / kg, about 0.26 mg / kg, about 0.27 mg / kg, about 0.28 mg / kg, about 0.29 mg / kg, about 0.30 mg / kg, about 0.31 mg / kg, about 0.32 mg / kg, about 0.34 mg / kg, about 0.36 mg / kg, about 0.38 mg / kg, about 0.40 mg / kg, about 0.42 mg / kg, about 0.44 mg / kg, about 0.46 mg / kg, about 0.48 mg / kg, about 0.50 mg / kg, about 0.55 mg / kg, about 0.60 mg / kg, about 0.65 mg / kg, about 0.70 mg / kg, about 0.75 mg / kg, about 0.80 mg / kg, about 0.85 mg / kg, about 0.90 mg / kg, about 0.95 mg / kg, or about 1.00 mg / kg.

[0109] In some embodiments, the incretin analog is administered once per week for a first period of one week at a dose of 0.04 to 0.08 mg / kg. hi some embodiments, the incretin analog is administered once per week for a first period of one week at a dose of about 0.04 mg / kg to about 0.08 mg / kg. In some embodiments, the incretin analog is administered once per week for a first period of one week at a dose of about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, or about 0.08 mg / kg.18325218025vlAttorney Docket No: 251609.000157

[0110] In some embodiments, the incretin analog is administered once per week. In some embodiments, the incretin analog is administered once per day, once every other day, once every three days, twice per week, once per week, once every other week, twice per month, or once per month.

[0111] In some embodiments, the incretin analog is administered once per week following the first period of one week at a dose of 0.04 to 0.08 mg / kg. In some embodiments, the incretin analog is administered once per week following the first period of one week at a dose of about 0.04 mg / kg to about 0.08 mg / kg. In some embodiments, the incretin analog is administered once per week following the first period of one week at a dose of about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, or about 0.08 mg / kg.

[0112] In some embodiments, the dose is the same in the first administration of the incretin analog compared to the dose of the following administrations of the incretin analog. In some embodiments, the dose is higher in the first administration of the incretin analog compared to the dose of the following administrations of the incretin analog. In some embodiments, the dose is lower in the first administration of the incretin analog compared to the dose of the following administrations of the incretin analog.

[0113] In some embodiments, the incretin analog is co-administered with leptin.

[0114] In some embodiments, the subject also receives counseling and / or therapy.

[0115] In some embodiments, the counseling is nutritional counseling.

[0116] Nutritional counseling is often provided by a registered dietitian (RD) or registered dietician nutritionist (RDN). Nutritional counseling provides guidance to individuals at nutritional risk due to their health or nutritional history, chronic illness, dietary intake, or medication use.

[0117] In some embodiments, the therapy is cognitive behavioral therapy.

[0118] Cognitive behavioral therapy is a structured type of psychotherapy that is used to treat many types of mental health conditions and emotional challenges, including anxiety, depression, obsessive-compulsive disorder, post-traumatic stress disorder, phobias, and eating disorders. It is used to unlearn negative behaviors and thoughts and to learn healthier thinking habits and patterns.Method of treating obsessive-compulsive disorder (OCD)

[0119] In another aspect, provided herein is a method of treating obsessive-compulsive disorder (OCD) in a subject in need thereof, the method comprising: administering a therapeutically effective amount of an incretin analog to the subject.19325218025vlAttorney Docket No: 251609.000157

[0120] OCD is a mental health condition characterized by recurrent, persistent, and intrusive thoughts, urges, or images (obsessions) that cause significant anxiety or distress, and by repetitive behaviors or mental acts (compulsions) that an individual feels driven to perform in response to these obsessions or according to rigid rules. These obsessions and compulsions are time¬ consuming and / or cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

[0121] In some embodiments, the incretin analog is a glucagon-like peptide 1 (GLP-1) receptor agonist.

[0122] In some embodiments, the incretin analog is selected from the group consisting of semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, CJC-1134-PC, taspoglutide, efpeglenatide, tirzepatide, and any combinations thereof.

[0123] The incretin analog of this invention can be administered by a variety of routes including oral, rectal, intraocular, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intradermal, directly into cerebrospinal fluid, intratracheal, and intranasal.Depending on the intended route of delivery, the compounds of this invention are preferably formulated as injectable compositions. Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. The active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.

[0124] In some embodiments, the incretin analog is administered parenterally, orally, or intranasally.

[0125] In some embodiments, the parenteral administration comprises subcutaneous injection, intramuscular injection, intraperitoneal injection, and / or intravenous injection.

[0126] In some embodiments, the oral administration comprises capsules, tablets, caplets, pills, troches, lozenges, powders, and granules, and optionally the incretin analog is administered with sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC).

[0127] In some embodiments, the intranasal administration comprises intranasal drops, intranasal sprays, and / or nebulized formulations.

[0128] The active compound can be effective over a wide dosage range and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician,20325218025vlAttorney Docket No: 251609.000157according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0129] In some embodiments, the incretin analog is administered in a dose of 0.04 to 0.32 mg / kg.

[0130] In some embodiments, the incretin analog is administered in a dose of about 0.04 mg / kg to about 0.32 mg / kg. In some embodiments, the incretin analog is administered in a dose of about 0.04 mg / kg to about 0.32 mg / kg, for example in a dose of about 0.04 mg / kg to about 0.08 mg / kg, about 0.04 mg / kg to about 0.16 mg / kg, about 0.08 mg / kg to about 0.16 mg / kg, about 0.08 mg / kg to about 0.24 mg / kg, about 0.16 mg / kg to about 0.24 mg / kg, about 0.16 mg / kg to about 0.32 mg / kg, or about 0.24 mg / kg to about 0.32 mg / kg. In some embodiments, the incretin analog is administered in a dose of about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.10 mg / kg, about 0.11 mg / kg, about 0.12 mg / kg, about 0.13 mg / kg, about 0.14 mg / kg, about 0.15 mg / kg, about 0.16 mg / kg, about 0.17 mg / kg, about 0.18 mg / kg, about 0.19 mg / kg, about 0.20 mg / kg, about 0.21 mg / kg, about 0.22 mg / kg, about 0.23 mg / kg, about 0.24 mg / kg, about 0.25 mg / kg, about 0.26 mg / kg, about 0.27 mg / kg, about 0.28 mg / kg, about 0.29 mg / kg, about 0.30 mg / kg, about 0.31 mg / kg, about 0.32 mg / kg, about 0.34 mg / kg, about 0.36 mg / kg, about 0.38 mg / kg, about 0.40 mg / kg, about 0.42 mg / kg, about 0.44 mg / kg, about 0.46 mg / kg, about 0.48 mg / kg, about 0.50 mg / kg, about 0.55 mg / kg, about 0.60 mg / kg, about 0.65 mg / kg, about 0.70 mg / kg, about 0.75 mg / kg, about 0.80 mg / kg, about 0.85 mg / kg, about 0.90 mg / kg, about 0.95 mg / kg, or about 1.00 mg / kg.

[0131] In some embodiments, the incretin analog is administered once per week for a first period of one week at a dose of 0.04 to 0.08 mg / kg. In some embodiments, the incretin analog is administered once per week for a first period of one week at a dose of about 0.04 mg / kg to about 0.08 mg / kg. In some embodiments, the incretin analog is administered once per week for a first period of one week at a dose of about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, or about 0.08 mg / kg.

[0132] In some embodiments, the incretin analog is administered once per week. In some embodiments, the incretin analog is administered once per day, once every other day, once every21325218025vlAttorney Docket No: 251609.000157three days, twice per week, once per week, once every other week, twice per month, or once per month.

[0133] In some embodiments, the incretin analog is administered once per week following the first period of one week at a dose of 0.04 to 0.32 mg / kg. In some embodiments, the incretin analog is administered once per week following the first period of one week at a dose of about 0.04 mg / kg to about 0.32 mg / kg. In some embodiments, the incretin analog is administered once per week following the first period of one week at a dose of about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.10 mg / kg, about 0.11 mg / kg, about 0.12 mg / kg, about 0.13 mg / kg, about 0.14 mg / kg, about 0.15 mg / kg, about 0.16 mg / kg, about 0.17 mg / kg, about 0.18 mg / kg, about 0.19 mg / kg, about 0.20 mg / kg, about 0.21 mg / kg, about 0.22 mg / kg, about 0.23 mg / kg, about 0.24 mg / kg, about 0.25 mg / kg, about 0.26 mg / kg, about 0.27 mg / kg, about 0.28 mg / kg, about 0.29 mg / kg, about 0.30 mg / kg, about 0.31 mg / kg, or about 0.32 mg / kg.

[0134] In some embodiments, the dose is the same in the first administration of the incretin analog compared to the dose of the following administrations of the incretin analog. In some embodiments, the dose is higher in the first administration of the incretin analog compared to the dose of the following administrations of the incretin analog. In some embodiments, the dose is lower in the first administration of the incretin analog compared to the dose of the following administrations of the incretin analog.

[0135] In some embodiments, the subject also receives counseling and / or therapy.

[0136] In some embodiments, the counseling is behavioral counseling.

[0137] Behavioral counseling is a type of therapy to modify maladaptive behaviors. It is action-based and greatly focused.

[0138] In some embodiments, the therapy is cognitive behavioral therapy and / or exposure and response prevention.

[0139] Exposure and response prevention involves an exposure component which refers to practicing confronting objects, situations, images, and thoughts that are anxiety inducing and / or obsession provoking and a response prevention component which refers to making a choice not to perform a compulsive behavior when the anxiety and / or obsession is triggered.22325218025vlAttorney Docket No: 251609.000157Method of treating anxiety

[0140] In a further aspect, provided herein is a method of treating anxiety in a subject in need thereof, the method comprising: administering a therapeutically effective amount of an incretin analog to the subject.

[0141] Anxiety is an emotional and physiological state characterized by feelings of tension, worried or apprehensive thoughts, and physical changes such as increased heart rate, restlessness, muscle tension, or difficulty concentrating, typically arising in anticipation of perceived threat or uncertainty. Anxiety becomes clinically significant when it is excessive, persistent, disproportionate to the actual situation, and interferes with daily functioning, relationships, or overall well-being.

[0142] In some embodiments, the incretin analog is a glucagon-like peptide 1 (GLP-1) receptor agonist.

[0143] In some embodiments, the incretin analog is selected from the group consisting of semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, CJC-1134-PC, taspoglutide, efpeglenatide, tirzepatide, and any combinations thereof.

[0144] The incretin analog of this invention can be administered by a variety of routes including oral, rectal, intraocular, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intradermal, directly into cerebrospinal fluid, intratracheal, and intranasal.Depending on the intended route of delivery, the compounds of this invention are preferably formulated as injectable compositions. Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. The active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.

[0145] In some embodiments, the incretin analog is administered parenterally, orally, or intranasally.

[0146] In some embodiments, the parenteral administration comprises subcutaneous injection, intramuscular injection, intraperitoneal injection, and / or intravenous injection.

[0147] In some embodiments, the oral administration comprises capsules, tablets, caplets, pills, troches, lozenges, powders, and granules, and optionally the incretin analog is administered with sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC).23325218025vlAttorney Docket No: 251609.000157

[0148] In some embodiments, the intranasal administration comprises intranasal drops, intranasal sprays, and / or nebulized formulations.

[0149] The active compound can be effective over a wide dosage range and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0150] In some embodiments, the incretin analog is administered in a dose of 0.04 to 0.32 mg / kg.

[0151] In some embodiments, the incretin analog is administered in a dose of about 0.04 mg / kg to about 0.32 mg / kg. In some embodiments, the incretin analog is administered in a dose of about 0.04 mg / kg to about 0.32 mg / kg, for example in a dose of about 0.04 mg / kg to about 0.08 mg / kg, about 0.04 mg / kg to about 0.16 mg / kg, about 0.08 mg / kg to about 0.16 mg / kg, about 0.08 mg / kg to about 0.24 mg / kg, about 0.16 mg / kg to about 0.24 mg / kg, about 0.16 mg / kg to about 0.32 mg / kg, or about 0.24 mg / kg to about 0.32 mg / kg. In some embodiments, the incretin analog is administered in a dose of about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.10 mg / kg, about 0.11 mg / kg, about 0.12 mg / kg, about 0.13 mg / kg, about 0.14 mg / kg, about 0.15 mg / kg, about 0.16 mg / kg, about 0.17 mg / kg, about 0.18 mg / kg, about 0.19 mg / kg, about 0.20 mg / kg, about 0.21 mg / kg, about 0.22 mg / kg, about 0.23 mg / kg, about 0.24 mg / kg, about 0.25 mg / kg, about 0.26 mg / kg, about 0.27 mg / kg, about 0.28 mg / kg, about 0.29 mg / kg, about 0.30 mg / kg, about 0.31 mg / kg, about 0.32 mg / kg, about 0.34 mg / kg, about 0.36 mg / kg, about 0.38 mg / kg, about 0.40 mg / kg, about 0.42 mg / kg, about 0.44 mg / kg, about 0.46 mg / kg, about 0.48 mg / kg, about 0.50 mg / kg, about 0.55 mg / kg, about 0.60 mg / kg, about 0.65 mg / kg, about 0.70 mg / kg, about 0.75 mg / kg, about 0.80 mg / kg, about 0.85 mg / kg, about 0.90 mg / kg, about 0.95 mg / kg, or about 1.00 mg / kg.

[0152] In some embodiments, the incretin analog is administered once per week for a first period of one week at a dose of 0.04 to 0.08 mg / kg. In some embodiments, the incretin analog is administered once per week for a first period of one week at a dose of about 0.04 mg / kg to about 0.08 mg / kg. In some embodiments, the incretin analog is administered once per week for a first24325218025vlAttorney Docket No: 251609.000157period of one week at a dose of about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, or about 0.08 mg / kg.

[0153] In some embodiments, the incretin analog is administered once per week. In some embodiments, the incretin analog is administered once per day, once every other day, once every three days, twice per week, once per week, once every other week, twice per month, or once per month.

[0154] In some embodiments, the incretin analog is administered once per week following the first period of one week at a dose of 0.04 to 0.32 mg / kg. In some embodiments, the incretin analog is administered once per week following the first period of one week at a dose of about 0.04 mg / kg to about 0.32 mg / kg. In some embodiments, the incretin analog is administered once per week following the first period of one week at a dose of about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.10 mg / kg, about 0.11 mg / kg, about 0.12 mg / kg, about 0.13 mg / kg, about 0.14 mg / kg, about 0.15 mg / kg, about 0.16 mg / kg, about 0.17 mg / kg, about 0.18 mg / kg, about 0.19 mg / kg, about 0.20 mg / kg, about 0.21 mg / kg, about 0.22 mg / kg, about 0.23 mg / kg, about 0.24 mg / kg, about 0.25 mg / kg, about 0.26 mg / kg, about 0.27 mg / kg, about 0.28 mg / kg, about 0.29 mg / kg, about 0.30 mg / kg, about 0.31 mg / kg, or about 0.32 mg / kg.

[0155] In some embodiments, the dose is the same in the first administration of the incretin analog compared to the dose of the following administrations of the incretin analog. In some embodiments, the dose is higher in the first administration of the incretin analog compared to the dose of the following administrations of the incretin analog. In some embodiments, the dose is lower in the first administration of the incretin analog compared to the dose of the following administrations of the incretin analog.

[0156] In some embodiments, the subject also receives counseling and / or therapy.

[0157] In some embodiments, the counseling is behavioral counseling.

[0158] In some embodiments, the therapy is pharmacotherapy, cognitive behavioral therapy, and / or exposure and response prevention. In some embodiments, the pharmacotherapy comprises the use of selective serotonin reuptake inhibitors (SSRIs).Administration of incretin analog

[0159] In some embodiments, the incretin analog is administered with an additional component (e.g., sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC) or leptin).25325218025vlAttorney Docket No: 251609.000157

[0160] In some embodiments, the incretin analog is administered with the additional component (e.g., SNAC or leptin) simultaneously, i.e., administered with a time separation of no more than about 15 minutes, such as no more than about any of 10, 5, or 1 minutes. When the incretin analog and the additional component are administered simultaneously, the incretin analog and the additional component may be contained in the same composition (e.g., a composition comprising both the incretin analog and the additional component) or in separate compositions (e.g., the incretin analog in one composition and the additional component in another composition).

[0161] In some embodiments, the incretin analog is administered with the additional component (e.g., SNAC or leptin) sequentially, i.e., administered with a time separation of more than about 15 minutes, such as more than about any of 20, 30, 40, 50, 60, or more minutes. Either the incretin analog or the additional component may be administered first. The incretin analog and the additional component are contained in separate compositions, which may be contained in the same or different packages or kits.

[0162] In some embodiments, the subject also receives counseling (e.g., nutritional counseling, behavioral counseling) and / or therapy (e.g., pharmacotherapy, cognitive behavioral therapy, exposure and response prevention).

[0163] In some embodiments, the incretin analog is administered with the performance of the counseling and / or therapy simultaneously, i.e., administered or performed with a time separation of no more than about 15 minutes, such as no more than about any of 10, 5, or 1 minutes. In some embodiments, the incretin analog is administered with the performance of the counseling and / or therapy sequentially, i.e., administered or performed with a time separation of more than about 15 minutes, such as more than about any of 20, 30, 40, 50, 60, or more minutes. Either the incretin analog or the counseling and / or therapy may be administered or performed first.

[0164] In some embodiments, the incretin analog is administered for a period of at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks,26325218025vlAttorney Docket No: 251609.000157about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, or longer.

[0165] The incretin analog as described herein can be present in a formulation that includes other agents, excipients, or stabilizers.

[0166] There are a wide variety of suitable formulations of the incretin analog disclosed herein. The formulations and methods described herein are merely exemplary and are in no way limiting. Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the incretin analog dissolved in diluents, such as water, saline, or orange juice, (b) capsules, sachets or tablets, each containing a predetermined amount of the incretin analog, as solids or granules, (c) suspensions in an appropriate liquid, and (d) suitable emulsions. Tablet forms can include one or more of lactose, mannitol, com starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients. Lozenge forms can comprise the incretin analog in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the incretin analog in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the incretin analog, such excipients as are known in the art.

[0167] Examples of suitable carriers, excipients, and diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline solution, syrup, methylcellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate, and mineral oil. In some embodiments, the incretin analog as discussed herein is present in a dry formulation (such as lyophilized composition). The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. Suitable carriers and formulations are known to the skilled artisan and are described in detail in the scientific and patent literature, see e.g., the latest edition of Remington's Pharmaceutical Science, Mack Publishing Company, Easton, Pa. (“Remington's”).27325218025vlAttorney Docket No: 251609.000157

[0168] In some embodiments, the formulations may be administered by any route which results in a therapeutically effective outcome. These include but are not limited to administered intravenously, intraarterially, intraperitoneally, intravesicularly, subcutaneously, intrathecally, intrapulmonarily, intramuscularly, intratracheally, intraocularly, transdermally, orally, or by inhalation.

[0169] Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation compatible with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described. Injectable formulations are preferred.

[0170] Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The formulations can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the incretin analog can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Suitable formulations for parenteral administration may contain substances which increase viscosity, for example, sodium carboxymethyl cellulose, sorbitol, and / or dextran. Optionally, the formulation may also contain stabilizers.

[0171] For administration by inhalation, the incretin analog according to the present disclosure can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoro-methane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the incretin analog and a suitable powder base such as lactose or starch.28325218025vlAttorney Docket No: 251609.000157

[0172] In some embodiments, the formulation has a pH range of about 4.5 to about 9.0, including for example pH ranges of about any of 5.0 to about 8.0, about 6.5 to about 7.5, and about 6.5 to about 7.0. In some embodiments, the pH of the composition is formulated to no less than about 6, including for example no less than about any of 6.5, 7, or 8 (such as about 8). The composition can also be made to be isotonic with blood by the addition of a suitable tonicity modifier, such as glycerol.

[0173] Dose-response curves derived from animal systems (e.g., mice) can be used to determine testing doses of the incretin analog for administration to humans. In safety determinations for the incretin analog, the dose and frequency of administration should meet or exceed those anticipated for use in any clinical trial.Compositions

[0174] In another aspect, provided herein is a composition comprising: a therapeutically effective amount of an incretin analog; and a food product and / or a beverage.

[0175] The composition for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. Liquid forms suitable for oral administration may include a suitable aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors, and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0176] In some embodiments, the incretin analog is a glucagon-like peptide 1 (GLP-1) receptor agonist.

[0177] In some embodiments, the incretin analog is selected from the group consisting of semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, CJC-1134-PC, taspoglutide, efpeglenatide, tirzepatide, and any combinations thereof.

[0178] In some embodiments, the composition further comprises sodium N-(8-[2-hydroxy benzoyl] amino) caprylate (SNAC).

[0179] In some embodiments, the food product is a nutritional bar or an energy bar.29325218025vlAttorney Docket No: 251609.000157

[0180] In some embodiments, the beverage is water, a nutritional beverage, an energy beverage, or a protein shake.

[0181] In some embodiments, the incretin analog is present in an amount of 1-7 mg. In some embodiments, the incretin analog is present in an amount of about 1 mg to about 7 mg. In some embodiments, the incretin analog is present in an amount of about 0.1 mg to about 100 mg. In some embodiments, the incretin analog is present in an amount of about 0.1 mg to about 100 mg, for example in an amount of about 0.1 mg to about 1 mg, about 1 mg to about 7 mg, about 1 mg to about 10 mg, about 5 mg to about 10 mg, about 10 mg to about 25 mg, about 10 mg to about 50 mg, or about 50 mg to about 100 mg. In some embodiments, the incretin analog is present in an amount of about 0.1 mg, about 0.25 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg. In some embodiments, the incretin analog is present in an amount of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, or about 7 mg.EXAMPLES

[0182] The following examples are provided to further describe some of the embodiments disclosed herein. The examples are intended to illustrate, not to limit, the disclosed embodiments.General Methods

[0183] Below are the methods used in the Examples.

[0184] Animal Model: The ABA model has been described (Routtenberg and Kuznesof, 1967).

[0185] ABA paradigm and treatment strategy: Chow-fed female C57BL / 6JC mice were subjected to the standard ABA protocol. Studies in Examples 1-4 used thirty-five (35) mice. On postnatal day 36 (P36), the mice were single housed and randomly assigned into two groups: control (vehicle) group and treatment (semaglutide) group. The paradigm is comprised of an acclimation phase, where the animals acclimate to their individual housing with the running wheel available all day and food available on an a d libitum basis. After four days of30325218025vlAttorney Docket No: 251609.000157acclimatization, mice were subject to three days of food restriction (Figure 7), with free access to food for only three hours each day. To avoid unnecessary death, animals were removed from the ABA when body weight dropped below 75% of baseline. Semaglutide was first administered in the second day of acclimatization and then daily via intraperitoneal (IP) injection at varying doses (0.04-0.32 mg / kg) (Peterson et al., 2017; Hansen et al., 2021; Ghidewon et al., 2022). Studies in Examples 1-4 used semaglutide administered at 0.04 mg / kg, or 9.70 nmol / kg.Corresponding control groups were administered daily IP injections of a vehicle (0.9% saline or PBS+1.6% DMSO) solution. Studies in Examples 1-4 used vehicle solution of PBS (8% DMSO). Since mice metabolize drugs more rapidly than humans, the protocol calls for daily injections with semaglutide, while weekly treatment is standard in humans. After the seventh day of the paradigm, the mice were given free access to food again, and the running wheel was taken out of the cage to facilitate recuperation for one week before undergoing the zero maze and marble bury behavioral tests. Injections persisted during the refeeding period. Measurements were collected with a Promethion™ high-definition multiplexed respirometry cage for mice, with compartments and components for water, food hopper, body mass habitat, and intake manifold (Figure 6). This Promethion™ Core® metabolic and behavioral phenotyping system for rodents from Sable Systems International was used to continuously track and analyze the behavioral and metabolic profile of the mice, including measurements of wheel-running activity, energy expenditure, respiratory exchange ratio, and anxiety-like behaviors. A 12 hour light / 12 hour dark cycle was defined with 7:00 AM as zeitgeber time zero (ZT0), and 19:00 as zeitgeber time twelve (ZT12)-

[0186] Metabolic assessments: Mice were single caged in metabolic chambers (Promethion™ Live v23.0.01, Sable Systems) for monitoring of food intake, body weight, energy expenditure, respiratory exchange rate (VCO2 / VO2), ambulatory and running activity. Body composition was measured through EchoMRI™. Serum leptin and insulin levels were measured through a commercial ELISA kit (Crystal Chem, Catalog # 90030 and #90080). Blood glucose and ketone bodies were measured through commercial detection strips (True Metrix or Precision Xtra).

[0187] RT-qPCR: Animals were deeply anesthetized with ketamine and xylazine and killed by decapitation. Tissues were collected and frozen in liquid nitrogen. Total RNA was extracted from mouse tissues using RNeasy® lipid mini kit (Qiagen). Complementary DNA was reverse transcribed (Qiagen) and amplified with SYBR Green Supermix (Bio-Rad) using a QuantStudio31325218025vlAttorney Docket No: 251609.0001576 Pro real-time PCR system (Applied Biosystems). Data was normalized to the expression of G3pdh. The following primers were used as in Table 1.Gene Primer sequenceAgrp Forward: 5’-CGG AGG TGC TAG ATC CAC AGA-3’ (SEQ ID NO: 1)Reverse: 5’-AGG ACT CGT GCA GCC TTA CAC-3’ (SEQ ID NO: 2) Npy Forward: 5’-CAG AAA ACG CCC CCA GAA-3' (SEQ ID NO: 3)Reverse: 5’-AAA AGT CGG GAG AAC AAG TTT CAT T-3’ (SEQ ID NO: 4)G3pdh Forward: 5’-GAGCTGAACGGGAAGCTCAC-3’ (SEQ ID NO: 5)Reverse: 5’-ACCACCCTGTTGCTGTAGC-3’ (SEQ ID NO: 6)Table 1. Primers for RT-qPCR.

[0188] Animals and drug administration: Animals (4-8 weeks old) were housed under standard laboratory conditions on a 12-hour light / 12-hour dark cycle with ad libitum access to standard chow and water. Animals were single caged either in standard animal facility cages or in the Promethion™ metabolic and behavioral phenotyping system. AgRPDTRor wild-type mice from the same litter were injected with diphtheria toxin (50 µg / kg) between P3-P5 and ablation was confirmed by immunohistochemistry. AgRP-Cre and AgRP-Sirtl KO lines have been previously described Cavalcanti-de- Albuquerque et al., 2019). Semaglutide (items no. 29969 and no. 40170) was purchased from Cayman Chemical, dissolved in either PBS or PBS+DMSO (1.6%), and administrated daily via i.p. injections (160 ng / g or 40nmol / kg / day).

[0189] Behavioral Tests: Open Field Test: The two-phase open field apparatus consists of a Plexiglas open field (37 cm x 37 cm x 37 cm). Mice were first put in the open field for 5 minutes (exploratory stage). Immediately after, mice were returned to their home cages for 2 minutes. A new object (an assembled Lego toy) was placed in the center of the arena. Mice were then returned to the open field for an additional 5 minutes (novelty phase). Animals were tracked and parameters were quantified through AnyMaze software (Stoelting). Marble-burying test: The marble-burying test was performed following the standard procedure (Deacon, 2006; Gyertyan, 1995 ). Animals were inserted in a cage containing 5 cm of corn-based animal bedding with 25 blue or white marbles, displayed in alternation in 5 different rows of 5 marbles, and allowed to interact with the marbles for 30 minutes. Marbles with 2 / 3 of the marble under the bedding were considered as buried. Spontaneous wheel running: Spontaneous activity was assessed through PromethionrMLive system, with animals with ad libitum access to a running wheel for three days. Nest building: Nest building test was performed by providing a cotton nest to the animals 32325218025vlAttorney Docket No: 251609.000157and weighing unused cotton after 24 hours. Nest formation was defined as subtraction between initial and final cotton weight. Elevated Zero-Maze: The zero maze comprises a raised circular platform with two opposite enclosed quadrants and two open quadrants. The apparatus has a 50-cm diameter, 5-cm lane width, 15-cm wall height and 40-cm elevation. Mice were allowed uninterrupted exploration and recorded for 10 minutes; mice were tracked using Zero-Maze Any- maze video tracking software (Stoelting, no. 60000). The zero maze comprises a raised circular platform with two enclosed quadrants and two open quadrants, opposite of one another. The platform has a diameter of 50 cm, a lane width of 5 cm, a wall height of 15 cm, and is elevated by 40 cm (Stoelting, no. 68016).

[0190] Statistical Analysis: GraphPad Prism (v.10.2.2) and Microsoft Excel Version 16.85 were used for the analysis and visualization of data. Sample sizes adhered to standard practices in animal behavior experiments. Data outliers were mined before statistical analysis. Data were expressed as mean + s.d. for metabolic parameters and mean + s.e.m for behavioral data.Statistical analysis was done through Student’s t-test or two-way ANOVA, whenever two variables were being assessed (e.g., treated vs. non-treated, non-mutant vs. mutant). Statistical significance was established whenever alpha levels were below 0.05.Example 1. Validating drug efficacy.

[0191] During acclimatization, no differences were found in food intake (Figure 8A) or body weight (Figure 8B) between the groups. Surprisingly, this trend continued during food restriction. While food intake progressively but sharply decreased throughout the paradigm, as expected, semaglutide did not significantly impact the rate of feeding (Figure 8A). hi 2022, the FDA approved semaglutide to treat obesity in children ages 12+ (BMI ≥ 95thpercentile). While GLP-1 agonists are known to reduce food intake resulting in significant weight loss (Dietrich and Horvath, 2012), these results have been tested exclusively on overweight and obese individuals and in lab animals with diet-induced obesity, not in lean peripubertal female mice. Semaglutide had not been tested on lean adolescents. This phenotypic difference in lean female mice caused questioning of the efficacy of the semaglutide administered. Thus, to validate these results, magnetic resonance imaging was used to analyze body composition. It was found that semaglutide significantly reduced fat mass in mice who have undergone the ABA paradigm, compared to controls (Figure 8C).33325218025vlAttorney Docket No: 251609.000157Example 2. Semaglutide decreased locomotion in ABA mice.

[0192] It was found that semaglutide notably decreased wheel running activity in mice exposed to the ABA model (Figures 8D-8G). Running activity, measured in number of wheel revolutions and distance traveled, decreased every day following the initial injection of semaglutide. There is statistical significance on the first day of drug administration and all three days of calorie restriction. During the traditional ABA model, mice paradoxically exhibit a hyperactive behavioral profile following the 24-hour onset of food restriction,modeling key phenotype development in AN. The negative energy balance is associated with repetitive and compulsive displacement behaviors, such as excessive exercise, which leads to further weight loss and exhaustion (Davis and Kaptein, 2006; Miletta, et al., 2020). Prolonged starvation promotes a negative-valence teaching signal (Betley, et al., 2015). Moreover, when the neural signal of hunger is ignored / suppressed, the central nervous system will orchestrate a complex series of anxiolytic behavioral responses and alter peripheral changes in metabolism (Betley, et al., 2015; Dietrich and Horvath, 2012; Davis and Kaptein, 2006). The satietogenic effect of semaglutide may justify the reduction of stereotypic displacement behaviors, such as wheel running, which arise in the absence of food. The mechanism of action in which semaglutide reduces hyperactivity is unknown. Patients with an excessive exercise counterpart to AN are more likely to have slower rates of recovery, higher chances of relapse, and longer and more frequent inpatient treatments (Davis and Kaptein, 2006; Casper, 1998; Strober et al., 1997; Carter et al., 2004). Thus, surprisingly, semaglutide may help patients recover from AN by reducing locomotion.Example 3. Semaglutide reduces basal metabolic rate (BMR) and respiratory quotient (RO).

[0193] Energy balance is found between energy intake (e.g., food intake) and energy expenditure (e.g., basal metabolism, thermogenesis, and physical activity) (Heaney, 2013). A lower basal metabolic rate and lower work energy leads to fewer calories burned and thus, minimizing the caloric deficit. Anorexic ABA mice given semaglutide experienced a decrease in BMR.34325218025vlAttorney Docket No: 251609.000157

[0194] The BMR of the mice was calculated using Promethion™ Core® metabolic and behavioral phenotyping system. The system calculates energy expenditure (EE) via the Weir RQ-free equation: metabolic rate (kcal / day) = (3.94 x VO2) + (1.1 x VCO2). VO2is oxygen consumption and VCO2is carbon dioxide production. The energy expenditure was measured in vehicle-treated mice vs. semaglutide -treated mice (Figures 9A, 9B).

[0195] Semaglutide was found to decrease energy expenditure in ABA mice. This decrease was observed one day before calorie restriction and continued the first day of intermittent fasting. A decrease was seen on days six and seven, though not significantly (Figures 9A, 9B).The reduction in BMR, along with the decrease in wheel running, show enhanced metabolic adaptive response to the ABA paradigm. These peripheral metabolic changes helped reduce the caloric deficit. In a study of humans with obesity, weight loss linked to semaglutide was not attributed to increased energy expenditure, but rather reduced caloric intake, changes in appetite, and a lower preference for high-fat foods (Blundell et al., 2017). The data herein suggest semaglutide may lower the metabolic rate in lean mice exposed to ABA conditions.

[0196] Semaglutide reduced respiratory quotient (RQ) in ABA mice. The RQ as the respiratory exchange ratio (RER) was measured in vehicle-treated mice vs. semaglutide-treated mice (Figure 9C). RER is the ratio between the amount of CO2being eliminated and the amount of O2being consumed. Higher values of RER indicate greater anaerobic metabolism, indicating a greater use of carbohydrates as the fuel source for the body (e.g., greater carbohydrate oxidation), whereas lower values of RER indicate greater aerobic metabolism, indicating a greater use of lipids as the fuel source for the body (e.g., greater fat oxidation). Semaglutide was found to reduce the RQ in ABA mice. This significant reduction in RER supports the hypothesis that semaglutide encourages lipid utilization (i.e., the process of metabolizing fat).

[0197] Surprisingly, AN patients have high serum cholesterol levels. Plasma cholesterol concentration has been shown to increase 300-500% during starvation (Swaner, 1975). This phenomenon may be due to cortisol-induced hyperglycemia (Schmalbach et al., 2020) and / or the release of cholesterol stored in lipid droplets of the adipose tissue into plasma (Swaner, 1975). This suggests that semaglutide could reduce hypercholesterolemia in AN.35325218025vlAttorney Docket No: 251609.000157Example 4. Semaglutide promotes exploratory behavior in weight-restored ABA mice.

[0198] Food restriction-evoked wheel-running is highly correlated with anxiety-like behaviors in female mice (Francois and Zeltser, 2022; Kucukdereli, et al., 2023; Miletta, et al., 2020). The prevalence of obsessive-compulsive symptoms often persists after body weight has been restored (O’Dwyer et al., 1996; Chen et al., 2017). The potential influence of semaglutide was assessed on the stereotypic behavior profile of mice after weight restoration from the ABA paradigm. On P43, all mice entered a week-long refeeding period, where free access to food again was returned, find the running wheel was taken away to facilitate recovery. Mice refed for a one-week minimum before they underwent behavioral testing.

[0199] Behavior was assessed in an elevated zero maze, a well-established apparatus for assessing anxiety-like behavior in rodents (Kulkarni et al., 2007). Various parameters of fin elevated zero maze test were measured in vehicle-treated mice vs. semaglu tide-treated mice (Figures lOB-lOC ). The elevated arena comprises two closed areas and two open areas (Figure 10A). The open areas are anxiogenic, i.e., anxiety inducing. Mice given semaglutide spent more time in the open-armed zone (Figure 10B) and had a greater latency to exit the open-armed zone (Figure IOC), known as the time before the first inhibitory avoidance behavior (Conde et al., 2000). Both results point to a reduction in harm-avoidance behaviors upon semaglutide treatment. This indicates less anxiety in mice treated with semaglutide. Hunger neurons transmit a negative- valence teaching signal (Betley et al., 2015). Semaglutide blunts this negative valence. This anxiolytic, i.e., anxiety reducing, effect promotes exploratory behavior. Mice given semaglutide spent a similar time freezing to mice treated with vehicle.

[0200] The marble-burying test was conducted, used as a metric for obsessive-compulsive behavior (Deacon, 2006; Gyertyan, 1995). The percent of marbles buried of a marble bury test was measured in vehicle-treated mice vs. semaglutide -treated mice (Figures 10D, 10E). The results of the marble burying test indicated that mice treated with semaglutide exhibited a decrease in the number of marbles buried compared to the control group. Semaglutide was found to reduce displacement behaviors and to prevent repetitive behavior in weight restored mice exposed to ABA paradigm. This anxiolytic, i.e., anxiety reducing, effect diminishes displacement behaviors. Indeed, the results indicate that semaglutide reduced the stereotypic behavioral phenotype development of mice in the ABA model.36325218025vlAttorney Docket No: 251609.000157

[0201] While it is intuitively presumed that anti-obesity drugs, such as semaglutide, would be detrimental to individuals with anorexia, the far-reaching effects of incretin analogs on reward and fear-related behaviors may suggest otherwise. Specifically, the data herein showed that semaglutide inhibited the advancement of stereotypic behaviors in mice exposed to the ABA paradigm, compared to controls. Unlike obese subjects, semaglutide did not significantly reduce food intake or body weight, but it did decrease fat mass in peri-pubertal female mice. Instead of adjusting food intake, semaglutide diminished phenotype development in the ABA paradigm by decreasing both wheel locomotion and basal metabolic rate. Further, semaglutide significantly reduced respiratory quotient, which indicates an increase in fat utilization and explains the observed changes in fat mass.

[0202] Semaglutide has not been shown to modulate substrate utilization in individuals with obesity (30thEuropean Congress on Obesity, 2023), pointing to another divergence in semaglutide efficacy between obese and anorexic subjects. Vulnerability to food restriction-evoked wheel running activity was highly correlated with anxiety-like behaviors in female mice (Davis and Kaptein, 2006; Wable, et al., 2015); consequently, previous studies of mice exposed to the ABA paradigm showed elevated anxiety-like behavior, even following weight restoration (Davis and Kaptein, 2006; Chen et al., 2017; Peterson, et al., 2017). Semaglutide blunted this hunger-induced hyperactivity in mice exposed to the ABA paradigm, which promotes exploratory behavior and minimizes negative behavioral consequences of anorexia nervosa in an animal model, as evidenced through behavioral testing. To identify the mechanism of action of semaglutide on AN-related phenotype development may be further studied. In addition, testing of the observed effects of semaglutide in other species, including humans, is warranted given the findings that support therapeutic value as provided herein.Example 5. AgRP neurons are necessary for semaglutide metabolic effects.

[0203] Agouti-related peptide (AgRP)-expressing neurons are fundamental for driving feeding and foraging behaviors (Dietrich, et al., 2017), as well as coordinating systemic metabolism to supply energetic demands (Cavalcanti-de-Albuquerque, et al., 2019; Steculorum, et al., 2016). While studies revealed that semaglutide inhibits AgRP activity (Dong, et al., 2021; Martins, et al., 2023), these effects appear to be indirectly mediated by other neuronal populations (Hansen, et al., 2021; Huang, et al., 2022; Su, et al., 2017; Webster, et al., 2024). It was studied herein37325218025vlAttorney Docket No: 251609.000157whether AgRP neurons are relevant for the sustained action of semaglutide on maintained lower weight loss and related behavior adaptations.

[0204] To study the impact of AgRP neurons on semaglutide activity, AgRP neurons were ablated through cell-specific expression of diphtheria toxin receptor (AgRPDTR, Figure HA). Female AgRPDTRmice treated daily with semaglutide lost weight to the same extent as their respective controls after one day of treatment, reached a plateau where they stopped losing weight despite maintained dosage, and then gradually returned to baseline levels after 9 days, as opposed to controls (Figure HB) and male AgRPDTRtreated mice, supporting a sex-specific role for AgRP neurons (Figures 14A, 14B). Drop in body weight was accompanied by acute decrease in energy expenditure in wild-type, but not in AgRPDTRfemale mice (Figure 11C). Ablation of AgRP also impaired the sustained hypoglycemic effects of semaglutide, as treated AgRPDTRmice displayed the same levels as their respective controls, without altering blood ketone bodies levels (Figure HD). Gene expression analysis revealed no alteration in hypothalamic Agrp and Npy levels 2 days post-injections (dpi), but both genes were upregulated after 15 days of treatment with semaglutide (Figure HE). To further explore a mechanism behind the AgRP-mediated sustained weight-loss, the effect of semaglutide on Sirtl expression was evaluated. Sirtuins are NAD+-dependent deacetylases activated under negative energy balance, known for promoting central metabolic adaptations via the melanocortin system, particularly through AgRP / NPY neurons (Dietrich, et al., 2010).

[0205] To assess the necessity of Sirtl signaling in AgRP neurons for the sustained effects of semaglutide, mice with AgRP-specific knockout of Sirtl were generated (AgRP-S7rt7 KO, Figure HF). This study showed the same gradual recovery of baseline body weight in AgRP-Sirtl KO mice treated daily with semaglutide, displaying partial and full recovery by the 5thand 9thday, respectively (Figure 11G). Nuclear magnetic resonance analysis revealed a reduction in body fat mass in both wild-type and AgRP-Szrt / KO mice 2 days after semaglutide injection (Figure 11H). However, in female KO mice, fat mass returns to control levels after 15 days, with no significant alteration in lean mass, indicating a crucial role for Sirtl signaling in AgRP neurons for sustained fat loss (Figure 11H). Semaglutide increased insulin and reduced leptin levels in the blood of wild-type mice (Figure HI). In contrast, Sirtl knockout in AgRP neurons blunted the effect on circulating insulin and increased leptin concentration in response to treatment (Figure HI). In agreement, AgRP-Sirtl KO mice were insensitive to the38325218025vlAttorney Docket No: 251609.000157hypoglycemic effects of semaglutide and have the same blood ketone levels in comparison to controls (Figure 11J). These data support that metabolic alterations promoted by semaglutide depend on activation of Sirtl in AgRP neurons, which is consistent with the described role of this protein in metabolic adaptations under negative energy states.Example 6. AgRP neurons are necessary for semaglutide anxiolytic effects.

[0206] Given the interaction of semaglutide with AgRP neurons, and their role in adaptative stereotypic behaviors, its effect was assessed on anxiety-like parameters. In a two-phase open field test, AgRP-Sj rtl KO mice displayed ari anxiogenic response, decreasing the time and number of explorations to the center zone, although increasing latency to the center (Figures 12A-12C). Semaglutide also significantly decreased nest building after short-term treatment (2 dpi) (Figure 12D), but not after long-term treatment (15 days) (Figure 12E), which was blunted by knockout of Sirtl in AgRP neurons. Additionally, semaglutide reduced marble burying (Figure 12F) and spontaneous wheel running in wild types, but not in mice with AgRP loss-of-function (Figure 12G), suggesting that semaglutide modulates compulsive-like behaviors through an AgRP- and Sirtl -dependent mechanism.

[0207] Based on the observed behavioral effects of semaglutide treatment, it was investigated whether semaglutide could mitigate anxiety-like related behaviors in metabolo-psychiatric conditions like anorexia nervosa (AN). To assess this, female mice were submitted to the activity- based anorexia (ABA) paradigm, a widely preclinical model of AN characterized by calorie restriction (CR)-induced compulsive running (see methods). Treatment with semaglutide significantly increased the time in the open arms of the Zero-Maze apparatus (Figure 12H), while simultaneously decreased latency to explore this compartment in mice submitted to the ABA (Figure 121) and decreased number of buried marbles (Figure 12J), suggesting that semaglutide prevents the development of anxiety- and compulsive-like behaviors in a model of AN. Because starvation promotes metabolic stress, incretin analogs may be a counterintuitive yet novel intervention for patients with AN. By diminishing the phenotype development of mice in an activity-based anorexia model, semaglutide could be a novel approach to treating AN. This idea is quite significant, as patients with an excessive exercise counterpart to AN are more likely to have slower rates of recovery, higher chances of relapse, and longer and more frequent inpatient treatments (Young, et al., 2018).39325218025vlAttorney Docket No: 251609.000157Example 7. Semaglutide prevents development of activity-based anorexia through AgRP.

[0208] To further characterize the therapeutic potential of semaglutide for AN, a dose-response curve (Figures 15A-15H) was established and the behavioral and metabolic profile of semaglutide-treated AgRPDTRand wild type mice submitted to the ABA were assessed through indirect calorimetry (Figure 13A). Control mice displayed increased running activity when calorie restricted, the major hallmark of the compulsive-like effects of the ABA paradigm (Figure 13B). Treated animals displayed decreased running activity during the CR phase (Figure 13B) with no significant effects on ambulatory activity, discarding a general locomotor impairment and supporting an anxiolytic-like effect (Figure 13C). Ablation of AgRP neurons blunted the effect of semaglutide on compulsive running, supporting an AgRP-dependent mechanism (Figure 13B). Despite its weight-loss effects, semaglutide had no synergic effect with CR on body weight and semaglutide-treated mice displayed stable body weight during food restriction (Figure 13D). Acute appetite-suppressing effects of semaglutide were observed, but no significant difference was detected during CR phase (Figure 13E). Control vehicle mice displayed high energy expenditure during CR, while semaglutide-treated mice had a reduced energy expenditure, consistent with its effects on running behavior (Figure 13F). Analysis of blood glucose and ketone bodies levels revealed that vehicle control animals displayed a drop in glucose (Figure 13G) and increase in ketone bodies (Figure 13H) when subjected to CR.Respiratory Exchange Rate (RER), a metric for substrate utilization, showed that semaglutide- treated control mice displayed lower RER (Figure 131), indicative of fat utilization as body fuel, while AgRPDIRtreated mice lacked this decrease in RER (Figure 131), supporting the necessity of these cells for semaglutide-induced changes in substrate utilization.

[0209] The data herein highlights the necessity of hypothalamic circuitry for the effects of GLP-1R agonists on glycemia and weight-loss (Huang, et al., 2022; Müller, et al., 2012; Secher, et al., 2014). Herein it is proposed that semaglutide operates through temporally distinct mechanisms that converge on AgRP neurons for sustained metabolic effects through a Sirtl- dependent pathway. Ablation of Glpl r-positive cells in the Arcuate Nucleus has no effect on semaglutide-induced weight loss and appetite suppression, describing a dispensable role for this region in the effects of GLP-1R agonists (Huang, et al., 2024). Previous findings were replicated40325218025vlAttorney Docket No: 251609.000157showing that AgRP neurons do not express GLP-1R (He, et al., 2019; Campbell, et al., 2017), and thus the above-mentioned method would not capture their role in the actions of semaglutide.

[0210] Measurement of in vivo calcium dynamics in AgRP neurons after acute administration of GLP-1R agonists showed no effect on neuronal activity (Beutler, et al., 2017; Su, et al., 2017), but a 24-hour pre-treatment with liraglutide completely mitigated AgRP activation in response to food, supporting an indirect but critical effect on AgRP activity (Dong, et al., 2021). The identity of the neuronal populations providing input to AgRP neurons in response to GLP-1R activation are unknown, but the paraventricular and dorsomedial hypothalamic nuclei are major sources of afferents to AgRP cells (Webster, et al., 2024).

[0211] The data herein showed a decrease in leptin and increase in insulin levels in semaglutide-treated mice, suggesting the potential use of GLP-1R agonists to restore leptin sensitivity and use it in combination with leptin analogs to enhance weight-loss (Clemmensen, et al., 2014; Müller, et al., 2012) or to improve glycemic control (Kapitza, et al., 2017). Knockout of AgRP-Szr / 7 increased leptin levels while blunting insulin release, supporting an unrecognized role for this protein in regulating systemic insulin and leptin levels in response to sustained treatment with a GLP-1R agonist.

[0212] In addition to their metabolic functions, AgRP neurons also coordinate foraging behaviors (Dietrich, et al., 2017). The data herein showed that semaglutide modulates anxietylike related behaviors, such as wheel running, nest building, and marble bury, through an AgRP-dependent pathway, and is therefore a potential treatment of metabolic-related psychiatric conditions (Miletta, et al., 2020), given the discovered effects on the ABA paradigm, i.e., the most widely used model for this condition. The data herein supports a critical role for AgRP neurons in the development of psychiatric disorders (Dietrich, et al., 2017; Miletta, et al., 2020), particularly those with a metabolic facet like Anorexia Nervosa.

[0213] Collectively, the present work provides evidence for the necessity of AgRP neurons in mediating the effect of semaglutide in the maintenance of body mass and for the control of anxiety-like behavior in female mice, and reports for the first time a role for central Sirtl signaling in AgRP cells for the maintenance of weight loss promoted by semaglutide. These findings have implications for understanding how GLP-1R agonists operate and, consequently, offer insight for optimization of their therapeutic use.41325218025vlAttorney Docket No: 251609.000157References1. 30thEuropean Congress on Obesity (ECO 2023). (2023). Obesity Facts, 16 (Suppl.1), 1- 351.2. American Psychiatric Association. (2013). Diagnostic & Statistical Manual of Mental Disorders, 5thedition.3. Anderson, I. M. (2000). Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J. Affect. Disord., 58(1): 19- 36. doi: 10.1016 / sOl 65-0327(99)00092-0.4. 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A., Frommolt, P., Brinkkotter, P. T., Hammerschmidt, P., Benzing, T., Rahmouni, K.,.. Bruning, J. C. (2016). AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue. Cell, 165(1), 125-138. doi: 10.1016 / j.cell.2016.02.04469. Strober, M., Freeman, R., & Morrell, W. (1997). The long-term course of severe anorexia nervosa in adolescents: Survival analysis of recovery, relapse, and outcome predictors over 10-15 years in a prospective study. International Journal of Eating Disorders, 22(4), 339-360.70. Su, Z„ Alhadeff, A. L., & Betley, J. N. (2017). Nutritive, Post-ingestive Signals Are the Primary Regulators of AgRP Neuron Activity. Cell Rep, 21(10), 2724-2736. doi:10.1016 / j.celrep.2017.11.03671. Swaner, J. C., Connor, W. E. (1975). Hypercholesterolemia of total starvation: its mechanism via tissue mobilization of cholesterol. American Journal of Physiology- Legacy Content. 229:2, 365-369.72. Toal, M. (2024). 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PMCID:PMC6097933.77. Wable, G. S., Min, J.-Y., Chen, Y.-W., Aoki, C. (2015). Anxiety is correlated with running in adolescent female mice undergoing activity-based anorexia. Behavioral Neuroscience, 129(2), 170-182.78. Webster, A. N., Becker, J. J., Li, C., Schwalbe, D. C., Kerspern, D., Karolczak, E. O., Bundon, ('.. Onoharigho, R. A., Crook, M., Jalil, M., Godschall, E. N., Dame, E. G., Dawer, A., Belmont-Rausch, D. M., Pers, T. H., Lutas, A., Habib, N., Guler, A. D., Krashes, M. J., & Campbell, J. N. (2024). Molecular Connectomics Reveals a Glucagon- Like Peptide 1 Sensitive Neural Circuit for Satiety. bioRxiv. doi:10.1101 / 2023.10.31.56499079. Wiepkema, P. R. (1987). Developmental aspects of motivated behavior in domestic animals. J Anim Sci, 65(5): 1220-7. doi: 10.2527 / asl987.6551220x. PMID: 3320004. 80. Young, S., Touyz, S., Meyer, C., Arcelus, J., Rhodes, P., Madden, S., Pike, K„ Attia, E., Crosby, R. D., & Hay, P. (2018). Relationships between compulsive exercise, quality of life, psychological distress and motivation to change in adults with anorexia nervosa. J Eat Disord, 6, 2. doi: 10.1186 / s40337-018-0188-081. Zribi, S., Chambon, ().. Cottraux, J. (1989). Anorexia nervosa. A frequent antecedent of obsessive-compulsive disorder. L’Encephale, 15(3), 355-358.50325218025vlAttorney Docket No: 251609.000157

[0214] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

[0215] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety as if physically present in this specification.51325218025vl

Claims

Attorney Docket No: 251609.000157CLAIMS1. A method of treating anorexia nervosa (AN) in a subject in need thereof, the method comprising:administering a therapeutically effective amount of an incretin analog to the subject.

2. The method of claim 1, wherein the incretin analog is a glucagon- like peptide 1 (GLP-1) receptor agonist.

3. The method of claim 1 or claim 2, wherein the incretin analog is selected from the group consisting of semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, CJC-1134-PC, taspoglutide, efpeglenatide, tirzepatide, and any combinations thereof.

4. The method of any one of claims 1-3, wherein the incretin analog is administered parenterally, orally, or intranasally.

5. The method of claim 4, wherein the parenteral administration comprises subcutaneous injection, intramuscular injection, intraperitoneal injection, and / or intravenous injection.

6. The method of claim 4, wherein the oral administration comprises administration with a food product and / or a beverage, and optionally wherein the incretin analog is administered with sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC).

7. The method of claim 6, wherein the food product is a nutritional bar or an energy bar.

8. The method of claim 6, wherein the beverage is water, a nutritional beverage, an energy beverage, or a protein shake.

9. The method of claim 4, wherein the intranasal administration comprises intranasal drops, intranasal sprays, and / or nebulized formulations.

10. The method of any of claims 1-9, wherein the incretin analog is administered in a dose of 0.04 to 0.32 mg / kg.

11. The method of any of claims 1-10, wherein the incretin analog is administered once per week for a first period of one week at a dose of 0.04 to 0.08 mg / kg.

12. The method of claim 11, wherein the incretin analog is administered once per week following the first period of one week at a dose of 0.04 to 0.08 mg / kg.52325218025vlAttorney Docket No: 251609.00015713. The method of any one of claims 1-12, wherein the incretin analog is co-administered with leptin.

14. The method of any one of claims 1-13, wherein the subject also receives counseling and / or therapy.

15. The method of claim 14, wherein the counseling is nutritional counseling.

16. The method of claim 14, wherein the therapy is cognitive behavioral therapy.

17. A method of treating obsessive-compulsive disorder (OCD) in a subject in need thereof, the method comprising:administering a therapeutically effective amount of an incretin analog to the subject.

18. The method of claim 17, wherein the incretin analog is a glucagon-like peptide 1 (GLP-1) receptor agonist.

19. The method of claim 17 or claim 18, wherein the incretin analog is selected from the group consisting of semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, CJC-1134- PC, taspoglutide, efpeglenatide, tirzepatide, and any combinations thereof.

20. The method of any one of claims 17-19, wherein the incretin analog is administered parenterally, orally, or intranasally.

21. The method of claim 20, wherein the parenteral administration comprises subcutaneous injection, intramuscular injection, intraperitoneal injection, and / or intravenous injection.

22. The method of claim 20, wherein the oral administration comprises capsules, tablets, caplets, pills, troches, lozenges, powders, and granules, and optionally wherein the incretin analog is administered with sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC).

23. The method of claim 20, wherein the intranasal administration comprises intranasal drops, intranasal sprays, and / or nebulized formulations.

24. The method of any of claims 17-23, wherein the incretin analog is administered in a dose of 0.04 to 0.32 mg / kg.

25. The method of any of claims 17-24, wherein the incretin analog is administered once per week for a first period of one week at a dose of 0.04 to 0.08 mg / kg.53325218025vlAttorney Docket No: 251609.00015726. The method of claim 25, wherein the incretin analog is administered once per week following the first period of one week at a dose of 0.04 to 0.32 mg / kg.

27. The method of any one of claims 17-26, wherein the subject also receives counseling and / or therapy.

28. The method of claim 27, wherein the counseling is behavioral counseling.

29. The method of claim 27, wherein the therapy is cognitive behavioral therapy and / or exposure and response prevention.

30. A method of treating anxiety in a subject in need thereof, the method comprising:administering a therapeutically effective amount of an incretin analog to the subject.

31. The method of claim 30, wherein the incretin analog is a glucagon-like peptide 1 (GLP-1) receptor agonist.

32. The method of claim 30 or claim 31, wherein the incretin analog is selected from the group consisting of semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, CJC-1134- PC, taspoglutide, efpeglenatide, tirzepatide, and any combinations thereof.

33. The method of any one of claims 30-32, wherein the incretin analog is administered parenterally, orally, or intranasally.

34. The method of claim 33, wherein the parenteral administration comprises subcutaneous injection, intramuscular injection, intraperitoneal injection, and / or intravenous injection.

35. The method of claim 33, wherein the oral administration comprises capsules, tablets, caplets, pills, troches, lozenges, powders, and granules, and optionally w'herein the incretin analog is administered with sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC).

36. The method of claim 33, wherein the intranasal administration comprises intranasal drops, intranasal sprays, and / or nebulized formulations.

37. The method of any of claims 30-36, wherein the incretin analog is administered in a dose of 0.04 to 0.32 mg / kg.

38. The method of any of claims 30-37, wherein the incretin analog is administered once per week for a first period of one week at a dose of 0.04 to 0.08 mg / kg.54325218025vlAttorney Docket No: 251609.00015739. The method of claim 38, wherein the incretin analog is administered once per week following the first period of one week at a dose of 0.04 to 0.32 mg / kg.

40. The method of any one of claims 30-39, wherein the subject also receives counseling and / or therapy.

41. The method of claim 40, wherein the counseling is behavioral counseling.

42. The method of claim 40, wherein the therapy is pharmacotherapy, cognitive behavioral therapy, and / or exposure and response prevention.

43. A composition comprising:a therapeutically effective amount of an incretin analog; anda food product and / or a beverage.

44. The composition of claim 43, wherein the incretin analog is a glucagon-like peptide 1 (GLP-1) receptor agonist.

45. The composition of claim 43 or claim 44, wherein the incretin analog is selected from the group consisting of semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, CJC-1134-PC, taspoglutide, efpeglenatide, tirzepatide, and any combinations thereof.

46. The composition of any one of claims 43-45, further comprising sodium N-(8-[2- hydroxy benzoyl] amino) caprylate (SNAC).

47. The composition of any one of claims 43-46, wherein the food product is a nutritional bar or an energy bar.

48. The composition of any one of claims 43-46, wherein the beverage is water, a nutritional beverage, an energy beverage, or a protein shake.

49. The composition of any one of claims 43-48, wherein the incretin analog is present in an amount of 1-7 mg.55325218025vl

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