Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice
Naima S. Dahir, … , Anna K. Mapp, Roger D. Cone
Naima S. Dahir, … , Anna K. Mapp, Roger D. Cone
Published July 15, 2024
Citation Information: J Clin Invest. 2024;134(14):e178250. https://doi.org/10.1172/JCI178250.
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Research Article Metabolism

Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice

Abstract

The melanocortin-3 receptor (MC3R) regulates GABA release from agouti-related protein (AgRP) nerve terminals and thus tonically suppresses multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of the MC3R and the melanocortin system in regulating the response to various anorexigenic agents. The genetic deletion or pharmacological inhibition of the MC3R, or subthreshold doses of an MC4R agonist, improved the dose responsiveness to glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss. An enhanced anorectic response to the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipostatic factor leptin demonstrated that increased sensitivity to anorectic agents was a generalized result of MC3R antagonism. We observed enhanced neuronal activation in multiple hypothalamic nuclei using Fos IHC following low-dose liraglutide in MC3R-KO mice (Mc3r–/–), supporting the hypothesis that the MC3R is a negative regulator of circuits that control multiple aspects of feeding behavior. The enhanced anorectic response in Mc3r–/– mice after administration of GLP1 analogs was also independent of the incretin effects and malaise induced by GLP1 receptor (GLP1R) analogs, suggesting that MC3R antagonists or MC4R agonists may have value in enhancing the dose-response range of obesity therapeutics.

Authors

Naima S. Dahir, Yijun Gui, Yanan Wu, Patrick R. Sweeney, Alix A.J. Rouault, Savannah Y. Williams, Luis E. Gimenez, Tomi K. Sawyer, Stephen T. Joy, Anna K. Mapp, Roger D. Cone

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Figure 1

MC3R loss increases responsiveness to GLP1 drugs.

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MC3R loss increases responsiveness to GLP1 drugs. Liraglutide (0.05–0.4 ...
Liraglutide (0.05–0.4 mg/kg) administration resulted in more significant inhibition of (A) food intake and (B) weight loss in Mc3r–/– male mice compared with Mc3r+/+ mice in a dose-dependent manner after 24 hours (n = 7–8/group). (C) Liraglutide-induced feeding and (D) body weight changes of Mc3r+/+ and Mc3r–/– female mice (n = 7–8/group; 0.05–0.4 mg/kg). Tirzepatide (TZ) (1–4 nmol/kg) and coadministration of tirzepatide and C11-induced (E) feeding responses and (F) body weight changes of WT male mice (vehicle, n = 10; all other groups, n = 8) at 24 hours after injection. (G) Twenty-four-hour feeding and (H) body weight changes after chronic injections of tirzepatide (2 nmol/kg), C11 (0.5 nmol), tirzepatide plus C11, and vehicle. Data are expressed as the mean ± SEM, and statistical tests were performed by 2-way ANOVA with Tukey’s test for post hoc analysis (G–H). For all the dose-response curve data, a repeated-measures 2-way ANOVA was corrected for multiple comparisons using the Tukey-Kramer method for each time point, and data were fitted with 4 parameters: nonlinear fit, **P < 0.01.