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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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 2

Mc3r deletion has no effect on the incretin activity or malaise associated with liraglutide.

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Mc3r deletion has no effect on the incretin activity or malaise associa...
(A–F) Glucose levels and AUC before and after oral administration of glucose (1 g/kg) after liraglutide (lira) (0.01–0.2 mg/kg) or vehicle (veh) treatment in Mc3r+/+ and Mc3r–/– male mice (n = 6–7/group). CTA test day 1 (G) and test day 2 (H) after liraglutide administration in Mc3r+/+ and Mc3r–/– male mice. (I) Representative images from the AP showing Fos IHC after saline or liraglutide injection from Mc3r+/+ and Mc3r–/– male mice. CC, central canal. Scale bars: 100 μm. (J) Quantification of cells expressing Fos after saline or liraglutide injection in Mc3r+/+ and Mc3r–/– male mice. (K) Representative images from the hypothalamus showing Fos IHC after liraglutide treatment in Mc3r+/+ and Mc3r–/– mice. Scale bars: 100 μm. (L) Quantification of cells expressing Fos in the ARH, VMH, and DMH after liraglutide treatment. Statistical analysis was done by 2-tailed Student’s t test, *P < 0.05, and ****P < 0.0001 (J, G, H, and L).