MON-677 Role Of The Melanocortin-3 Receptor In Regulation Of Lean Mass, Muscle Function, And Exercise-induced Hyperphagia

Abstract Disclosure: N. Danjo: None. A. Carvalho da Silva: None. R.D. Cone: Courage Therapeutics. Neuronal networks of the central melanocortin system have long been known to be involved in regulation of energy homeostasis, and the amount of long-term energy stored in adipose tissue. However, it has been noted that MC4R-deficient mice and humans have an increase in lean mass compared with BMI matched controls. The melanocortin-3 receptor acts as the major inhibitory/modulatory regulator of the central melanocortin MC4R-anorexigenic pathways via its presence on GABAergic agouti-related peptide (AgRP) nerve terminals. In the absence of the MC3R, both mice and humans manifest reduced lean mass and linear growth, which mirror classical symptoms of growth axis dysfunction. In this study, we sought to advance our understanding of the role of the MC3R in the regulation of lean mass. To this end, we studied the development and function of lean mass in WT and MC3RKO mice. Our results revealed that male MC3RKO mice at different ages manifest reduced tissue growth, and poor endurance capacity. While WT 5-month-old male (21-23weeks) WT mice are capable of 37min of high intensity exercise on the treadmill, age and sex matched MC3RKO mice could only sustain 26min of exercise. Furthermore, we show that the increased food intake after endurance or moderate intensity exercise requires the presence of MC3R. For example, 45 min of moderate intensity running on a treadmill significantly increases 3hr food intake by 96% in WT mice, but only by 43% in MC3RKO mice. Therefore, MC3R is critical not only in the normal growth of lean body mass, but also in the stimulatory effects of physical exercise on food intake and growth. Ghrelin has been proposed to function in mediating exercise-induced hyperphagia in the mouse, and future work will will be focused on understanding the role of MC3R in ghrelin and other potential mechanisms involved in exercise-mediated hyperphagia. Presentation: Monday, July 14, 2025