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Although mammals resist both acute weight loss and weight gain, the neural circuitry mediating bi-directional defense against weight change is incompletely understood. Global constitutive deletion of the melanocortin-3-receptor (MC3R) impairs the behavioural response to both anorexic and orexigenic stimuli, with MC3R knockout mice demonstrating increased weight gain following anabolic challenges and increased weight loss following anorexic challenges (i.e. impaired energy rheostasis). However, the brain regions mediating this phenotype are not well understood. Here, we utilized MC3R floxed mice and viral injections of Cre-recombinase to selectively delete MC3R from the medial hypothalamus (MH) in adult mice. Behavioural assays were performed on these animals to test the role of MC3R in MH in the acute response to orexigenic and anorexic challenges. Complementary chemogenetic approaches were used in MC3R-Cre mice to localize and characterize the specific medial hypothalamic brain regions mediating the role of MC3R in energy homeostasis. Finally, we performed RNAscope in situ hybridization to map changes in the mRNA expression of MC3R, pro-opiomelanocortin and agouti-related peptide following energy rheostatic challenges, as well as to characterize the MC3R expressing cells in dorsal MH. Our results demonstrate that MC3R deletion in MH increases feeding and weight gain following high-fat diet feeding, and enhances the anorexic effects of semaglutide, in a sexually dimorphic manner. Furthermore, although the arcuate nucleus exerts an important role in MC3R-mediated effects on energy homeostasis, viral deletion in the dorsal MH also resulted in altered energy rheostasis, indicating that brain regions outside of the arcuate nucleus also contribute to the role of MC3R in energy rheostasis. Together, these results demonstrate that MC3R-mediated effects on energy rheostasis result from the loss of MC3R signalling in medial hypothalamic neurons and suggest an important role for dorsal-MH MC3R signalling in energy rheostasis. KEY POINTS: Melanocortin-3-receptor (MC3R) signalling regulates energy rheostasis in adult mice. Medial hypothalamus regulates energy rheostasis in adult mice. Energy rheostatic stimuli alter mRNA levels of agouti-related peptide, pro-opiomelanocortin and MC3R. Dorsal-medial hypothalamus (DMH) MC3R neurons increase locomotion and energy expenditure. MC3R cell types in DMH are sexually dimorphic.
