Melanocortin-3 Receptors Expressed on Agouti-Related Peptide Neurons Inhibit Feeding Behavior in Female Mice

Objective: Activation of hypothalamic agouti-related peptide expressing (AgRP)^+ve neurons during energy deficit is a negative valence signal, rapidly activating food-seeking behaviors. This study examined the roles of melanocortin-3 receptors (MC3Rs) coexpressed in a subpopulation of AgRP^+ve neurons. Methods: AgRP-MC3R mice expressing MC3Rs selectively in AgRP^+ve neurons were generated by crossing AgRP-IRES-Cre mice with LoxTBMc3r mice containing a “loxP-STOP-loxP” sequence in the 5′ untranslated region. Body weight, body composition, and feeding behavior were assessed during ad libitum and time-restricted feeding conditions. Results: In females, food intake of AgRP-IRES-Cre^+ve (n = 7) or AgRP-IRES-Cre^-ve (n = 9) mice was not significantly different; these mice were therefore pooled to form the “control” group. Female AgRP-MC3R mice exhibited lower food intake (25.4 ± 2.4 kJ/12 h; n = 6) compared with controls (35.3 ± 1.8 kJ/12 h; n = 16) and LoxTBMc3r mice (32.1 ± 2.1 kJ/12 h; n = 9) in the active phase during the dark period. Food intake during the rest phase (lights on) when mice consume less food (9-10 kJ) was normal between genotypes. Body weight and composition of AgRP-MC3R and LoxTBMc3r mice were similar, suggesting compensatory mechanisms for reduced calorie intake. Remarkably, AgRP-MC3R mice continued to consume less food during refeeding after fasting and time-restricted feeding. Conclusions: MC3Rs expressed on AgRP^+ve neurons appear to exert a strong inhibitory signal on hypothalamic networks governing feeding behavior.