Melanocortin-3 receptors expressed on agouti-related peptide neurons inhibit feeding behavior in female mice.

OBJECTIVE: Activation of hypothalamic agouti-related peptide (AgRP)(+ve) neurons during energy deficit is a negative valence signal, rapidly activating food seeking behaviors. This study examined the roles of MC3Rs expressed by 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’ UTR. Body weight, body composition and feeding behavior were assessed during ad libitum and timed-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/12h, n=6) compared to controls (35.3±1.8 kJ/12h, n=16) and LoxTBMc3r mice (32.1±2.1 kJ/12h, 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 was similar, suggesting compensatory mechanisms for reduced calorie intake. Remarkably, AgRP-MC3R mice continued to consume less food during re-feeding after fasting and timed-restricted feeding. CONCLUSIONS: MC3Rs expressed on AgRP(+ve) neurons appear to exert a strong inhibitory signal on hypothalamic networks governing feeding behavior.