The MC4R regulates energy homeostasis, and haploinsufficiency produces hyperphagia, hypometabolism, and early onset obesity. In contrast, homozygous deletion of the MC3R does not cause hyperphagia or hypometabolism under normal conditions, producing a mild, late-onset obesity. However, the MC3R plays a critical role in regulating energy homeostasis in response to external and internal nutritional challenges. First, the MC3R regulates energy stores in response to fasting and chronic food restriction. Additionally, there are multiple roles for MC3R in regulation of energy homeostasis in response to reproductive state. MC3R KO mice exhibit defective pregnancy-induced hyperphagia and defective control of energy stores in response to ovariectomy. Thus, MC3R deletion results in defective homeostatic boundary control and rheostasis. Additional data demonstrate a molecular mechanism by which MC3R regulates homeostatic boundary control: MC3R on AgRP neurons acts presynaptically to provide autoregulatory feedback onto MC4R PVN neurons.