MC4R and hyperinsulinism: In contrast, Mc3r deletion does not produce hyperphagia or hyperinsulinemia in ad libitum–fed animals (4, 5) However, the MC3R acts as a negative regulator of the MC4R system, controlling responses of the melanocortin system to both internal and external challenges (6–10), controlling the upper and lower boundaries of energy homeostasis (9), and providing sexually dimorphic inputs to the system (8, 10, 11).