A novel selective melanocortin-4 receptor agonist reduces food intake in rats and mice without producing aversive consequences

Studies using nonselective agonists and antagonists of melanocortin-3 recep tor (MC3R) and MC4R point to the importance of the CNS melanocortin system in the control of food intake. We describe here a novel compound that is hi ghly selective as an agonist at the MC4 receptor but has minimal activity a t the MC3 receptor. When administered centrally to rats, this selective ago nist increased Fos-like immunoreactivity in the paraventricular nucleus, ce ntral nucleus of the amygdala, nucleus of the solitary tract, and area post rema, a pattern of neuronal activation that is similar to that induced by a nonselective MC3/4R agonist. Additionally, it suppresses food intake when administered centrally to rats or peripherally to db/db mice that lack func tional leptin receptors via a mechanism that is not accompanied by illness or other nonspecific effects. Conversely, a related compound that is a sele ctive MC4R antagonist potently increased food intake when administered cent rally in rats. These results support the hypothesis that the brain MC4R is intimately involved in the control of food intake and body weight and provi de evidence that selective activation of MC4R causes anorexia that is not s econdary to aversive effects.