TARGETED DISRUPTION OF THE MELANOCORTIN-4 RECEPTOR RESULTS IN OBESITYIN MICE

The melanocortin-4 receptor (MC4-R) is a G protein-coupled, seven-tran smembrane receptor expressed in the brain. Inactivation of this recept or by gene targeting results in mice that develop a maturity onset obe sity syndrome associated with hyperphagia, hyperinsulinemia, and hyper glycemia. This syndrome recapitulates several of the characteristic fe atures of the agouti obesity syndrome, which results from ectopic expr ession of agouti protein, a pigmentation factor normally expressed in the skin. Our data identify a novel signaling pathway in the mouse for body weight regulation and support a model in which the primary mecha nism by which agouti induces obesity is chronic antagonism of the MC4- R.