Expression of Agouti protein is normally limited to the skin where it affects pigmentation, but ubiquitous expression causes obesity. An expressed sequence tag was identified that encodes Agouti-related protein, whose RNA is normally expressed in the hypothalamus and whose levels were increased eightfold in ob/ob mice. Recombinant Agoutirelated protein was a potent, selective antagonist of Mc3r and Mc4r, melanocortin receptor subtypes implicated in weight regulation, Ubiquitous expression of human AGRP complementary DNA in transgenic mice caused obesity without altering pigmentation, Thus, Agouti-related protein is a neuropeptide implicated in the normal control of body weight downstream of leptin signaling.