Agouti-Related Protein (AgRP), the protein product of the Agouti-Related Transcript (ART), is a neuroprotein that regulates energy metabolism and the development of obesity by antagonizing alpha -melanocyte stimulating hormone ( alpha -MSH) action on MC-3 and MC-4 receptors (1-4). AgRP is predominantly expressed in the hypothalamus and adrenal medulla (5). Mature mouse AgRP is a 111 amino acid (aa) polypeptide; its C-terminal portion contains ten conserved cysteines that form five disulfide bonds (5, 6). Within the C-terminal region, mouse AgRP shares 80% and 90% aa sequence identity with human and rat AgRP, respectively. It also shares 44% aa sequence identity with Agouti. As with Agouti, the C-terminal cysteine-rich region is sufficient for biological activity (7). AgRP, however, is 100 times more potent than Agouti in antagonizing MC-3 and MC-4 receptors (8). AgRP also induces the beta -arrestin dependent endocytosis of MC-3 and MC-4 (9). Hypothalamic expression of AgRP is up-regulated in obesity and diabetes (5, 10), and chronic AgRP administration increases food intake and weight gain in rats (11). Genetically-linked polymorphisms of AgRP in humans are associated with susceptibility to anorexia nervosa (12, 13). In addition, AgRP inhibits the ACTH-induced synthesis of steroid hormones via a mechanism that does not involve melanocortin receptors (14).