Recombinant Human AgRP Protein

Agouti-Related Protein (AgRP), the protein product of the Agouti-Related Transcript (ART), is a neuropeptide that regulates energy metabolism and the development of obesity by antagonizing alpha-melanocyte stimulating hormone ( alpha-MSH) on MC-3 and MC-4 receptors (1-4). AgRP is predominantly expressed in the hypothalamus and adrenal medulla (5). Mature human AgRP is a 112 amino acid (aa) peptide; its C-terminal portion contains ten conserved cysteines that form five disulfide bonds (5, 6). Human AgRP shares 82% and 72% aa sequence identity with mouse and rat AgRP, respectively. It shares 32% aa sequence identity with Agouti. As in the case of Agouti, the C-terminal cysteine-rich region is sufficient for biological activity (7). AgRP 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 in a mechanism that does not involve melanocortin receptors (14).