Antagonism of Central Melanocortin Receptors in Vitro and in Vivo by Agouti-Related Protein

TLDR

Agouti protein is normally expressed in skin to influence pigmentation, but widespread expression is linked to obesity. Agouti‑related protein, expressed in the hypothalamus and upregulated in ob/ob mice, acts as a potent selective antagonist of melanocortin receptors Mc3r and Mc4r, and its ubiquitous expression in transgenic mice induces obesity without affecting pigmentation, indicating a role in leptin‑mediated weight regulation.

Abstract

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 Agouti-related 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.