Abstract
The hypothalamic melanocortin system is unique among neuropeptide systems controlling energy homeostasis, in that both anorexigenic proopiomelanocortin (POMC)-derived and orexigenic Agouti related-peptide (AgRP)-derived ligands act at the same receptors, namely melanocortin 3 and 4 receptors (MC3/4R). AgRP clearly acts as a competitive antagonist at MC3R and MC4R but may also have an inverse agonist action at these receptors. The physiological relevance of this remains uncertain. We generated a mouse lacking both POMC and AgRP [double knockout (DKO) mouse]. Phenotyping was performed in the absence and presence of glucocorticoids, and the response to central peptide administration was studied. The phenotype of DKO mice is indistinguishable from that of mice lacking Pomc alone, with both exhibiting highly similar degrees of hyperphagia and increased body length, fat, and lean mass compared with wild-type controls. After a 24-h fast, there was no difference in the refeeding response between Pomc(-/-) and DKO mice. Similarly, corticosterone supplementation caused an equivalent increase in food intake and body weight in both genotypes. Although the central administration of [Nle&sup4;, d-Phe&sup7;]-α-MSH to DKO mice caused a decrease in food intake and an increase in brown adipose tissue Ucp1 expression, both of which could be antagonized with the coadministration of AgRP, there was no effect of AgRP alone. These data suggest AgRP acts predominantly as a melanocortin antagonist. If AgRP has significant melanocortin-independent actions, these are of insufficient magnitude in vivo to impact any of the detailed phenotypes we have measured under a wide variety of conditions.