Loss of agouti-related peptide does not significantly impact the phenotype of murine POMC deficiency.

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 [Nle4, d-Phe7]-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.

Melanocortins and body weight regulation: glucocorticoids, Agouti-related protein and beyond.

In the intervening three decades since Panksepp observed for the first time that centrally administered α-melanocyte stimulating hormone decreased food intake (Panksepp and Meeker, 1976), a wealth of data have accrued to firmly establish melanocortin signaling as a central regulator of food intake and fat mass. Advances in molecular biology have not only allowed detailed studies of spontaneously occurring obese mice with altered melanocortin signaling to be undertaken but also permitted the generation of a plethora of mouse models with precise perturbations at critical steps in the melanocortin system to finesse further the cellular and molecular architecture of relevant pathways. In this article we focus in upon a number of these mouse models which continue to help us tease apart the complexities of this critical system. Further, we review data on the important interaction between pro-opiomelanocortin derived peptides and the adrenal system and the relationship between agonist and antagonist peptides acting at central melanocortin receptors.