Implication of the melanocortin-3 receptor in the regulation of food intake.

The melanocortin system is well recognized to be involved in the regulation of food intake, body weight, and energy homeostasis. To probe the role of the MC(3) in the regulation of food intake, JRH322-18 a mixed MC(3) partial agonist/antagonist and MC(4) agonist tetrapeptide was examined in wild type (WT) and melanocortin 4 receptor (MC(4)) knockout mice and shown to reduce food intake in both models. In the wild type mice, 2.0 nmol of JRH322-18 statistically reduced food intake 4h post icv treatment into satiated nocturnally feeding wild type mice. The same dose in the MC(4)KO mice significantly reduced cumulative food intake 24h post treatment. Conditioned taste aversion as well as activity studies supports that the decreased food intake was not due to visceral illness. Since these studies resulted in loss-of-function results, the SHU9119 and agouti-related protein (AGRP) melanocortin receptor antagonists were administered to wild type as well as the MC(3) and MC(4) knockout mice in anticipation of gain-of-function results. The SHU9119 ligand produced an increase in food intake in the wild type mice as anticipated, however no effect was observed in the MC(3) and MC(4) knockout mice as compared to the saline control. The AGRP ligand however, produced a significant increase in food intake in the wild type as well as the MC(3) and MC(4) knockout mice and it had a prolonged affect for several days. These data support the hypothesis that the MC(3) plays a subtle role in the regulation of food intake, however the mechanism by which this is occurring remains to be determined.