Anatomy of an endogenous antagonist: Relationship between Agouti-related protein and proopiomelanocortin in brain

Agouti-related protein (AGRP) is a recently discovered orexigenic neuropept ide that inhibits the binding and action of alpha-melanocyte-stimulating ho rmone derived from proopiomelanocortin (POMC) at the melanocortin 3 recepto r (MC3R) and melanocortin 4 receptor (MC4R) and has been proposed to functi on primarily as an endogenous melanocortin antagonist. To better understand the interplay between the AGRP and melanocortin signaling systems, we comp ared their nerve fiber distributions with each other by immunohistochemistr y and their perikarya distribution with MC3R and MC4R by double in situ hyb ridization. Although deriving from distinct cell groups, AGRP and melanocor tin terminals project to identical brain areas. Both AGRP and melanocortin neurons selectively express the MC3R, which provides a neuroanatomical basi s for a dual-input circuit with biological amplification and feedback inhib ition. These studies highlight a broader complexity in POMC-mediated behavi or in the brain.