Melanocortins

Melanocortins are a group of pituitary peptide hormones including adrenocorticotropin (ACTH) and the alpha-, beta-, and gamma-melanocyte-stimulating [Page 453]hormones. Five melanocortin receptors (MC1 through MC5) have different physiological functions.

MC1R expression occurs in macrophage/monocytic cells, lymphocytes with antigen-presenting and cytotoxic functions, neutrophils, endothelial cells, astrocytes, and fibroblasts. MC2 is also known as the adrenocorticotrophic receptor because it selectively binds ACTH. The MC3R gene encodes a G protein-linked receptor, coupled to both cAMP- and inositol phospholipid-Ca2+-mediated signaling systems. MC3R expression occurs in brain, placenta, and gut, but not in melanoma cells or in the adrenal gland.

Melanocortin-4 receptor is expressed in the brain, including in hypothalamic nuclei known to be involved in feeding behavior. It is involved in integrating long-term adipostatic signals from leptin and insulin. MC5R contributes to regulation of exocrine gland function and to certain immune responses. It is expressed in peripheral tissues and occurs in the adrenal glands, fat cells, kidney, liver, lung, lymph nodes, bone marrow, thymus, mammary glands, testis, ovary, pituitary testis, uterus, esophagus, stomach, duodenum, skin, lung, skeletal muscle, and exocrine glands. Melanocortins are known to modulate fever, inflammation, and immunity by acting both on peripheral targets and within the brain. Data from both rodent models and humans suggest that intact neuronal melanocortin signaling is essential to prevent obesity. Melanocortins are also involved in the pathogenesis of disorders at the opposite end of the spectrum of energy homeostasis, the anorexia and weight loss associated with inflammatory and neoplastic disease processes.

Decreased melanocortin signaling via pharmacological or genetic means results in increased food intake and weight gain. Activation of central melanocortin receptors inhibits feeding and leads to weight loss, whereas blockade of the central melanocortin signaling pathway increases food consumption and promotes weight gain. Melanocortin system agonism promotes weight loss through decreasing appetite, increasing sympathetic nervous system activity, and modulating thyroid-releasing hormone, corticotropin-releasing hormone, brain-derived neurotrophic factor, melanin-concentrating hormone and orexin. Recent studies suggest that melanocortins could be involved in mediating the effects of leptin, and in controlling the expression of neuropeptide Y (NPY).