Melanocortin receptors: more than skin deep!

The Melanocortin Receptorsedited by Roger D. Cone,Humana Press, 2000. $145.00 (x + 551)ISBN 0896 03579 4The melanocortins (MCs) have been implicated in a wide array of biological functions, including cardiovascular function, immune systems, learning and memory, in addition to pigmentation and obesity. Literature searches for MCs, melanocyte-stimulating hormone (MSH), and a variety of MC-receptor keywords will yield more published reports than could easily be consumed by researchers in any of the several fields in which a member of this family of peptides finds a home. Luckily, the many and varied roles of the MC systems are often well defined and separated by anatomical location. On the one hand, pigmentation is obviously controlled in peripheral melanocytes. On the other hand, a role for obesity and energy regulation has been found for MC peptides located in hypothalamic brain structures. However, the endogenous agonist for both these functions is αMSH, a product of the MC precursor molecule, pro-opiomelanocortin (POMC).Although there are several endogenous agonists and at least two endogenous antagonists in this family of peptides, it is clear that the varied functions of this peptide system rely on several different receptor subtypes (MCR1–MCR5). These receptors are often found in different physiological systems and with different anatomical distributions. For example, the MC receptor associated with skin color is MCR1, whereas the receptor most associated with obesity and food intake is MCR4 (1xObesity, diabetes and functions for proopiomelanocortin-derived peptides. Mountjoy, K. and Wong, J. Mol. Cell Endocrinol. 1997; 128: 171–177Crossref | Scopus (133)See all References1).The Melanocortin Receptors is a timely and important work that details much of the recent research on the MC system with an emphasis on the differences found between the five MC-receptor subtypes. The first two sections of the book describe the history of the MC research and provide detailed analyses of the various POMC products, receptor expression, and biochemistry. Subsequent chapters detail the discovery, cloning, and research on the five MC receptors. Included in the chapter by Cone is a discussion of one of the more interesting and serendipitous discoveries involving the MC system. The agouti mouse is yellow and obese, having dysregulations in both pigmentation and energy balance systems. After cloning of the MCR1 and the agouti gene product, it was hypothesized that another MC receptor, located in the brain, might be involved in food intake. Indeed such a receptor was found, and ectopically expressed agouti protein acted as an antagonist at this receptor 2xAgouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Lu, D. et al. Nature. 1994; 371: 799–802Crossref | Scopus (761)See all References2. Thus, the study of a yellow mouse led to the discovery of an important control of energy balance.The discovery of hypothalamic MC receptors, which control food intake, led to a renewed interest in the MC peptides, including work supporting the hypothesis that these receptors mediate the energy regulation effects of the adipocyte hormone, leptin. Indeed, there is little doubt that these receptors are involved in energy balance. Infusion of MC agonists (endogenous or synthetic) into the brain led to significant reductions in food intake and body weight. By contrast, administration of antagonists [e.g. agouti-related peptide (AgRP)] led to marked and prolonged increases in food intake 3xA C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Rossi, M. et al. Endocrinology. 1998; 139: 4428–4431Crossref | PubMedSee all References3. Many other lines of evidence support this hypothesis, including the fact that expression of the precursor for MC (POMC) is regulated by energy balance. In addition, mice that lack the MRC4 receptor gene are profoundly obese, and administration of normally anorexic MC agonists, fails to reduce their food intake 4xResponse of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Marsh, D. et al. Nat. Gen. 1999; 21: 119–122Crossref | Scopus (390)See all References4.Most evidence suggests that the crucial receptor for energy balance is MCR4. For example, non-selective MCR3/4 receptor agonists decrease food intake, whereas non-selective antagonists increase food intake. Several recent reports show that MCR4 receptor-selective compounds have similar effects on food intake. Further, γ1-MSH, which selectively activates MC3R, does not reduce food intake 5xDifferential effects of melanocortin peptides on ingestive behaviour in rats: evidence against the involvement of MC(3) receptor in the regulation of food intake. Kask, A. et al. Neurosci Lett. 2000; 283: 1–4Crossref | Scopus (53)See all References5. These data suggest that the MCR4 receptor mediates the food intake effects of MCR3/4 compounds. However, other recent work suggests that the MCR3 receptor might also play a role in food intake. When injected with the endogenous MCR3/4 receptor antagonist, AgRP, MCR4−/− knockout mice increase their food intake. Understanding the role of the CNS MC system in the control of energy balance will ultimately include an understanding of the relative importance and contribution of these two receptor subtypes.The Melanocortin Receptors is an excellent introduction to the current research on MC peptides and their receptors. It is also a valuable tool for reference. In no other source will the reader find such a complete discussion of the current understanding of the physiology, anatomy, and function of this interesting family of peptides.