Anticatabolic properties of melanocortin-4 receptor antagonists

Health problems related to weight regulation are increasingly common in the USA and around the world. Although obesity and associated complications garner the most attention in the media, clinical problems at the opposite end of the spectrum, such as involuntary disease-associated weight loss or cachexia, are equally devastating. This review focuses on the role of the central melanocortin system in body weight regulation, and specifically on the anticatabolic properties of antagonists of the melanocortin-4 receptor.

Over the past several years, the central melanocortin system has emerged as a major contributor to the body weight regulatory system in both animals and humans. In particular, the melanocortin-4 receptor, its endogenous agonist alpha-melanocyte stimulating hormone, and its endogenous antagonist agouti-related protein have been shown to be vital to the maintenance of normal body weight in both genetic and physiologic experiments. This system is now the target of multiple drug discovery endeavors, as the search continues for effective treatments for both obesity and cachexia. Several investigators have recently shown that selective synthetic antagonists of the melanocortin-4 receptor can prevent or attenuate the development of cachexia in animal models of acute and chronic disease.

An understanding of the biology of weight regulation, including both appetite regulation and energy metabolism, is vital if we are to unravel the etiology of and develop effective treatment for obesity and cachexia. The data reviewed here supporting a role for melanocortin-4 receptor antagonists in the treatment of catabolism represent an important advance in this field.