Therapy insight: Use of melanocortin antagonists in the treatment of cachexia in chronic disease

Abstract

Cachexia is a process that accompanies many chronic diseases, and consists of a combination of wasting of lean body mass, increased energy expenditure, and a paradoxical loss of appetite. Cachexia both worsens quality of life and negatively affects treatment of the underlying disease. Conditions as diverse as cancer, renal failure, and heart failure show a remarkable similarity in their associated cachexia, exhibiting changes in metabolism and endocrinology, including marked increases in levels of cytokines that accompany these diseases. So far, it has been difficult to treat disease-associated cachexia successfully. One treatment that has shown promise in animal trials, however, involves antagonism of the central melanocortin system, an anorexigenic pathway in the hypothalamus and brainstem. Humans who have genetic mutations involving pro-opiomelanocortin or the melanocortin 4 receptor in this pathway exhibit increased appetite and increased lean body mass. Recent research has shown that in rodent models of cancer and renal failure, administration of melanocortin 4 receptor antagonists results in an attenuation of symptoms of cachexia, including maintenance of appetite, lean body mass, and basal energy expenditure. Although this research needs to be substantiated in humans, it provides a promising direction for treating the wasting that is associated with a variety of disease states.