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

Nature Clinical Practice Endocrinology & Metabolism volume 2, pages 459–466 (2006)Cite this article

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.

Key Points

  • Cachexia is associated with chronic diseases and involves a paradoxical decrease in appetite, loss of lean body mass, and increase in total energy expenditure

  • Current therapies to treat cachexia have not shown significant effects in alleviating the associated loss of appetite and lean body mass

  • Many of the diseases associated with cachexia have a component of inflammation that seems to be involved in the development of these symptoms

  • Recent research has shown that the action of inflammatory cytokines on the melanocortin system might have a role in the anorexia and loss of lean body mass seen in cachexia

  • Use of small-molecule antagonists to components of the melanocortin system in animals has proven useful in alleviating the anorexia and loss of lean body mass associated with multiple models of chronic disease

  • Trials in humans with cachexia will be necessary to further delineate the usefulness of these molecules in alleviating these symptoms in the setting of chronic illness in humans

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Figure 1: A model for the production of cachexia by three common disease states (heart failure, renal failure, and cancer)

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Authors and Affiliations

  1. Department of Pediatrics,

    Mark D DeBoer & Daniel L Marks

  2. Center for the Study of Weight Regulation, Oregon Health and Science University, Portland, OR, USA

    Mark D DeBoer & Daniel L Marks

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  1. Mark D DeBoer
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  2. Daniel L Marks
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Correspondence to Daniel L Marks.

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Competing interests

Dr Daniel L Marks serves as a scientific consultant for Neurocrine Biosciences, Inc. and Ipsen, Inc. MD DeBoer declared he has no competing interests.

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DeBoer, M., Marks, D. Therapy insight: use of melanocortin antagonists in the treatment of cachexia in chronic disease. Nat Rev Endocrinol 2, 459–466 (2006). https://doi.org/10.1038/ncpendmet0221

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