The regulation of feeding and metabolic rate and the prevention of murine cancer cachexia with a small-molecule melanocortin-4 receptor antagonist

Stacy Markison, Alan C. Foster, Chen Chen, Gregor B. Brookhart, Amy Hesse, Sam R.J. Hoare, Beth A. Fleck, Brock T. Brown, Daniel L. Marks

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80 Scopus citations

Abstract

Cachexia is metabolic disorder characterized by anorexia, an increased metabolic rate, and loss of lean body mass. It is a relatively common disorder, and is a pathological feature of diseases such as cancer, HIV infection, and renal failure. Recent studies have demonstrated that cachexia brought about by a variety of illnesses can be attenuated or reversed by blocking activation of the melanocortin 4 subtype receptor (MC4-R) within the central nervous system. Although the potential use of central MC4-R antagonists for the treatment of cachexia, was supported by these studies, utility was limited by the need to deliver these agents intracerebroventricularly. In the current study, we present a series of experiments demonstrating that peripheral administration of a small molecule MC4-R antagonist can effectively stimulate daytime (satiated) food intake as well as decrease basal metabolic rate in normal animals. Furthermore, this compound attenuated cachexia and preserved lean body mass in a murine cancer model. These data clearly demonstrate the potential of small molecule MC4-R antagonists in the treatment of cachexia and underscore the importance of melanocortin signaling in the development of this metabolic disorder.

Original languageEnglish (US)
Pages (from-to)2766-2773
Number of pages8
JournalEndocrinology
Volume146
Issue number6
DOIs
StatePublished - Jun 1 2005

ASJC Scopus subject areas

  • Endocrinology

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    Markison, S., Foster, A. C., Chen, C., Brookhart, G. B., Hesse, A., Hoare, S. R. J., Fleck, B. A., Brown, B. T., & Marks, D. L. (2005). The regulation of feeding and metabolic rate and the prevention of murine cancer cachexia with a small-molecule melanocortin-4 receptor antagonist. Endocrinology, 146(6), 2766-2773. https://doi.org/10.1210/en.2005-0142