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Neurocrine Biosciences (S.M., A.C.F., C.C., S.R.J.H., B.A.F., B.T.B.), San Diego, California 92130; and Department of Pediatrics (G.B.B., A.H., D.L.M.), Center for the Study of Weight Regulation (D.L.M.), Oregon Health & Sciences University, Portland, Oregon 97239
Address all correspondence and requests for reprints to: Daniel L. Marks M.D., Ph.D., Department of Pediatrics, Mailcode CDRCP, 707 Southwest Gaines Road, Portland, Oregon 97239. E-mail: marksd{at}ohsu.edu.
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.
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 L. D Madison, J. M Scarlett, P. Levasseur, X. Zhu, K. Newcomb, A. Batra, D. Bowe, and D. L Marks Prostacyclin signaling regulates circulating ghrelin during acute inflammation J. Endocrinol., February 1, 2008; 196(2): 263 - 273. [Abstract] [Full Text] [PDF]
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 E. R. Ropelle, J. R. Pauli, K. G. Zecchin, M. Ueno, C. T. de Souza, J. Morari, M. C. Faria, L. A. Velloso, M. J. A. Saad, and J. B. C. Carvalheira A Central Role for Neuronal Adenosine 5'-Monophosphate-Activated Protein Kinase in Cancer-Induced Anorexia Endocrinology, November 1, 2007; 148(11): 5220 - 5229. [Abstract] [Full Text] [PDF]
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 W. W. Cheung, H.-J. Kuo, S. Markison, C. Chen, A. C. Foster, D. L. Marks, and R. H. Mak Peripheral Administration of the Melanocortin-4 Receptor Antagonist NBI-12i Ameliorates Uremia-Associated Cachexia in Mice J. Am. Soc. Nephrol., September 1, 2007; 18(9): 2517 - 2524. [Abstract] [Full Text] [PDF]
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 J. R. Nicholson, G. Kohler, F. Schaerer, C. Senn, P. Weyermann, and K. G. Hofbauer Peripheral Administration of a Melanocortin 4-Receptor Inverse Agonist Prevents Loss of Lean Body Mass in Tumor-Bearing Mice J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 771 - 777. [Abstract] [Full Text] [PDF]
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 A. Wilcock Anorexia: a taste of things to come? Palliative Medicine, January 1, 2006; 20(1): 43 - 45. [PDF]
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