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Ghrelin Treatment Causes Increased Food Intake and Retention of Lean Body Mass in a Rat Model of Cancer Cachexia

Center for the Study of Weight Regulation (M.D.B., X.X.Z., P.L., D.L.M.), Oregon Health and Science University, Portland, Oregon 97239; Surgical Metabolism and Nutrition Laboratory (M.M.M., S.S.), Department Surgery, State University of New York Upstate Medical University, Syracuse, New York 13210; Department of Behavioral Medicine (A.I.), Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan; and IPSEN (J.E.T., H.A.H., J.Z.D., R.D., M.D.C.), Milford, Massachusetts 01757

Address all correspondence and requests for reprints to: Daniel L. Marks, 707 SW Gaines Road, CDRC-P, Portland, Oregon 97239. E-mail: marksd{at}ohsu.edu.

Cancer cachexia is a debilitating syndrome of anorexia and loss of lean body mass that accompanies many malignancies. Ghrelin is an orexigenic hormone with a short half-life that has been shown to improve food intake and weight gain in human and animal subjects with cancer cachexia. We used a rat model of cancer cachexia and administered human ghrelin and a synthetic ghrelin analog BIM-28131 via continuous infusion using sc osmotic minipumps. Tumor-implanted rats receiving human ghrelin or BIM-28131 exhibited a significant increase in food consumption and weight gain vs. saline-treated animals. We used dual-energy x-ray absorptiometry scans to show that the increased weight was due to maintenance of lean mass vs. a loss of lean mass in saline-treated animals. Also, BIM-28131 significantly limited the loss of fat mass normally observed in tumor-implanted rats. We further performed real-time PCR analysis of the hypothalami and brainstems and found that ghrelin-treated animals exhibited a significant increase in expression of orexigenic peptides agouti-related peptide and neuropeptide Y in the hypothalamus and a significant decrease in the expression of IL-1 receptor-I transcript in the hypothalamus and brainstem. We conclude that ghrelin and a synthetic ghrelin receptor agonist improve weight gain and lean body mass retention via effects involving orexigenic neuropeptides and antiinflammatory changes.

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