This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wisse, B. E. Articles by Cummings, D. E. Search for Related Content PubMed PubMed Citation Articles by Wisse, B. E. Articles by Cummings, D. E.

Reversal of Cancer Anorexia by Blockade of Central Melanocortin Receptors in Rats

Division of Metabolism, Endocrinology and Nutrition (B.W., R.S.F., D.E.C.), Department of Medicine, Veterans Affairs Puget Sound Health Care System, and Harborview Medical Center (M.W.S.), University of Washington, Seattle, Washington 98108

Address all correspondence and requests for reprints to: David E. Cummings, M.D., VA Puget Sound Health Care System, 1660 South Columbian Way, Endo/111, Seattle, Washington 98108-1597. E-mail: davidec{at}u.washington.edu

Anorexia is a debilitating manifestation of many malignancies. The etiology of cancer anorexia is poorly understood, and effective treatment options are limited. To investigate the role of central melanocortin receptor signaling in the pathogenesis of cancer anorexia, we assessed the effects on food intake of the melanocortin receptor antagonist SHU9119 administered into the third cerebral ventricle of Lobund-Wistar rats that were anorexic from prostate cancer. In anorexic tumor-bearing rats, daily treatment with SHU9119 (0.35 nmol, intracerebroventricularly) increased food intake from 71 ± 3% to 110 ± 6% of preanorectic baseline and caused significant weight gain (13 ± 5 vs. 5 ± 1 g/3 d, SHU9119 vs. baseline in tumor-bearing rats). In control rats pair-fed to the intake of tumor-bearing animals, SHU9119 was ineffective at increasing food intake. The specificity of the SHU9119 feeding response was assessed using two other orexigenic peptides, NPY and the novel hormone ghrelin. Treatment of tumor-bearing rats with intracerebroventricular ghrelin (10 µg) increased food intake, but the effect was blunted relative to that in controls. Intracerebroventricular injections of NPY (1 µg) also failed to reverse anorexia in tumor-bearing rats. Because SHU9119 completely reverses cancer anorexia in this model, whereas ghrelin and NPY do not, increased central nervous system melanocortin signaling is implicated in the pathogenesis of this disorder. This suggests that new targets for the treatment of cancer anorexia may be found in the melanocortin pathways.

This article has been cited by other articles:

				J. M. Scarlett, X. Zhu, P. J. Enriori, D. D. Bowe, A. K. Batra, P. R. Levasseur, W. F. Grant, M. M. Meguid, M. A. Cowley, and D. L. Marks Regulation of Agouti-Related Protein Messenger Ribonucleic Acid Transcription and Peptide Secretion by Acute and Chronic Inflammation Endocrinology, October 1, 2008; 149(10): 4837 - 4845. [Abstract] [Full Text] [PDF]

				S. Strassburg, S. D. Anker, T. R. Castaneda, L. Burget, D. Perez-Tilve, P. T. Pfluger, R. Nogueiras, H. Halem, J. Z. Dong, M. D. Culler, et al. Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats Am J Physiol Endocrinol Metab, July 1, 2008; 295(1): E78 - E84. [Abstract] [Full Text] [PDF]

				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]

				M. D. DeBoer, X. X. Zhu, P. Levasseur, M. M. Meguid, S. Suzuki, A. Inui, J. E. Taylor, H. A. Halem, J. Z. Dong, R. Datta, et al. Ghrelin Treatment Causes Increased Food Intake and Retention of Lean Body Mass in a Rat Model of Cancer Cachexia Endocrinology, June 1, 2007; 148(6): 3004 - 3012. [Abstract] [Full Text] [PDF]

				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]

				G. Bronner, A. M. Sattler, A. Hinney, M. Soufi, F. Geller, H. Schafer, B. Maisch, J. Hebebrand, and J. R. Schaefer The 103I Variant of the Melanocortin 4 Receptor Is Associated with Low Serum Triglyceride Levels J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 535 - 538. [Abstract] [Full Text] [PDF]

				J.N. Gordon, S.R. Green, and P.M. Goggin Cancer cachexia QJM, November 1, 2005; 98(11): 779 - 788. [Abstract] [Full Text] [PDF]

				S. Markison, A. C. Foster, C. Chen, G. B. Brookhart, A. Hesse, S. R. J. Hoare, B. A. Fleck, B. T. Brown, and D. L. Marks The Regulation of Feeding and Metabolic Rate and the Prevention of Murine Cancer Cachexia with a Small-Molecule Melanocortin-4 Receptor Antagonist Endocrinology, June 1, 2005; 146(6): 2766 - 2773. [Abstract] [Full Text] [PDF]

				D. L. Williams and D. E. Cummings Regulation of Ghrelin in Physiologic and Pathophysiologic States J. Nutr., May 1, 2005; 135(5): 1320 - 1325. [Abstract] [Full Text] [PDF]

				K. E. Foster-Schubert, A. McTiernan, R. S. Frayo, R. S. Schwartz, K. B. Rajan, Y. Yasui, S. S. Tworoger, and D. E. Cummings Human Plasma Ghrelin Levels Increase during a One-Year Exercise Program J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 820 - 825. [Abstract] [Full Text] [PDF]

				A. J. van der Lely, M. Tschop, M. L. Heiman, and E. Ghigo Biological, Physiological, Pathophysiological, and Pharmacological Aspects of Ghrelin Endocr. Rev., June 1, 2004; 25(3): 426 - 457. [Abstract] [Full Text] [PDF]

				N. M. Neary, C. J. Small, A. M. Wren, J. L. Lee, M. R. Druce, C. Palmieri, G. S. Frost, M. A. Ghatei, R. C. Coombes, and S. R. Bloom Ghrelin Increases Energy Intake in Cancer Patients with Impaired Appetite: Acute, Randomized, Placebo-Controlled Trial J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2832 - 2836. [Abstract] [Full Text] [PDF]

				M. P. Davis, R. Dreicer, D. Walsh, R. Lagman, and S. B. LeGrand Appetite and Cancer-Associated Anorexia: A Review J. Clin. Oncol., April 15, 2004; 22(8): 1510 - 1517. [Abstract] [Full Text] [PDF]

				J. F. Kelly, C. F. Elias, C. E. Lee, R. S. Ahima, R. J. Seeley, C. Bjorbaek, T. Oka, C. B. Saper, J. S. Flier, and J. K. Elmquist Ciliary Neurotrophic Factor and Leptin Induce Distinct Patterns of Immediate Early Gene Expression in the Brain Diabetes, April 1, 2004; 53(4): 911 - 920. [Abstract] [Full Text] [PDF]

				A. INUI, A. ASAKAWA, C. Y. BOWERS, G. MANTOVANI, A. LAVIANO, M. M. MEGUID, and M. FUJIMIYA Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ FASEB J, March 1, 2004; 18(3): 439 - 456. [Abstract] [Full Text] [PDF]

				D. L. Williams, H. J. Grill, D. E. Cummings, and J. M. Kaplan Vagotomy Dissociates Short- and Long-Term Controls of Circulating Ghrelin Endocrinology, December 1, 2003; 144(12): 5184 - 5187. [Abstract] [Full Text] [PDF]

				T. Matsuki, R. Horai, K. Sudo, and Y. Iwakura IL-1 Plays an Important Role in Lipid Metabolism by Regulating Insulin Levels under Physiological Conditions J. Exp. Med., September 15, 2003; 198(6): 877 - 888. [Abstract] [Full Text] [PDF]

				J. M. Zigman and J. K. Elmquist Minireview: From Anorexia to Obesity--The Yin and Yang of Body Weight Control Endocrinology, September 1, 2003; 144(9): 3749 - 3756. [Abstract] [Full Text] [PDF]

				D. E. Cummings and M. H. Shannon Ghrelin and Gastric Bypass: Is There a Hormonal Contribution to Surgical Weight Loss? J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 2999 - 3002. [Full Text] [PDF]

				D. L. Marks, A. A. Butler, R. Turner, G. Brookhart, and R. D. Cone Differential Role of Melanocortin Receptor Subtypes in Cachexia Endocrinology, April 1, 2003; 144(4): 1513 - 1523. [Abstract] [Full Text] [PDF]

				D. E. Cummings and M. H. Shannon Roles for Ghrelin in the Regulation of Appetite and Body Weight Arch Surg, April 1, 2003; 138(4): 389 - 396. [Full Text] [PDF]

				H. Hosoda, M. Kojima, and K. Kangawa Ghrelin and the Regulation of Food Intake and Energy Balance Mol. Interv., December 1, 2002; 2(8): 494 - 503. [Abstract] [Full Text]

				C. Fekete, S. Sarkar, W. M. Rand, J. W. Harney, C. H. Emerson, A. C. Bianco, and R. M. Lechan Agouti-Related Protein (AGRP) Has a Central Inhibitory Action on the Hypothalamic-Pituitary-Thyroid (HPT) Axis; Comparisons between the Effect of AGRP and Neuropeptide Y on Energy Homeostasis and the HPT Axis Endocrinology, October 1, 2002; 143(10): 3846 - 3853. [Abstract] [Full Text] [PDF]

				T. M. Reyes and P. E. Sawchenko Involvement of the Arcuate Nucleus of the Hypothalamus in Interleukin-1-Induced Anorexia J. Neurosci., June 15, 2002; 22(12): 5091 - 5099. [Abstract] [Full Text] [PDF]

				A. Inui Cancer Anorexia-Cachexia Syndrome: Current Issues in Research and Management CA Cancer J Clin, March 1, 2002; 52(2): 72 - 91. [Abstract] [Full Text] [PDF]

				R. M. Lechan and J. B. Tatro Editorial: Hypothalamic Melanocortin Signaling in Cachexia Endocrinology, August 1, 2001; 142(8): 3288 - 3291. [Full Text] [PDF]