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The Role of Central Melanocortins in Cachexia

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Energy Metabolism and Obesity

Part of the book series: Contemporary Endocrinology ((COE))

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Abstract

Cachexia is a clinical syndrome of wasting that accompanies many chronic diseases including cancer, renal failure, and heart failure. This condition is marked by an increase in energy expenditure and preferential loss of lean body mass, creating a striking catabolic state. Cachexia contrasts with starvation, a state in which energy expenditure decreases and muscle mass is maintained while fat stores are consumed. In contrast, cachexia is accompanied by a paradoxical anorexia that occurs despite ongoing weight loss and negative calorie balance. This loss of appetite is a significant component of the decreased quality of life experienced by patients with cachexia. Few treatments have proved to be of significant benefit to patients suffering from cachexia. One new treatment that shows promise is pharmacologic blockade of the central melanocortin system. The importance of this system in maintaining normal body weight in humans is highlighted by the finding that disordered melanocortin signaling results in early-onset morbid obesity and dramatic increases in lean body mass in humans. Emerging evidence suggests that blocking this system via pharmacologic antagonists to the type 4 melanocortin receptor (MC4R) may restore appetite and lean body mass in subjects with cachexia caused by a variety of underlying disorders. This review will focus on current pathophysiologic mechanisms involved in cachexia and will outline the central melanocortin pathway as pertaining to these diseases and summarize early animal data using MC4R antagonists to treat cachexia.

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  1. Katz, AM and Katz, PB, Diseases of the heart in the works of Hippokrates. Br Heart J, 1962. 24: p. 257–264.

    Article  PubMed  CAS  Google Scholar 

  2. Deans, C and Wigmore, SJ, Systemic inflammation, cachexia and prognosis in patients with cancer. Curr Opin Clin Nutr Metab Care, 2005. 8(3): p. 265–269.

    Article  PubMed  CAS  Google Scholar 

  3. Larkin, M, Thwarting the dwindling progression of cachexia. Lancet, 1998. 351: p. 1336.

    Article  PubMed  CAS  Google Scholar 

  4. Laviano, A, Meguid, MM, Inui, A, et al., Therapy insight: Cancer anorexia-cachexia syndrome–when all you can eat is yourself. Nat Clin Pract Oncol, 2005. 2(3): p. 158–165.

    Article  PubMed  CAS  Google Scholar 

  5. Maltoni, M, Caraceni, A, Brunelli, C, et al., Prognostic factors in advanced cancer patients: evidence-based clinical recommendations–a study by the Steering Committee of the European Association for Palliative Care. J Clin Oncol, 2005. 23(25): p. 6240–6248.

    Article  PubMed  Google Scholar 

  6. Guenter, P, Muurahainen, N, Simons, G, et al., Relationships among nutritional status, disease progression, and survival in HIV infection. J Acquir Immune Defic Syndr, 1993. 6(10): p. 1130–1138.

    PubMed  CAS  Google Scholar 

  7. Anker, SD and Sharma, R, The syndrome of cardiac cachexia. Int J Cardiol, 2002. 85(1): p. 51–66.

    Article  PubMed  Google Scholar 

  8. Mehrotra, R and Kopple, JD, Nutritional management of maintenance dialysis patients: why aren’t we doing better? Annu Rev Nutr, 2001. 21: p. 343–379.

    Article  PubMed  CAS  Google Scholar 

  9. Qureshi, AR, Alvestrand, A, Divino-Filho, JC, et al., Inflammation, malnutrition, and cardiac disease as predictors of mortality in hemodialysis patients. J Am Soc Nephrol, 2002. 13 Suppl 1: p. S28–36.

    PubMed  Google Scholar 

  10. Tisdale, MJ, Cachexia in cancer patients. Nat Rev Cancer, 2002. 2(11): p. 862–871.

    Article  PubMed  CAS  Google Scholar 

  11. Gelin, J, Moldawer, LL, Lonnroth, C, et al., Role of endogenous tumor necrosis factor alpha and interleukin 1 for experimental tumor growth and the development of cancer cachexia. Cancer Res, 1991. 51(1): p. 415–421.

    PubMed  CAS  Google Scholar 

  12. Plata-Salaman, CR, Immunomodulators and feeding regulation: A humoral link between the immune and nervous systems. Br Behav Immun, 1989. 3: p. 193–213.

    Article  CAS  Google Scholar 

  13. Moldawer, LL, Andersson, C, Gelin, J, et al., Regulation of food intake and hepatic protein synthesis by recombinant-derived cytokines. Am J Physiol, 1988. 254(3 Pt 1): p. G450–456.

    PubMed  CAS  Google Scholar 

  14. Plata-Salaman, CR, Immunomodulators and feeding regulation: a humoral link between the immune and nervous systems. Brain Behav Immun, 1989. 3(3): p. 193–213.

    Article  PubMed  CAS  Google Scholar 

  15. Scott, HR, McMillan, DC, Crilly, A, et al., The relationship between weight loss and interleukin 6 in non-small-cell lung cancer. Br J Cancer, 1996. 73(12): p. 1560–1562.

    PubMed  CAS  Google Scholar 

  16. Abad, LW, Schmitz, HR, Parker, R, et al., Cytokine responses differ by compartment and wasting status in patients with HIV infection and healthy controls. Cytokine, 2002. 18(5): p. 286–293.

    Article  PubMed  CAS  Google Scholar 

  17. Bonfield, TL, Panuska, JR, Konstan, MW, et al., Inflammatory cytokines in cystic fibrosis lungs. Am J Respir Crit Care Med, 1995. 152(6 Pt 1): p. 2111–2118.

    PubMed  CAS  Google Scholar 

  18. Levine, B, Kalman, J, Mayer, L, et al., Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med, 1990. 323(4): p. 236–241.

    Article  PubMed  CAS  Google Scholar 

  19. Roubenoff, R, Roubenoff, RA, Cannon, JG, et al., Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation. J Clin Invest, 1994. 93(6): p. 2379–2386.

    PubMed  CAS  Google Scholar 

  20. Torre-Amione, G, Kapadia, S, Benedict, C, et al., Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol, 1996. 27(5): p. 1201–1206.

    Article  PubMed  CAS  Google Scholar 

  21. Wigmore, SJ, Fearon, KC, Maingay, JP, et al., Down-regulation of the acute-phase response in patients with pancreatic cancer cachexia receiving oral eicosapentaenoic acid is mediated via suppression of interleukin-6. Clin Sci (Lond), 1997. 92(2): p. 215–221.

    CAS  Google Scholar 

  22. Inui, A, Cancer Anorexia-Cachexia Syndrome: Are Neuropeptides the Key? Cancer Res, 1999. 59: p. 4493–4501.

    PubMed  CAS  Google Scholar 

  23. Plata-Salaman, CR, Brain mechanisms in cytokine-induced anorexia. Psychoneuroendocrinology, 1998. 24: p. 25–41.

    Article  Google Scholar 

  24. Turrin, NP, Ilyin, SE, Gayle, DA, et al., Interleukin-1beta system in anorectic catabolic tumor-bearing rats. Curr Opin Clin Nutr Metab Care, 2004. 7(4): p. 419–426.

    Article  PubMed  CAS  Google Scholar 

  25. Plata-Salaman, CR and Borkoski, JP, Chemokines/intercrines and central regulation of feeding. Am J Physiol, 1994. 266: p. R1711–R1715.

    PubMed  CAS  Google Scholar 

  26. Plata-Salaman, CR, Sonti, G, Borkoski, JP, et al., Anorexia induced by chronic central administration of cytokines at estimated pathophysiological concentrations. Phys Behav, 1996. 60: p. 867–875.

    Article  CAS  Google Scholar 

  27. Szelenyi, J, Cytokines and the central nervous system. Brain Res Bull, 2001. 54(4): p. 329–338.

    Article  PubMed  CAS  Google Scholar 

  28. Barber, MD, Fearon, KC, Delmore, G, et al., Should cancer patients with incurable disease receive parenteral or enteral nutritional support? Eur J Cancer, 1998. 34(3): p. 279–285.

    Article  PubMed  CAS  Google Scholar 

  29. Della Cuna, GR, Pellegrini, A, and Piazzi, M, Effect of methylprednisolone sodium succinate on quality of life in preterminal cancer patients: a placebo-controlled, multicenter study. The Methylprednisolone Preterminal Cancer Study Group. Eur J Cancer Clin Oncol, 1989. 25(12): p. 1817–1821.

    Article  PubMed  CAS  Google Scholar 

  30. Loprinzi, CL, Schaid, DJ, Dose, AM, et al., Body-composition changes in patients who gain weight while receiving megestrol acetate. J Clin Oncol, 1993. 11(1): p. 152–154.

    PubMed  CAS  Google Scholar 

  31. Mann, M, Koller, E, Murgo, A, et al., Glucocorticoidlike activity of megestrol. A summary of Food and Drug Administration experience and a review of the literature. Arch Intern Med, 1997. 157(15): p. 1651–1656.

    Article  PubMed  CAS  Google Scholar 

  32. Eriksson, C, Nobel, S, Winblad, B, et al., Expression of interleukin 1 alpha and beta, and interleukin 1 receptor antagonist mRNA in the rat central nervous system after peripheral administration of lipopolysaccharides. Cytokine, 2000. 12(5): p. 423-431.

    Article  PubMed  CAS  Google Scholar 

  33. Gayle, D, Ilyin, SE, Flynn, MC, et al., Lipopolysaccharide (LPS)- and muramyl dipeptide (MDP)-induced anorexia during refeeding following acute fasting: Characterization of brain cytokine and neuropeptide systems mRNAs. Brain Res, 1998. 795: p. 77–86.

    Article  PubMed  CAS  Google Scholar 

  34. Laye, S, Gheusi, G, Cremona, S, et al., Endogenous brain IL-1 mediates the response to peripheral LPS. Am J Phys Reg Integr Comp Physiol, 2000. 279(1): p. R93–R98.

    CAS  Google Scholar 

  35. Takao, T, Hashimoto, K, and De Souza, EB, Modulation of interleukin-1 receptors in the neuro-endocrine-immune axis. Int J Dev Neurosci, 1995. 13(3-4): p. 167–178.

    Article  PubMed  CAS  Google Scholar 

  36. Ericsson, A, C., L, Hart, RP, et al., Type 1 interleukin-1 receptor in the rat brain: distribution, regulation, and relationship to sites of IL-1-induced cellular activation. J Comp Neurol, 1995. 361(4): p. 681–698.

    Article  PubMed  CAS  Google Scholar 

  37. Nadeau, S and Rivest, S, Effects of circulating tumor necrosis factor on the neuronal activity and expression of the genes encoding the tumor necrosis factor receptors (p55 and p75) in the rat brain: a view from the blood-brain barrier. Neuroscience, 1999. 93(4): p. 1449–1464.

    Article  PubMed  CAS  Google Scholar 

  38. Utsuyama, M and Hirokawa, K, Differential expression of various cytokine receptors in the brain after stimulation with LPS in young and old mice. Exp Gerontol, 2002. 37(2-3): p. 411–420.

    Article  PubMed  CAS  Google Scholar 

  39. Yamakuni, H, Minami, M, and Satoh, M, Localization of mRNA for leukemia inhibitory factor receptor in the adult rat brain. J Neuroimmunol, 1996. 70(1): p. 45–53.

    Article  PubMed  CAS  Google Scholar 

  40. Elmquist, JK, Scammell, TE, Jacobsen, CD, et al., Distribution of Fos-like immunoreactivity in the rat brain following intravenous lipopolysaccharide administration. J Comp Neurol, 1996. 371(1): p. 85–103.

    Article  PubMed  CAS  Google Scholar 

  41. Laflamme, N and Rivest, S, Effects of systemic immunogenic insults and circulating proinflammatory cytokines on the transcription of the inhibitory factor kappaB alpha within specific cellular populations of the rat brain. J Neurochem, 1999. 73(1): p. 309–321.

    Article  PubMed  CAS  Google Scholar 

  42. Broback, JR, Tepperman, J, and Long, CNH, Experimental hypothalamic hyperphagia in the albino rat. Yale Journal of Biological Medicine, 1943. 15: p. 831–853.

    Google Scholar 

  43. Hotheriogtoa, AW and Ranson, SW, Hypothalamic lesions and adiposity in the rat. Anatomical Record, 1940. 78: p. 149–172.

    Google Scholar 

  44. Muller, HL, Bruhnken, G, Emser, A, et al., Longitudinal study on quality of life in 102 survivors of childhood craniopharyngioma. Childs Nerv Syst, 2005. 21(11): p. 975–980.

    Article  PubMed  Google Scholar 

  45. Cone, RD, Cowley, MA, Butler, AA, et al., The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis. Int J Obes Relat Metab Disord, 2001. 25 Suppl 5: p. S63–67.

    Article  PubMed  CAS  Google Scholar 

  46. Cowley, MA, Smith, RG, Diano, S, et al., The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron, 2003. 37(4): p. 649–661.

    Article  PubMed  CAS  Google Scholar 

  47. Schwartz, MW, Seeley, RJ, Campfield, LA, et al., Identification of targets of leptin action in rat hypothalamus. J Clin Invest, 1996. 98(5): p. 1101–1106.

    Article  PubMed  CAS  Google Scholar 

  48. Rizk, NM, Joost, HG, and Eckel, J, Increased hypothalamic expression of the p75 tumor necrosis factor receptor in New Zealand obese mice. Horm Metab Res, 2001. 33(9): p. 520–524.

    Article  PubMed  CAS  Google Scholar 

  49. Yabuuchi, K, Minami, M, Katsumata, S, et al., Localization of type-1 interleukin-1 receptor mRNA in the rat brain. Brain Res Mol Brain Res, 1994. 27(1): p. 27–36.

    Article  PubMed  CAS  Google Scholar 

  50. Jacobowitz, DM and O’Donohue, TL, a-Melanocyte-stimulating hormone: immunohistochemical identification and mapping in neurons of rat brain. Proc Natl Acad Sci USA, 1978. 75: p. 6300–6304.

    Article  PubMed  CAS  Google Scholar 

  51. Benoit, S, Schwartz, M, Baskin, D, et al., CNS melanocortin system involvement in the regulation of food intake. Horm Behav, 2000. 37(4): p. 299–305.

    Article  PubMed  CAS  Google Scholar 

  52. Cone, RD, Anatomy and regulation of the central melanocortin system. Nat Neurosci, 2005. 8(5): p. 571–578.

    Article  PubMed  CAS  Google Scholar 

  53. Fan, W, Boston, BA, Kesterson, RA, et al., Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature, 1997. 385: p. 165–168.

    Article  PubMed  CAS  Google Scholar 

  54. Huszar, D, Lynch, CA, Fairchild-Huntress, V, et al., Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell, 1997. 88: p. 131–141.

    Google Scholar 

  55. Vaisse, C, Clement, K, Guy-Grand, B, et al., A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nature Genetics, 1998. 20: p. 113–114.

    Article  PubMed  CAS  Google Scholar 

  56. Yeo, GS, Farooqi, IS, Aminian, S, et al., A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet, 1998. 20(2): p. 111–112.

    Article  PubMed  CAS  Google Scholar 

  57. Farooqi, IS, Keogh, JM, Yeo, GS, et al., Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med, 2003. 348(12): p. 1085–1095.

    Article  PubMed  CAS  Google Scholar 

  58. Fan, W, Dinulescu, DM, Butler, AA, et al., The central melanocortin system can directly regulate serum insulin levels. Endocrinology, 2000. 141(9): p. 3072–3079.

    Article  PubMed  CAS  Google Scholar 

  59. Haskell-Luevano, C, Chen, P, Li, C, et al., Characterization of the neuroanatomical distribution of agouti-related protein immunoreactivity in the rhesus monkey and the rat. Endocrinology, 1999. 140(3): p. 1408–1415.

    Article  PubMed  CAS  Google Scholar 

  60. Fong, TM, Mao, C, MacNeil, C, et al., ART (protein product of agouti-related transcript) as an antagonist of MC-3 and MC-4 receptors. Biochem Biophys Res Commun, 1997. 237: p. 629–631.

    Article  PubMed  CAS  Google Scholar 

  61. Ollmann, MM, Wilson, BD, Yang, YK, et al., Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science, 1997. 278(5335): p. 135–138.

    Article  PubMed  CAS  Google Scholar 

  62. Mizuno, TM and Mobbs, CV, Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. Endocrinology, 1999. 140(2): p. 814–817.

    Article  PubMed  CAS  Google Scholar 

  63. Hagan, MM, Rushing, PA, Pritchard, LM, et al., Long-term orexigenic effects of AgRP-(83-132) involve mechanisms other than melanocortin receptor blockade. Am J Physiol Regul Integr Comp Physiol, 2000. 279(1): p. R47–R52.

    PubMed  CAS  Google Scholar 

  64. Nijenhuis, WA, Oosterom, J, and Adan, RA, AGRP (83-132) acts as an inverse agonist on the human melanocortin-4 receptor. Mol Endocrinol, 2001. 15(1): p. 164–171.

    Article  PubMed  CAS  Google Scholar 

  65. Rivest, S and Laflamme, N, Neuronal activity and neuropeptide gene transcription in the brains of immune-challenged rats. J Neuroendocrinol, 1995. 7(7): p. 501–525.

    Article  PubMed  CAS  Google Scholar 

  66. Scarlett, JM, Joppa, MA, Markison, S, et al., Direct activation of the hypothalamic melanocortin system by interleukin-1. Abs Endocr Soc (2004):OR6-3, 2005.

    Google Scholar 

  67. Lennie, TA, Relationship of body energy status to inflammation-induced anorexia and weight loss. Physiol Behav, 1998. 64(4): p. 475–481.

    Article  PubMed  CAS  Google Scholar 

  68. Lennie, TA, Wortman, MD, and Seeley, RJ, Activity of body energy regulatory pathways in inflammation-induced anorexia. Physiol Behav, 2001. 73(4): p. 517–523.

    Article  PubMed  CAS  Google Scholar 

  69. Sergeyev, V, Broberger, C, and Hokfelt, T, Effect of LPS administration on the expression of POMC, NPY, galanin, CART and MCH mRNAs in the rat hypothalamus. Brain Res Mol Brain Res, 2001. 90(2): p. 93–100.

    Article  PubMed  CAS  Google Scholar 

  70. Huang, QH, Hruby, VJ, and Tatro, JB, Role of central melanocortins in endotoxin-induced anorexia. Am J Physiol, 1999. 276(3 pt 2): p. R864–R871.

    PubMed  CAS  Google Scholar 

  71. Tatro, JB, Huszar, D, Fairchild-Huntress, V, et al., Role of the melanocortin-4 receptor in thermoregulatory responses to central IL-1 Society for Neuroscience Abstracts, 1999. 25(624.4): p. 558.

    Google Scholar 

  72. Lawrence, CB and Rothwell, NJ, Anorexic but not pyrogenic actions of interleukin-1 are modulated by central melanocortin-3/4 receptors in the rat. J Neuroendocrinol, 2001. 13(6): p. 490–495.

    Article  PubMed  CAS  Google Scholar 

  73. Marks, DL, Butler, AA, Turner, R, et al., Differential role of melanocortin receptor subtypes in cachexia. Endocrinology, 2003. 144(4): p. 1513–1523.

    Article  PubMed  CAS  Google Scholar 

  74. Marks, DL, Ling, N, and Cone, RD, Role of the Central Melanocortin System in Cachexia. Cancer Res, 2001. 61(4): p. 1432–1438.

    PubMed  CAS  Google Scholar 

  75. Wisse, BE, Frayo, RS, Schwartz, MW, et al., Reversal of cancer anorexia by blockade of central melanocortin receptors in rats. Endocrinology, 2001. 142(8): p. 3292–3301.

    Article  PubMed  CAS  Google Scholar 

  76. Cheung, W, Yu, PX, Little, BM, et al., Role of leptin and melanocortin signaling in uremia-associated cachexia. J Clin Invest, 2005. 115(6): p. 1659–1665.

    Article  PubMed  CAS  Google Scholar 

  77. Vos, TJ, Caracoti, A, Che, JL, et al., Identification of 2-[2-[2-(5-bromo-2- methoxyphenyl)-ethyl]-3-fluorophenyl]-4,5-dihydro-1H-imidazole (ML00253764), a small molecule melanocortin 4 receptor antagonist that effectively reduces tumor-induced weight loss in a mouse model. J Med Chem, 2004. 47(7): p. 1602–1604.

    Article  PubMed  CAS  Google Scholar 

  78. Markison, S, Foster, AC, Chen, C, et al., The regulation of feeding and metabolic rate and the prevention of murine cancer cachexia with a small-molecule melanocortin-4 receptor antagonist. Endocrinology, 2005. 146(6): p. 2766–2773.

    Article  PubMed  CAS  Google Scholar 

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  1. University of lowa, lowa City, IA

    Patricia A. Donohoue MD

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Marks, D.L. (2007). The Role of Central Melanocortins in Cachexia. In: Donohoue, P.A. (eds) Energy Metabolism and Obesity. Contemporary Endocrinology. Humana Press. https://doi.org/10.1007/978-1-60327-139-4_4

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  • DOI: https://doi.org/10.1007/978-1-60327-139-4_4

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