Drugs, Exercise, and the Melanocortin-4 Receptor— Different Means, Same Ends: Treating Obesity

  • Jay W. Schaub
  • Erin B. Bruce
  • Carrie Haskell-Luevano
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 681)


As the percentage of obese humans expands, new options for weight loss are being explored. Body weight homeostasis is the result of a balance between energy intake (food) and expenditure (activity). A shift in homeostasis into a negative balance results in weight loss. Two potential options available for the management of body weight, as related to the melanocortin system, are exercise (increase energy expenditure) and drugs targeting the melanocortin-4 receptors for satiety.


Energy Homeostasis Arcuate Nucleus Voluntary Exercise Obese Phenotype POMC Neuron 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell 2001; 104:531–543.CrossRefPubMedGoogle Scholar
  2. 2.
    Obesity: Preventing and managing the global epidemic: Report of a WHO consultation. Geneva, Switzerland: World Health Organization; 1999.Google Scholar
  3. 3.
    O’Brien PE, Dixon JB. The extent of the problem of obesity. Am J Surg 2002; 184(6):S4–S8.CrossRefGoogle Scholar
  4. 4.
    West DB, Boozer CN, Moody DL et al. Dietary obesity in nine inbred mouse strains. Am J Physiol Regul Integr Comp Physiol 1992; 262(6):R1025–1032.Google Scholar
  5. 5.
    Vaisse C, Clement K, Guy-Grand B et al. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 1998; 20:113–114.CrossRefPubMedGoogle Scholar
  6. 6.
    Yeo GSH, Farooqi IS, Aminian S et al. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 1998; 20:111–112.CrossRefPubMedGoogle Scholar
  7. 7.
    Krude H, Biebermann H, Luck W et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998; 19:155–157.CrossRefPubMedGoogle Scholar
  8. 8.
    Marti A, Corbalan M, Forga L et al. A novel nonsense mutation in the melanocortin-4 receptor associated with obesity in a Spanish population. Int J Obes Relat Metab Disord 2003; 27(3):385–388.CrossRefPubMedGoogle Scholar
  9. 9.
    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):1085–1095.CrossRefPubMedGoogle Scholar
  10. 10.
    Mountjoy KG, Robbins LS, Mortrud MT et al. The cloning of a family of genes that encode the melanocortin receptors. Science 1992; 257(5074):1248–1251.CrossRefPubMedGoogle Scholar
  11. 11.
    Chhajlani V, Wikberg JE. Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA. FEBS Lett 1992; 309(3):417–420.CrossRefPubMedGoogle Scholar
  12. 12.
    Gantz I.; Konda, Y.; Tashiro, T et al. Molecular cloning of a novel melanocortin receptor. J Biol Chem 1993; 268:8246–8250.PubMedGoogle Scholar
  13. 13.
    Roselli-Rehfuss L,; Mountjoy, K.G.; Robbins, L.S. et al. Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc Natl Acad Sci USA 1993; 90:8856–8860.CrossRefPubMedGoogle Scholar
  14. 14.
    Gantz I, Miwa H, Konda Y et al. Molecular cloning, expression and gene localization of a fourth melanocortin receptor. J Biol Chem 1993; 268(20):15174–15179.PubMedGoogle Scholar
  15. 15.
    Gantz I, Shimoto Y, Konda Y et al. Molecular cloning, expression and characterization of a fifth melanocortin receptor. Biochem Biophys Res Commun 1994; 200(3):1214–1220.CrossRefPubMedGoogle Scholar
  16. 16.
    Mountjoy K.G.; Mortrud, M.T.; Low M.J. et al. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol 1994; 8:1298–1308.CrossRefPubMedGoogle Scholar
  17. 17.
    Buckley DI, Ramachandran J. Characterization of corticotropin receptors on andrenocortical cells. PNAS 1981; 78(12):7431–7435.CrossRefPubMedGoogle Scholar
  18. 18.
    Gerst JE, Sole J, Saloman Y. Dual regulation of beta-melanotropin receptor function and adenylate cyclase by calcium and guanosine nucleotides in the M2R melanoma cell line. Mol Pharmacol 1987; 31:81–88.PubMedGoogle Scholar
  19. 19.
    Mertz LM, Catt KJ. Adrenocorticotropin receptors functional expression from rat adrenal mRNA in xenopus laevis oocytes. PNAS 1991; 88(19):8525–8529.CrossRefPubMedGoogle Scholar
  20. 20.
    Konda Y, Gantz I, DelValle J et al. Interaction of dual intracellular signaling pathways activated by the melanocortin-3 receptor. J Biol Chem 1994; 269(18):13162–13166.PubMedGoogle Scholar
  21. 21.
    Mountjoy KG, Kong PL, Taylor JA et al. Melanocortin receptor-mediated mobilization of intracellular free calcium in HEK293 cells. Physiol Genomics 2001; 5:11–19.PubMedGoogle Scholar
  22. 22.
    Newman EA, Chai B-X, Zhang W et al. Activation of the melanocortin-4 receptor mobilizes intracellular free calcium in immortalized hypothalamic neurons. J Invest Surg 2006; 132:201–207.Google Scholar
  23. 23.
    Al-Majed H, Jones P, Persaud S et al. ACTH stimulates insulin secretion from MIN6 cells and primary mouse and human islets of Langerhans. J Endocrinol. 2004; 180:155–166.CrossRefPubMedGoogle Scholar
  24. 24.
    Lerner AB, McGuire JS. Effect of alpha-and beta-melanocyte stimulating hormones on the skin colour of man. Nature 1961; 189:176–179.CrossRefPubMedGoogle Scholar
  25. 25.
    Eberle AN. The melanotropins: Chemistry, physiology and mechanisms of action. Karger: Basel; 1988.Google Scholar
  26. 26.
    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):135–138.CrossRefPubMedGoogle Scholar
  27. 27.
    Shutter J, Graham M, Kinsey A et al. Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev 1997; 11(5):593–602.CrossRefPubMedGoogle Scholar
  28. 28.
    Graham M, Shutter J, Sarmiento U et al. Overexpression of AGRT leads to obesity in transgenic mice. Nat Genet 1997; 17:273–274.CrossRefPubMedGoogle Scholar
  29. 29.
    Giraudo SQ, Billington CJ, Levine AS. Feeding effects of hypothalamic injection of melanocortin 4 receptor ligands. Brain Research 1998; 809:302–306.CrossRefPubMedGoogle Scholar
  30. 30.
    Fan W, Boston BA, Kesterson RA et al. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 1997; 385:165–168.CrossRefPubMedGoogle Scholar
  31. 31.
    Thiele TE, Dijk GV, Yagaloff KA et al. Central infusion of melanocortin agonist MTII in rats assessment of c-Fos expression and taste aversion. Am J Physiol Regulatory Integrative Comp Physiol 1998; 274:248–254.Google Scholar
  32. 32.
    Boston BA, Cone RD. Characterization of melanocortin receptor subtype expression in murine adipose tissues and in the 3T3-L1 cell line. Endocrinology 1996; 137(5):2043–2050.CrossRefPubMedGoogle Scholar
  33. 33.
    Butler AA, Kesterson RA, Khong K et al. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 2000; 141(9):3518–3521.CrossRefPubMedGoogle Scholar
  34. 34.
    Chen AS, Marsh DJ, Trumbauer ME et al. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet 2000; 26:97–102.CrossRefPubMedGoogle Scholar
  35. 35.
    Kishi T, Aschkenasi CJ, Lee CE et al. Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J Comp Neurol 2003; 457(213–235).CrossRefPubMedGoogle Scholar
  36. 36.
    Liu H, Kishi T, Rosenberry AG et al. Transgenic mice expressing green fluorescent protein under the control of the melanocortin-4 receptor promoter. J Neurosci 2003; 23(18):7143–7154.PubMedGoogle Scholar
  37. 37.
    Van Der Ploeg LH, Martin WJ, Howard AD et al. A role for the melanocortin 4 receptor in sexual function. Proc Natl Acad Sci USA 2002; 99:11381–11386.CrossRefPubMedGoogle Scholar
  38. 38.
    Huszar D, Lynch CA, Fairchild-Huntress V et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997; 88:131–141.CrossRefPubMedGoogle Scholar
  39. 39.
    Chen W, Kelly MA, Opitz-Araya X et al. Exocrine gland dysfunction in MC5-R deficient mice: Evidence for coordinated regulation of exocrine gland functions by melanocortin peptides. Cell 1997; 91:789–798.CrossRefPubMedGoogle Scholar
  40. 40.
    Lu D, Willard D, Patel IR et al. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 1994; 371:799–802.CrossRefPubMedGoogle Scholar
  41. 41.
    McNulty JC, Jackson PJ, Thompson DA et al. Structures of the agouti signaling protein. J Mol Biol 2005; 346(4):1059–1070.CrossRefPubMedGoogle Scholar
  42. 42.
    Bultman SJ, Michaud EJ, Woychick RP. Molecular characterization of the mouse agouti locus. Cell 1992; 71:1195–1204.CrossRefPubMedGoogle Scholar
  43. 43.
    Butler AA, Marks DL, Fan W et al. Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. Nat Neurosci 2001; 4(6):605–611.CrossRefPubMedGoogle Scholar
  44. 44.
    Haskell-Luevano C, Schaub JW, Andreasen A et al. Voluntary exercise prevents the obese and diabetic metabolic syndrome of the melanocortin-4 receptor knockout mouse. FASEB J 2009; 23(2):642–655.CrossRefPubMedGoogle Scholar
  45. 45.
    Haskell-Luevano C, Todorovic A, Gridley K et al. The melanocortin pathway: effects of voluntary exercise on the melanocortin-4 receptor knockout mice and ACTH(1–24) ligand SAR at the Melanocortin-2 Receptor. Endocr Res 2004; 30(4):591–597.CrossRefPubMedGoogle Scholar
  46. 46.
    Irani BG, Xiang Z, Moore MC et al. Voluntary exercise delays monogenetic obesity and overcomes reproductive dysfunction of the melanocortin-4 receptor knockout mouse. Biochem Biophys Res Commun 2005; 326:638–644.CrossRefPubMedGoogle Scholar
  47. 47.
    Sutton GM, Trevaskis JL, Hulver MW et al. Diet-genotype interactions in the development of the obese, insulin-resistant phenotype of C57BL/6J mice lacking melanocortin-3 or-4 receptors. Endocrinology 2006; 147(5):2183–2196.CrossRefPubMedGoogle Scholar
  48. 48.
    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):1408–1415.CrossRefPubMedGoogle Scholar
  49. 49.
    Chronwall B, DiMaggio D, Massari V et al. The anatomy of neuropeptide Y containing neurons in the rat brain. Neuroscience 1985; 15:1159–1181.CrossRefPubMedGoogle Scholar
  50. 50.
    deQuidt M, Emson P. Distribution of Neuropeptide Y-like immunoreactivity in the rat central nervous system. II. Immunohistochemical analysis. Neuroscience 1986; 18:545–618.CrossRefGoogle Scholar
  51. 51.
    Allen Y, Adrian T, Allen J et al. Neuropeptide Y distribution in the rat brain. Science 1983; 221:877–879.CrossRefPubMedGoogle Scholar
  52. 52.
    Broberger C, Visser TJ, Kuhar MJ et al. Neuropeptide Y innervation and neuropeptide-Y-Y1-receptor-expressing neurons in the paraventricular hypothalamic nucleus of the mouse. Neuroendocrinology 1999; 70:295–305.CrossRefPubMedGoogle Scholar
  53. 53.
    Hahn TM, Breininger JF, Baskin DG et al. Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nat Neurosci 1998; 1(4):271–272.CrossRefPubMedGoogle Scholar
  54. 54.
    Jacobowitz DM, O’Donohue TL. Alpha-melanocyte stimulation hormone Immunohistochemical identification and mapping in neurons of rat brain. PNAS 1978; 75(12):6300–6304.CrossRefPubMedGoogle Scholar
  55. 55.
    Wilcox JN, Roberts JL, Chronwall BM et al. Localization of proopiomelanocortin mRNA in functional subsets of neurons defined by axonal projections. J Neurosci Res 1986; 16:89–96.CrossRefPubMedGoogle Scholar
  56. 56.
    Elias CF, Lee C, Kelly J et al. Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron 1998; 21:1375–1385.CrossRefPubMedGoogle Scholar
  57. 57.
    Couceyro PR, Koylu EO, Kuhar MJ. Further studies on the anatomical distribution of CART by in situ hybridization. J Chem Neuroanat 1997; 12:229–241.CrossRefPubMedGoogle Scholar
  58. 58.
    Douglass J, McKinzie AA, Couceyro P. PCR differential display identifies a rat brain mRNA that is transcriptionally regulated by cocaine and amphetamine. J Neurosci 1995; 15(3):2471–2481.PubMedGoogle Scholar
  59. 59.
    Low MJ, Simerly RB, Cone RD. Receptors for the melanocortin peptides in the central nervous system. Curr Opin Endocrinol Diabetes 1994; 1:79–88.CrossRefGoogle Scholar
  60. 60.
    Cowley MA, Smart JL, Rubinstein M et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus 2001; 411(6836):480–484.Google Scholar
  61. 61.
    Halaas JL, Gajiwala KS, Maffei M et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269:543–546.CrossRefPubMedGoogle Scholar
  62. 62.
    Satoh N, Ogawa Y, Katsuura G et al. Satiety effect and the sympathetic activation of leptin are mediated by hypothalamic melanocortin system. Neurosci Lett 1998; 249:107–110.CrossRefPubMedGoogle Scholar
  63. 63.
    Cheung CC, Clifton DK, Steiner RA. Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology 1997; 138(10):4489–4492.CrossRefPubMedGoogle Scholar
  64. 64.
    Niswender K, Baskin D, Schwartz M. Insulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis. Trends Endocrinol Metab 2004; 15:362–369.PubMedGoogle Scholar
  65. 65.
    Minokoshi Y, Haque M, Shimazu T. Microinjection of leptin into the ventromedial hypothalamus increases glucose uptake in peripheral tissues in rats. Diabetes 1999; 48(2):287–291.CrossRefPubMedGoogle Scholar
  66. 66.
    Fan W, Dinulescu D, Butler A et al. The central melanocortin system can directly regulate serum insulin levels. Endocrinology 2000; 141:3072–3079.CrossRefPubMedGoogle Scholar
  67. 67.
    Obici S, Feng Z, Tan J et al. Central melanocortin receptors regulate insulin action. J Clin Invest 2001; 108:1079–1085.PubMedGoogle Scholar
  68. 68.
    Benoit SC, Air EL, Coolen LM et al. The catabolic action of insulin in the brain is mediated by melanocortins. J Neurosci 2002; 22(20):9048–9052.PubMedGoogle Scholar
  69. 69.
    Heisler LK, Cowley MA, Tecott LH et al. Activation of central melanocortin pathways by fenfluramine. Science 2002; 297(5581):609–611.CrossRefPubMedGoogle Scholar
  70. 70.
    Heisler LK, Jobst EE, Sutton GM et al. Serotonin reciprocally regulates melanocortin neurons to modulate food intake. Neuron 2006; 51(2):239–249.CrossRefPubMedGoogle Scholar
  71. 71.
    Lam DD, Przydzial MJ, Ridley SH et al. Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors. Endocrinology 2008; 149(3):1323–1328.CrossRefPubMedGoogle Scholar
  72. 72.
    Davidson SR, Burnett M, Hoffman-Goetz L. Training effects in mice after long-term voluntary exercise. Med Sci Sports Exerc 2006; 250–255.Google Scholar
  73. 73.
    Fediuc S, Campbell JE, Riddell MC. Effect of voluntary wheel running on circadian corticosterone release and on HPA axis responsiveness to restraint stress in Sprague-Dawley rats. J Appl Physiol 2006; 100:1867–1875.CrossRefPubMedGoogle Scholar
  74. 74.
    Flores M.B.; Fernandes, M.F.; Ropelle, E.R. et al. Exercise improves insulin and leptin sensitivity in hypothalamus of wistar rats. Diabetes 2006; 55:2554–2561.CrossRefPubMedGoogle Scholar
  75. 75.
    Ji LL. Modulation of skeletal muscle antioxidant defense by exercise: Role of redox signaling. Free Radic Biol Med 2008; 44:142–152.CrossRefPubMedGoogle Scholar
  76. 76.
    Martins C, Morgan LM, Bloom SR et al. Effects of exercise on gut peptides, energy uptake and appetite. J Endocrinol 2007; 193:251–258.CrossRefPubMedGoogle Scholar
  77. 77.
    Nadel ER. Physiological adaptations to aerobic training. American Scientist 1985; 73:334–343.Google Scholar
  78. 78.
    Noland RC, Thyfault JP, Henes ST et al. Artificial selection for high-capactity endurance running is protective against high-fat diet-induced insulin resistance. Am J Physiol Endocrinol Metab 2007; 293:E31–E41.CrossRefPubMedGoogle Scholar
  79. 79.
    Patterson CM, Levin BE. Role of exercise in the central regulation of energy homeostasis and in the prevention of obesity. Neuroendocrinology 2008; 87:65–70.CrossRefPubMedGoogle Scholar
  80. 80.
    Youngstedt SD. Effects of exercise on sleep. Clin Sports Med 2005; 24:355–336.CrossRefPubMedGoogle Scholar
  81. 81.
    Thompson HJ. Effects of physical activity and exercise on experimentally-induced mammary carcinogenesis. Breast Cancer Res Treat 1997; 46:135–141.CrossRefPubMedGoogle Scholar
  82. 82.
    Pitts G, Bull L. Exercise, dietary obesity and growth in the rat. Am J Physiol Regul Integr Comp Physiol 1977; 232:38–44.Google Scholar
  83. 83.
    Tsai AC, Rosenberg R, Borer KT. Metabolic alterations induced by voluntary exercise and discontinuation of exercise in hamsters. Am J Clin Nutr 1982; 35:943–949.PubMedGoogle Scholar
  84. 84.
    Yuan Q, Fontenele-Neto JD, Fricker LD. Effect of voluntary exercise on genetically obese Cpefat/fat mice quantitative proteomics of serum. Obes Res 2004; 12(7):1179–1188.CrossRefPubMedGoogle Scholar
  85. 85.
    Coutinho AE, Fediuc S, Campbell JE et al. Metabolic effects of voluntary wheel running in young and old Syrian golden hamsters. Physiol Behav 2005; 87:360–367.CrossRefGoogle Scholar
  86. 86.
    Barbour KA, Edenfield TM, Blumenthal JA. Exercise as a treatment for depression and other psychiatric disorders. J Cardiopulm Rehabil Prev 2007; 27:359–367.PubMedGoogle Scholar
  87. 87.
    Bono JPD, Adlam D, Paterson DJ et al. Novel quantitative phenotypes of exercise training in mouse models. Am J Physiol Regulatory Integrative Comp Physiol 2005; 290:926–934.Google Scholar
  88. 88.
    Sutton GM, Perez-Tilve D, Nogueiras R et al. The melanocortin-3 receptor is required for entrainment to meal intake. J Neurosci 2008; 28(48):12946–12955.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Jay W. Schaub
    • 1
  • Erin B. Bruce
    • 1
  • Carrie Haskell-Luevano
    • 1
  1. 1.Department of PharmacodynamicsUniversity of FloridaGainesvilleUSA

Personalised recommendations