Abstract
We evaluated the role of the melanocortin-4 receptor (MC-4R) in the control of metabolic rate and food intake in mice. Intraperitoneal administration of the non-selective MC-R agonist melanotan II (MT-II; a cyclic heptapeptide) increases metabolic rate in wildtype mice, while MC-4R knockout mice are insensitive to the effects of MT-II on metabolic rate. MC-4R knockout mice are also insensitive to the effects of MT-II on reducing food intake. We conclude that MC-4R can mediate control of both metabolic rate and food intake in mice. We infer that a role for MC-3R in mediating the acute effects of MT-II on basal metabolic rate and food intake in wildtype mice seems limited.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Boston BA, Blaydon KM, Varnerin J and Cone RD (1997) Independent and additive effects of central POMC and leptin pathways on murine obesity. Science 278: 1641–1644.
Breslow MJ, Min-Lee K, Brown DR, Chacko VP, Palmer D and Berkowitz DE (1999) Effect of leptin deficiency on metabolic rate in ob/ob mice. Am J Physiol 276 (Endocrinol Metab 39): E443–449.
Chen P, Li C, Haskell-Luevano C, Cone RD and Smith MS (1999) Altered expression of agouti-related protein and its colocalization with neuropeptide Y in the arcuate nucleus of the hypothalamus during lactation. Endocrinology 140: 2645–2650.
Dinulescu DM, Fan W, Boston BA, McCall K, Lamoreux ML, Moore KJ, Montagno J and Cone RD (1998) Mahogany (mg) stimulates feeding and increases metabolic rate independent of its suppression of agouti. Proc Natl Acad Sci 95: 12707–12712.
Elias CF, Lee C, Kelly J, Aschkenasi C, Ahima RS, Couceyro PR, Kuhar MJ, Saper CB and Elmquist JK (1998) Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron 21: 1375–1385.
Fan W, Boston BA, Kesterson RA, Hruby VJ and Cone RD (1997) Role of melanocortigenic neurons in feeding and the agouti obesity syndrome. Nature 385: 165–168.
Feng JD, Dao T, Lipton JM (1987) Effects of preoptic microinjections of alpha-MSH on fever and normal temperature control in rabbits. Brain Res 18: 473–477.
Finn PD, Cunningham MJ, Pau KY, Spies HG, Clifton DK and Steiner RA (1998) The stimulatory effect of leptin on the neuroendocrine reproductive axis of the monkey. Endocrinology 239: 4652–4662.
Fong TM, Mao C, MacNeil T, Kalyani R, Smith T, Weinberg D, Tota MR and Van der Ploeg LHT (1997) ART (protein product of the agouti-related transcript) as an antagonist of MC-3 and MC-4 receptors. Biochem Biophys Res Comm 237: 629–631.
Guan XM, Yu H and Van der Ploeg LHT (1998) Evidence of altered hypothalamic proopiomelanocortin/neuropeptide Y mRNA expression in tubby mice. Mol Brain Res 59: 273–279.
Gunn TM, Miller KA, Hyman W, Davis RW, Azarani A, Schlossman SF, Duke-Cohan JS and Barsh GS (1999) The mousemahogany locus encodes a transmembrane form of human attractin. Nat 398: 152–156.
Hadley ME, Hruby VJ, Blanchard J, Dorr RT, Levine N, Dawson BV, al-Obedi F and Sawyer TK (1998) Discovery and development of novel melanogenic drugs Melanotan-I and II. Pharm-Biotechnol 11: 575–595.
Hahn TM, Breininger JF, Baskin DG and Schwartz MVV (1998) Co-expression of AGRP and NPY in fasting-activated hypothalamic neurons. Nature Neurosci 1: 271–272.
Haynes WG, Morgan DA, Walsh SA, Mark AL and Sivitz WI (1997) Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest 100: 270–278.
Haynes WG, Morgan DA, Djalali A, Sivitz WI and Mark AL (1999) Interactions between the melanocortin system and leptin in control of sympathetic nerve traffic. Hypertension 33: 542–547.
Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Smith FJ, Campfield LA, Burn P and Lee F (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88: 131–141.
Kalra SP, Dube MG, Pu S, Xu B, Horvath TL and Kalra PS (1999) Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endoc Rev 20: 68–100.
Kelly TL, Berger N and Richardson TL (1998) DXA body composition: theory and practice. Appl Radiat Isol 49: 511–513.
Krude H, Biebermann H, Luck W, Horn R, Barbant G and Gruter A (1998) Severe early-onset obesity adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19: 155–157.
Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RP, Wilkison WO, et al. (1994) Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 37: 799–802.
Marsh DJ, Hollopeter G, Huszar D, Laufer R, Yaglaoff KA, Fisher SL, Burn P and Palmiter RD (1999) Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Nat Genet 22: 119–122.
Miltenberger RJ, Mynatt RL, Wilkinson JE and Woychik RP (1997) The role of the agouti gene in the yellow obese syndrome. J Nutr 127: 1902S–1907S.
Mountjoy KG and Wong J (1997) Obesity, diabetes and functions for proopiomelanocortin peptides. Mol Cell Endocrinol 128: 171–177.
Nagle DL, McGrail SH, Vitale J, Woolf EA, Dussault BJ, DiRocco L, Holmgren L, Montagno J, Bork P, Huszar D, Fairchild-Huntress V, Ge P, Keilty J, Ebeling C, Baldini L, Gilchrist J, Burn P, Carlon GA and Moore KJ (1999) The mahogany protein is a receptor involved in suppression of obesity. Nature 398: 148–152.
Ollman MM, Wilson BD, Yang Y-K, Kerns JA, Chen Y, Gantz I and Barsh GS (1997) Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278: 135–138.
Poehlman ET and Toth MJ (1995) Mathematical ratios lead to spurious conclusions regarding age-and sex-related differences in resting metabolic rate. Am J Clin Nutr 61: 482–486.
Ravussin E and Swinburn BA (1996) Energy expenditure and obesity. Diabetes Rev 4: 403–422.
Roberts SB and Greenberg AS (1996) The new obesity genes. Nutr Rev 54: 41–49.
Shutter JR, Graham M, Kinsey AC, Scully S, Luthy R and Stark KL (1997) Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Devel 11: 593–602.
Theile TE, van Dijk D, Yagaloff KA, Fisher SL, Schwartz M, Burn P and Seeley RJ (1998) Central infusion of melanocortin agonist MTII in rats: assessment of c-Fos expression and taste aversion. Am J Physiol 274: R248–R254.
Vaisse C, Clement K, Guy-Grand B and Froquel P (1998) A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 20: 113–114.
Von Koch C, Zheng H, Chen H, Trumbauer M, Thinakaran G, Van der Ploeg LHT, Price D and Sisodia S (1997) Generation of APLP2KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiol Aging 18: 661–669.
Yang YK, Thompson DA, Dickinson CJ, Wilken J, Barsh GS, Kent SB and Gantz I (1999) Characterization of Agouti-related protein binding to melanocortin receptors. Mol Endocrinol 131: 148–155.
Yen TT, Gill AM, Frigeri LG, Barsh GS and Wolff GL (1994) Obesity, diabetes, and neoplasia in yellow Avy/-mice: ectopic expression of the agouti gene. FASEB J 8: 479–488.
Yeo G, Farooqi I, Aminian S, Halsall D, Stanhope R and O'Rahilly S (1998) A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 20:111–112.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Chen, A.S., Metzger, J.M., Trumbauer, M.E. et al. Role of the melanocortin-4 receptor in metabolic rate and food intake in mice. Transgenic Res 9, 145–154 (2000). https://doi.org/10.1023/A:1008983615045
Issue Date:
DOI: https://doi.org/10.1023/A:1008983615045