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Gene Review

Mc4r  -  melanocortin 4 receptor

Mus musculus

Synonyms: Fatboy, Glu3, MC4-R, Melanocortin receptor 4
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Disease relevance of Mc4r


Psychiatry related information on Mc4r


High impact information on Mc4r


Chemical compound and disease context of Mc4r

  • Interestingly, the 10- to 20-fold increase in liver triglyceride in the outbred strain of Mc4r-/- mice is not always associated with fasting hyperinsulinemia or increased FAS mRNA expression [5].
  • To assess the physiological effects of MGRN1 on energy and glucose homeostasis, we generated animals doubly mutant for Mgrn1(md) and A(y), Lep(ob), or a null allele of Mc4r, and diet-induced obesity (DIO) mice segregating for Mgrn1(md) [11].
  • Here we demonstrate that cachexia induced by lipopolysaccharide administration and by tumor growth is ameliorated by central MC4-R blockade [12].
  • In this study, we used the newly discovered selective MC4R antagonist HS014 for increasing food intake in free-feeding rats and evaluated the effects of the NPY Y1 receptor antagonist 1229U91 and the selective serotonin uptake inhibitor fluoxetine on this increased feeding behavior [13].

Biological context of Mc4r


Anatomical context of Mc4r

  • AGRP or artificial cerebrospinal fluid was administered daily into the lateral ventricle of adult, male MC4-R knockout and wild-type (WT) mice for 3 d [15].
  • Furthermore, co-localization analyses in mice showed co-expression of ALP in cells expressing MC4-R in a number of regions known to be important in the regulation of energy homoeostasis by melanocortins, such as the paraventricular nucleus of hypothalamus and the dorsal motor nucleus of the vagus [16].
  • Negative feedback control by body fat content on ARC neuropeptide expression is present in young animals but vanishes with age and is modulated by MC4R deficiency [17].
  • The absence of MCR4 blocked leptin's ability to increase UCP1 mRNA in both brown and white adipose tissue, but not its ability to reduce food consumption [18].
  • The presence of MC4R in rat adipocytes (RT-PCR and restriction digest) supports the involvement of this receptor subtype in this interaction [19].

Associations of Mc4r with chemical compounds

  • Furthermore, ICV infusion of the MC4R agonist significantly reduced ethanol drinking, whereas ICV infusion of AgRP-(83-132) significantly increased ethanol drinking in C57BL/6J mice [20].
  • The effect of Mgrn1(md) on circulating insulin concentrations was not due primarily to reductions in fat mass, since the plasma insulin concentrations of Mgrn1(md) mice segregating for either A(y) or Mc4r-null alleles, adjusted for fat mass and plasma glucose, were reduced compared with A(y) and Mc4r mice, respectively [11].
  • In addition, it appears that the histamine H(1)-R signaling pathway may be independent or downstream of the POMC/MC-4R signaling [21].
  • Mutation of Phe117 to alanine causes a similar increase in agouti KI app at melanocortin receptor 4 [22].
  • The data presented here show that GT1-1 cells specifically express a functional MC4-R that couples to GnRH release [23].

Regulatory relationships of Mc4r


Other interactions of Mc4r


Analytical, diagnostic and therapeutic context of Mc4r

  • In vivo, administration of the melanocortin agonist MTII (10 microg per mouse equivalent to 9.3 nmol) 30 min prior to ischemia (25 min) attenuated mouse heart 2 h reperfusion injury by approximately 40%, an effect prevented by the mixed MC3/4-R antagonist SHU9119 but not by the selective MC4-R antagonist HS204 [27].
  • Using the technique of fluorescent in situ hybridization, the gene encoding the melanocortin-4 receptor was localized to chromosome 18 (q21.3) [28].
  • Twenty- to 22-week-old male wild-type (WT) C57BL/6J and obese MC4R (-/-) mice (N=5 to 6 per group) were implanted with radiotelemetric transmitters and catheters for measuring mean arterial pressure (MAP) and heart rate 24 hours per day and intravenous infusions [29].
  • This ligand possesses novel melanocortin receptor pharmacology, as compared to previously reported peptides, and is potentially useful for in vivo studies to differentiate MC3R vs MC4R physiological roles in animal models, such as primates, where "knockout" animals are not viable options [30].
  • In light of previous findings that melanocortins antagonize opiate self-administration, analgesic tolerance, and physical dependence, we hypothesize that decreased melanocortin function, via down-regulation of MC4-R expression, may contribute to the development of these opiate-induced behaviors [7].


  1. Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Marsh, D.J., Hollopeter, G., Huszar, D., Laufer, R., Yagaloff, K.A., Fisher, S.L., Burn, P., Palmiter, R.D. Nat. Genet. (1999) [Pubmed]
  2. A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Ste Marie, L., Miura, G.I., Marsh, D.J., Yagaloff, K., Palmiter, R.D. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  3. Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. Butler, A.A., Marks, D.L., Fan, W., Kuhn, C.M., Bartolome, M., Cone, R.D. Nat. Neurosci. (2001) [Pubmed]
  4. Leptin and inflammation-associated cachexia in chronic kidney disease. Mak, R.H., Cheung, W., Cone, R.D., Marks, D.L. Kidney Int. (2006) [Pubmed]
  5. Impaired coordination of nutrient intake and substrate oxidation in melanocortin-4 receptor knockout mice. Albarado, D.C., McClaine, J., Stephens, J.M., Mynatt, R.L., Ye, J., Bannon, A.W., Richards, W.G., Butler, A.A. Endocrinology (2004) [Pubmed]
  6. Mahogany (mg) stimulates feeding and increases basal metabolic rate independent of its suppression of agouti. Dinulescu, D.M., Fan, W., Boston, B.A., McCall, K., Lamoreux, M.L., Moore, K.J., Montagno, J., Cone, R.D. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  7. Morphine down-regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction. Alvaro, J.D., Tatro, J.B., Quillan, J.M., Fogliano, M., Eisenhard, M., Lerner, M.R., Nestler, E.J., Duman, R.S. Mol. Pharmacol. (1996) [Pubmed]
  8. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Balthasar, N., Dalgaard, L.T., Lee, C.E., Yu, J., Funahashi, H., Williams, T., Ferreira, M., Tang, V., McGovern, R.A., Kenny, C.D., Christiansen, L.M., Edelstein, E., Choi, B., Boss, O., Aschkenasi, C., Zhang, C.Y., Mountjoy, K., Kishi, T., Elmquist, J.K., Lowell, B.B. Cell (2005) [Pubmed]
  9. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Chen, A.S., Marsh, D.J., Trumbauer, M.E., Frazier, E.G., Guan, X.M., Yu, H., Rosenblum, C.I., Vongs, A., Feng, Y., Cao, L., Metzger, J.M., Strack, A.M., Camacho, R.E., Mellin, T.N., Nunes, C.N., Min, W., Fisher, J., Gopal-Truter, S., MacIntyre, D.E., Chen, H.Y., Van der Ploeg, L.H. Nat. Genet. (2000) [Pubmed]
  10. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Huszar, D., Lynch, C.A., Fairchild-Huntress, V., Dunmore, J.H., Fang, Q., Berkemeier, L.R., Gu, W., Kesterson, R.A., Boston, B.A., Cone, R.D., Smith, F.J., Campfield, L.A., Burn, P., Lee, F. Cell (1997) [Pubmed]
  11. The mahoganoid mutation (Mgrn1md) improves insulin sensitivity in mice with mutations in the melanocortin signaling pathway independently of effects on adiposity. Phan, L.K., Chung, W.K., Leibel, R.L. Am. J. Physiol. Endocrinol. Metab. (2006) [Pubmed]
  12. Role of the central melanocortin system in cachexia. Marks, D.L., Ling, N., Cone, R.D. Cancer Res. (2001) [Pubmed]
  13. Evidence that orexigenic effects of melanocortin 4 receptor antagonist HS014 are mediated by neuropeptide Y. Kask, A., Rägo, L., Korrovits, P., Wikberg, J.E., Schiöth, H.B. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  14. Double leptin and melanocortin-4 receptor gene mutations have an additive effect on fat mass and are associated with reduced effects of leptin on weight loss and food intake. Trevaskis, J.L., Butler, A.A. Endocrinology (2005) [Pubmed]
  15. Effect of Agouti-related protein in regulation of the hypothalamic-pituitary-thyroid axis in the melanocortin 4 receptor knockout mouse. Fekete, C., Marks, D.L., Sarkar, S., Emerson, C.H., Rand, W.M., Cone, R.D., Lechan, R.M. Endocrinology (2004) [Pubmed]
  16. Characterization of a novel binding partner of the melanocortin-4 receptor: attractin-like protein. Haqq, A.M., René, P., Kishi, T., Khong, K., Lee, C.E., Liu, H., Friedman, J.M., Elmquist, J.K., Cone, R.D. Biochem. J. (2003) [Pubmed]
  17. Age-dependent hypothalamic expression of neuropeptides in wild-type and melanocortin-4 receptor-deficient mice. Arens, J., Moar, K.M., Eiden, S., Weide, K., Schmidt, I., Mercer, J.G., Simon, E., Korf, H.W. Physiol. Genomics (2003) [Pubmed]
  18. Targeted deletion of melanocortin receptor subtypes 3 and 4, but not CART, alters nutrient partitioning and compromises behavioral and metabolic responses to leptin. Zhang, Y., Kilroy, G.E., Henagan, T.M., Prpic-Uhing, V., Richards, W.G., Bannon, A.W., Mynatt, R.L., Gettys, T.W. FASEB J. (2005) [Pubmed]
  19. Regulation of adipose tissue leptin secretion by alpha-melanocyte-stimulating hormone and agouti-related protein: further evidence of an interaction between leptin and the melanocortin signalling system. Hoggard, N., Hunter, L., Duncan, J.S., Rayner, D.V. J. Mol. Endocrinol. (2004) [Pubmed]
  20. Effects of melanocortin receptor activation and blockade on ethanol intake: a possible role for the melanocortin-4 receptor. Navarro, M., Cubero, I., Chen, A.S., Chen, H.Y., Knapp, D.J., Breese, G.R., Marsh, D.J., Thiele, T.E. Alcohol. Clin. Exp. Res. (2005) [Pubmed]
  21. Neuronal histamine regulates food intake, adiposity, and uncoupling protein expression in agouti yellow (A(y)/a) obese mice. Masaki, T., Chiba, S., Yoshimichi, G., Yasuda, T., Noguchi, H., Kakuma, T., Sakata, T., Yoshimatsu, H. Endocrinology (2003) [Pubmed]
  22. Melanocortin receptor binding determinants in the agouti protein. Kiefer, L.L., Veal, J.M., Mountjoy, K.G., Wilkison, W.O. Biochemistry (1998) [Pubmed]
  23. Expression of functional melanocortin-4 receptor in the hypothalamic GT1-1 cell line. Khong, K., Kurtz, S.E., Sykes, R.L., Cone, R.D. Neuroendocrinology (2001) [Pubmed]
  24. 11 beta-hydroxysteroid dehydrogenase type 1 induction in the arcuate nucleus by high-fat feeding: A novel constraint to hyperphagia? Densmore, V.S., Morton, N.M., Mullins, J.J., Seckl, J.R. Endocrinology (2006) [Pubmed]
  25. Neuropeptide Y Y1 receptor mRNA in rodent brain: distribution and colocalization with melanocortin-4 receptor. Kishi, T., Aschkenasi, C.J., Choi, B.J., Lopez, M.E., Lee, C.E., Liu, H., Hollenberg, A.N., Friedman, J.M., Elmquist, J.K. J. Comp. Neurol. (2005) [Pubmed]
  26. A novel selective melanocortin-4 receptor agonist reduces food intake in rats and mice without producing aversive consequences. Benoit, S.C., Schwartz, M.W., Lachey, J.L., Hagan, M.M., Rushing, P.A., Blake, K.A., Yagaloff, K.A., Kurylko, G., Franco, L., Danhoo, W., Seeley, R.J. J. Neurosci. (2000) [Pubmed]
  27. MC-3 receptor and the inflammatory mechanisms activated in acute myocardial infarct. Getting, S.J., Di Filippo, C., Christian, H.C., Lam, C.W., Rossi, F., D'Amico, M., Perretti, M. J. Leukoc. Biol. (2004) [Pubmed]
  28. Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. Gantz, I., Miwa, H., Konda, Y., Shimoto, Y., Tashiro, T., Watson, S.J., DelValle, J., Yamada, T. J. Biol. Chem. (1993) [Pubmed]
  29. Melanocortin-4 receptor mediates chronic cardiovascular and metabolic actions of leptin. Tallam, L.S., da Silva, A.A., Hall, J.E. Hypertension (2006) [Pubmed]
  30. Structure-activity relationships of the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH(2) at the mouse melanocortin receptors: part 2 modifications at the Phe position. Holder, J.R., Bauzo, R.M., Xiang, Z., Haskell-Luevano, C. J. Med. Chem. (2002) [Pubmed]
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