Melanocortin 4 receptor is a protein that in humans is encoded by the MC4Rgene. It encodes the MC4 protein, a G protein-coupled receptor that binds α-melanocyte stimulating hormone (α-MSH). In murine models MC4 receptors have been found to be involved in feeding behaviour, the regulation of metabolism, sexual behaviour, and male erectile function.
In 2008, MC4R mutations were reported to be associated with inherited human obesity. They were found in heterozygotes, suggesting an autosomal dominant inheritance pattern. However, based on other research and observations, these mutations seem to have an incomplete penetrance and some degree of codominance. It has a prevalence of 1.0–2.5% in people with body mass indices greater than 30, making it the most commonly known genetic defect predisposing people to obesity.
In 2009, two very large genome-wide association studies of body mass index (BMI) confirmed the association of variants about 150 kilobases downstream of the MC4R gene with insulin resistance, obesity, and other anthropometric traits.MC4R may also have clinical utility as a biomarker for predicting individual susceptibility to drug-induced adverse effects causing weight gain and related metabolic abnormalities. Another GWAS performed in 2012 identified twenty SNPs located ~190 Kb downstream of MC4R in association with severe antipsychotic-induced weight gain. This locus overlapped with the region previously identified in the 2009 studies. The rs489693 polymorphism, in particular, sustained a statistically robust signal across three replication cohorts and demonstrated consistent recessive effects. This finding was replicated again by another research group in the following year. In accordance with the above, MC4 receptor agonists have garnered interest as potential treatments for obesity and insulin resistance, while MC4 receptor antagonists have attracted interest as potential treatments for cachexia.
The MC4 receptor has been shown to interact with proopiomelanocortin (POMC). POMC is a precursor peptide pro-hormone which is cleaved into several other peptide hormones. All of the endogenous ligands of MC4 are produced by cleaving this one precursor peptide. These endogenous agonists include α-MSH, β-MSH, γ-MSH, and ACTH.
^Magenis RE, Smith L, Nadeau JH, Johnson KR, Mountjoy KG, Cone RD (August 1994). "Mapping of the ACTH, MSH, and neural (MC3 and MC4) melanocortin receptors in the mouse and human". Mammalian Genome. 5 (8): 503–8. doi:10.1007/BF00369320. PMID7949735.
^Sundaramurthy D, Campbell DA, Leek JP, Markham AF, Pieri LF (November 1998). "Assignment of the melanocortin 4 receptor (MC4R) gene to human chromosome band 18q22 by in situ hybridisation and radiation hybrid mapping". Cytogenetics and Cell Genetics. 82 (1–2): 97–8. doi:10.1159/000015074. PMID9763669.
^Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD (January 1997). "Role of melanocortinergic neurons in feeding and the agouti obesity syndrome". Nature. 385 (6612): 165–8. doi:10.1038/385165a0. PMID8990120.
^Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F (January 1997). "Targeted disruption of the melanocortin-4 receptor results in obesity in mice". Cell. 88 (1): 131–41. doi:10.1016/S0092-8674(00)81865-6. PMID9019399.
^Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A, et al. (January 2009). "Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity". Nature Genetics. 41 (1): 18–24. doi:10.1038/ng.274. PMID19079260.
^Czerwensky F, Leucht S, Steimer W (October 2013). "MC4R rs489693: a clinical risk factor for second generation antipsychotic-related weight gain?". The International Journal of Neuropsychopharmacology. 16 (9): 2103–9. doi:10.1017/S1461145713000849. PMID23920449.
^Wikberg JE, Mutulis F (April 2008). "Targeting melanocortin receptors: an approach to treat weight disorders and sexual dysfunction". Nature Reviews. Drug Discovery. 7 (4): 307–23. doi:10.1038/nrd2331. PMID18323849.
^Foster AC, Chen C (2007). "Melanocortin-4 receptor antagonists as potential therapeutics in the treatment of cachexia". Current Topics in Medicinal Chemistry. 7 (11): 1131–6. doi:10.2174/156802607780906663. PMID17584133.
^Shadiack AM, Sharma SD, Earle DC, Spana C, Hallam TJ (2007). "Melanocortins in the treatment of male and female sexual dysfunction". Current Topics in Medicinal Chemistry. 7 (11): 1137–44. doi:10.2174/156802607780906681. PMID17584134.
^Evans-Brown M, Dawson RT, Chandler M, McVeigh J (February 2009). "Use of melanotan I and II in the general population". BMJ. 338: b566. doi:10.1136/bmj.b566. PMID19224885.
^Giuliani D, Neri L, Canalini F, Calevro A, Ottani A, Vandini E, Sena P, Zaffe D, Guarini S (July 2015). "NDP-α-MSH induces intense neurogenesis and cognitive recovery in Alzheimer transgenic mice through activation of melanocortin MC4 receptors". Molecular and Cellular Neurosciences. 67: 13–21. doi:10.1016/j.mcn.2015.05.004. PMID26003413.
^Ramírez D, Saba J, Carniglia L, Durand D, Lasaga M, Caruso C (August 2015). "Melanocortin 4 receptor activates ERK-cFos pathway to increase brain-derived neurotrophic factor expression in rat astrocytes and hypothalamus". Molecular and Cellular Endocrinology. 411: 28–37. doi:10.1016/j.mce.2015.04.008. PMID25892444.
^Serova LI, Laukova M, Alaluf LG, Sabban EL (August 2013). "Intranasal infusion of melanocortin receptor four (MC4R) antagonist to rats ameliorates development of depression and anxiety related symptoms induced by single prolonged stress". Behavioural Brain Research. 250: 139–47. doi:10.1016/j.bbr.2013.05.006. PMID23680165.
^Chaki S, Okubo T (2007). "Melanocortin-4 receptor antagonists for the treatment of depression and anxiety disorders". Current Topics in Medicinal Chemistry. 7 (11): 1145–51. doi:10.2174/156802607780906618. PMID17584135.
^Yang YK, Fong TM, Dickinson CJ, Mao C, Li JY, Tota MR, Mosley R, Van Der Ploeg LH, Gantz I (December 2000). "Molecular determinants of ligand binding to the human melanocortin-4 receptor". Biochemistry. 39 (48): 14900–11. doi:10.1021/bi001684q. PMID11101306.
^Yang YK, Ollmann MM, Wilson BD, Dickinson C, Yamada T, Barsh GS, Gantz I (March 1997). "Effects of recombinant agouti-signaling protein on melanocortin action". Molecular Endocrinology. 11 (3): 274–80. doi:10.1210/me.11.3.274. PMID9058374.
Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone RD (October 1994). "Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain". Molecular Endocrinology. 8 (10): 1298–308. doi:10.1210/me.8.10.1298. PMID7854347.
Gantz I, Miwa H, Konda Y, Shimoto Y, Tashiro T, Watson SJ, DelValle J, Yamada T (July 1993). "Molecular cloning, expression, and gene localization of a fourth melanocortin receptor". The Journal of Biological Chemistry. 268 (20): 15174–9. PMID8392067.
Alvaro JD, Tatro JB, Quillan JM, Fogliano M, Eisenhard M, Lerner MR, Nestler EJ, Duman RS (September 1996). "Morphine down-regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction". Molecular Pharmacology. 50 (3): 583–91. PMID8794897.
Yang YK, Ollmann MM, Wilson BD, Dickinson C, Yamada T, Barsh GS, Gantz I (March 1997). "Effects of recombinant agouti-signaling protein on melanocortin action". Molecular Endocrinology. 11 (3): 274–80. doi:10.1210/me.11.3.274. PMID9058374.
Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O'Rahilly S (October 1998). "A frameshift mutation in MC4R associated with dominantly inherited human obesity". Nature Genetics. 20 (2): 111–2. doi:10.1038/2404. PMID9771698.
Vaisse C, Clement K, Guy-Grand B, Froguel P (October 1998). "A frameshift mutation in human MC4R is associated with a dominant form of obesity". Nature Genetics. 20 (2): 113–4. doi:10.1038/2407. PMID9771699.
Hinney A, Schmidt A, Nottebom K, Heibült O, Becker I, Ziegler A, Gerber G, Sina M, Görg T, Mayer H, Siegfried W, Fichter M, Remschmidt H, Hebebrand J (April 1999). "Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans". The Journal of Clinical Endocrinology and Metabolism. 84 (4): 1483–6. doi:10.1210/jc.84.4.1483. PMID10199800.
Yang YK, Dickinson CJ, Zeng Q, Li JY, Thompson DA, Gantz I (May 1999). "Contribution of melanocortin receptor exoloops to Agouti-related protein binding". The Journal of Biological Chemistry. 274 (20): 14100–6. doi:10.1074/jbc.274.20.14100. PMID10318826.
Ho G, MacKenzie RG (December 1999). "Functional characterization of mutations in melanocortin-4 receptor associated with human obesity". The Journal of Biological Chemistry. 274 (50): 35816–22. doi:10.1074/jbc.274.50.35816. PMID10585465.
Yang YK, Fong TM, Dickinson CJ, Mao C, Li JY, Tota MR, Mosley R, Van Der Ploeg LH, Gantz I (December 2000). "Molecular determinants of ligand binding to the human melanocortin-4 receptor". Biochemistry. 39 (48): 14900–11. doi:10.1021/bi001684q. PMID11101306.
Mergen M, Mergen H, Ozata M, Oner R, Oner C (July 2001). "A novel melanocortin 4 receptor (MC4R) gene mutation associated with morbid obesity". The Journal of Clinical Endocrinology and Metabolism. 86 (7): 3448. doi:10.1210/jc.86.7.3448. PMID11443223.
McNulty JC, Thompson DA, Bolin KA, Wilken J, Barsh GS, Millhauser GL (December 2001). "High-resolution NMR structure of the chemically-synthesized melanocortin receptor binding domain AGRP(87-132) of the agouti-related protein". Biochemistry. 40 (51): 15520–7. doi:10.1021/bi0117192. PMID11747427.
Brocke KS, Neu-Yilik G, Gehring NH, Hentze MW, Kulozik AE (February 2002). "The human intronless melanocortin 4-receptor gene is NMD insensitive". Human Molecular Genetics. 11 (3): 331–5. doi:10.1093/hmg/11.3.331. PMID11823452.
Yang Y, Chen M, Lai Y, Gantz I, Georgeson KE, Harmon CM (June 2002). "Molecular determinants of human melanocortin-4 receptor responsible for antagonist SHU9119 selective activity". The Journal of Biological Chemistry. 277 (23): 20328–35. doi:10.1074/jbc.M201343200. PMID11912210.
Hansen MJ, Morris MJ (May 2002). "Evidence for an interaction between neuropeptide Y and the melanocortin-4 receptor on feeding in the rat". Neuropharmacology. 42 (6): 792–7. doi:10.1016/S0028-3908(02)00025-4. PMID12015205.
Miraglia Del Giudice E, Cirillo G, Nigro V, Santoro N, D'Urso L, Raimondo P, Cozzolino D, Scafato D, Perrone L (May 2002). "Low frequency of melanocortin-4 receptor (MC4R) mutations in a Mediterranean population with early-onset obesity". International Journal of Obesity and Related Metabolic Disorders. 26 (5): 647–51. doi:10.1038/sj.ijo.0801983. PMID12032748.
Kim CS, Lee SH, Kim RY, Kim BJ, Li SZ, Lee IH, Lee EJ, Lim SK, Bae YS, Lee W, Baik JH (August 2002). "Identification of domains directing specificity of coupling to G-proteins for the melanocortin MC3 and MC4 receptors". The Journal of Biological Chemistry. 277 (35): 31310–7. doi:10.1074/jbc.M112085200. PMID12045190.