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.[11][12][13][14]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.[15] This finding was replicated again by another research group in the following year.[16] In accordance with the above, MC4 receptor agonists have garnered interest as potential treatments for obesity and insulin resistance,[17][18] while MC4 receptor antagonists have attracted interest as potential treatments for cachexia.[19] The structures of the receptor in complex with the agonist setmelanotide[20] and the antagonist SHU9119[21] have been determined.
In 2008, MC4R mutations were reported to be associated with inherited human obesity.[30] 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.[31]
In an exome-wide meta-analysis across three cohorts (UKB,GHS and MCPS), there were 16 genes for which there genetic variants was associated with BMI.
Among the 16 genes, the analysis identified two for which rare mutations are known to cause monogenic obesity: MC4R and PCSK1 (proprotein convertase subtilisin/kexin type 1). One study provides genetic evidence linking rare coding variation to BMI and obesity-related phenotypes.[citation needed]
MC4R gene mutations are associated with early-onset severe obesity they effect of mutations on opacity in these two heterozygous coding genes among mutations in the MC4R gene (C293R and S94N) are:
• Rapid weight gains from early age (the most important feature).
• Development of severe obesity (BMI ≫97th percentile) at early ages, usually <3 years of age.
• Persistent food-seeking behavior, mostly reported from six months of age.
• Parental/siblings anthropometric data: suspect if relatives present normal anthropometric data.
• Tall stature/increased growth velocity (MC4R monogenic diabetes).[citation needed]
There is limited treatment options for the most common form of monogenic obesity, MC4R mutations symptoms can be treated with a Glucagon-like Peptide-1 Receptor Agonist liraglutide which cause weight loss by reducing appetite. They found that the effects of liraglutide 3.0 mg daily for 16 weeks causes weight reducing and glucose lowering and may be relevant treatment in the most common form of monogenic obesity.[citation needed]
Interactions
The MC4 receptor has been shown to interact with proopiomelanocortin (POMC).[32][33] 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.
Ca2+ as a cofactor for ligand binding
GPCRs can bind a wide variety of extracellular ligands including physiological cations. Biological and pharmacological studies have previously implicated both Zn2+ and Ca2+ in the function of multiple members of the melanocortin receptor family. There is Ca2+ in the agonist-bound structure. The researches hypothesize that Ca2+ stabilizes the ligand-binding pocket and functions as an endogenous cofactor for the binding of α-MSH to MC4 receptor. Ca2+ is likely to bind when the receptor is exposed to extracellular Ca2+ concentrations (~1.2 mM in the extracellular space of the central nervous system) but might not be bound intracellularly (Ca2+ concentration: 100 nm), thus suggesting a potential regulatory role for Ca2+ in α-MSH–binding dynamics.
Signaling along the phospholipase C pathway can significantly raise the intracellular Ca2+ concentration, and this may constitute positive feedback from signaling of MC4 receptor or other receptors that result in Ca2+ flux. This discovery highlights the plasticity and multipronged regulation and control of this receptor and will aid in next-generation structure-based drug design of therapeutics for MC4R-related obesity.
Setmelanotide was approved by FDA as first-ever therapy for chronic weight management (IMCIVREE).The setmelanotide was advanced first-in-class, precision medicine that is designed to directly address the underlying cause of obesities driven by genetic deficits in the melanocortin-4 (MC4) receptor pathway.
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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. S2CID24047677.
^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. S2CID21946787.
^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. S2CID764409.
^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. S2CID22103245.
^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. S2CID35953386.
^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. S2CID43121906.
^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.
^Giuliani D, Neri L, Canalini F, Calevro A, Ottani A, Vandini E, et al. (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. hdl:11380/1067772. PMID26003413. S2CID22132459.
^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. hdl:11336/15275. PMID25892444. S2CID20727709.
^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. S2CID25321970.
^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, et al. (December 2000). "Molecular determinants of ligand binding to the human melanocortin-4 receptor". Biochemistry. 39 (48): 14900–11. doi:10.1021/bi001684q. PMID11101306.
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. S2CID7287831.
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. S2CID40193066.
Yang YK, Fong TM, Dickinson CJ, Mao C, Li JY, Tota MR, et al. (December 2000). "Molecular determinants of ligand binding to the human melanocortin-4 receptor". Biochemistry. 39 (48): 14900–11. doi:10.1021/bi001684q. PMID11101306.
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. S2CID29068487.
"Melanocortin Receptors: MC4". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2008-12-05.
