melanocortin 4 receptor


Gene Symbol: melanocortin 4 receptor
Description: melanocortin 4 receptor
Alias: melanocortin receptor 4, MC4-R
Species: human
Products:     melanocortin 4 receptor

Top Publications

  1. Rouskas K, Meyre D, Stutzmann F, Paletas K, Papazoglou D, Vatin V, et al. Loss-of-function mutations in MC4R are very rare in the Greek severely obese adult population. Obesity (Silver Spring). 2012;20:2278-82 pubmed publisher
    ..Our data suggest that MC4R loss-of-function mutations are rare in the Greek population. MC4R genetic deficiency is unlikely to explain the high propensity to develop severe obesity in this specific population. ..
  2. Rutanen J, Pihlajamaki J, Karhapää P, Vauhkonen I, Kuusisto J, Moilanen Mykkänen L, et al. The Val103Ile polymorphism of melanocortin-4 receptor regulates energy expenditure and weight gain. Obes Res. 2004;12:1060-6 pubmed
    ..78 +/- 3.98 vs. -0.82 +/- 3.98 kg, p = 0.038). The Val103Ile polymorphism of the MC4R gene is associated with energy expenditure in humans. Furthermore, it may associate with glucose oxidation, free fatty acid levels, and weight gain. ..
  3. Xi B, Takeuchi F, Chandak G, Kato N, Pan H, Zhou D, et al. Common polymorphism near the MC4R gene is associated with type 2 diabetes: data from a meta-analysis of 123,373 individuals. Diabetologia. 2012;55:2660-2666 pubmed publisher
    Genome-wide association studies have shown that variants near the melanocortin 4 receptor gene (MC4R) (rs17782313 and rs12970134) are associated with risk of obesity in Europeans...
  4. Rouskas K, Kouvatsi A, Paletas K, Papazoglou D, Tsapas A, Lobbens S, et al. Common variants in FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 show evidence of association with adult obesity in the Greek population. Obesity (Silver Spring). 2012;20:389-95 pubmed publisher
    ..722) in comparison with nongenetic factors analyzed alone (AUC = 0.685). Our data suggest that SNPs in or near the FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 loci contribute to obesity risk in the Greek population. ..
  5. Larsen L, Echwald S, Sørensen T, Andersen T, Wulff B, Pedersen O. Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity. J Clin Endocrinol Metab. 2005;90:219-24 pubmed
    Mutations in the gene encoding the melanocortin 4 receptor (MC4R) are associated with the most common monogenic form of obesity. We examined 750 Danish men with juvenile-onset obesity (body mass index 33.3 +/- 2...
  6. Xiang Z, Pogozheva I, Sorenson N, Wilczynski A, Holder J, Litherland S, et al. Peptide and small molecules rescue the functional activity and agonist potency of dysfunctional human melanocortin-4 receptor polymorphisms. Biochemistry. 2007;46:8273-87 pubmed
    ..Thus, these ligands could generically rescue the potency and stimulatory response of the abnormally functioning hMC4Rs studied and may provide tools to further clarify the molecular mechanism(s) involving these receptor modifications. ..
  7. Beckers S, Zegers D, de Freitas F, Mertens I, Van Gaal L, Van Hul W. Association study of MC4R with complex obesity and replication of the rs17782313 association signal. Mol Genet Metab. 2011;103:71-5 pubmed publisher
    ..In conclusion, we could replicate the previously reported association between rs17782313 and complex obesity. Furthermore, our data do not support the hypothesis that a SNP in MC4R causes the rs17782313 association signal. ..
  8. Hohenadel M, Thearle M, Grice B, Huang H, Dai M, Tao Y, et al. Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants. Int J Obes (Lond). 2014;38:1068-74 pubmed publisher
  9. Chen M, Cai M, Aprahamian C, Georgeson K, Hruby V, Harmon C, et al. Contribution of the conserved amino acids of the melanocortin-4 receptor in [corrected] [Nle4,D-Phe7]-alpha-melanocyte-stimulating [corrected] hormone binding and signaling. J Biol Chem. 2007;282:21712-9 pubmed
    b>Melanocortin 4 receptor (MC4R) plays an important role in the regulation of food intake and body weight...

More Information

Publications139 found, 100 shown here

  1. Donohoue P, Tao Y, Collins M, Yeo G, O Rahilly S, Segaloff D. Deletion of codons 88-92 of the melanocortin-4 receptor gene: a novel deleterious mutation in an obese female. J Clin Endocrinol Metab. 2003;88:5841-5 pubmed
    ..We conclude that this novel mutation is the cause of obesity of this patient. ..
  2. Martinelli C, Keogh J, Greenfield J, Henning E, van der Klaauw A, Blackwood A, et al. Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with increased linear growth and final height, fasting hyperinsulinemia, and incompletely suppressed growth hormone secretion. J Clin Endocrinol Metab. 2011;96:E181-8 pubmed publisher
    b>Melanocortin receptor 4 (MC4R) deficiency is characterized by increased linear growth greater than expected for the degree of obesity...
  3. Gantz I, Miwa H, Konda Y, Shimoto Y, Tashiro T, Watson S, et al. Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J Biol Chem. 1993;268:15174-9 pubmed
    ..Using the technique of fluorescent in situ hybridization, the gene encoding the melanocortin-4 receptor was localized to chromosome 18 (q21.3). ..
  4. Thomsen M, Dahl M, Tybjærg Hansen A, Nordestgaard B. ?2-adrenergic receptor Thr164Ile polymorphism, obesity, and diabetes: comparison with FTO, MC4R, and TMEM18 polymorphisms in more than 64,000 individuals. J Clin Endocrinol Metab. 2012;97:E1074-9 pubmed publisher
    ..Also, TMEM18rs6548238 associated with risk of diabetes after adjustment for BMI. These findings need confirmation in other studies. ..
  5. Mountjoy K, Mortrud M, Low M, Simerly R, Cone R. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol. 1994;8:1298-308 pubmed
    ..The high degree of conservation, distinct pharmacology, and unique neuronal distribution of the MC4 receptor suggest specific and complex roles for the melanocortin peptides in neuroendocrine and autonomic control. ..
  6. Ahn J, Dubern B, Lubrano Berthelier C, Clement K, Karsenty G. Cart overexpression is the only identifiable cause of high bone mass in melanocortin 4 receptor deficiency. Endocrinology. 2006;147:3196-202 pubmed
    ..CART expression in the hypothalamus is increased in mice lacking melanocortin 4 receptor (Mc4r(-/-) mice)...
  7. Pogozheva I, Chai B, Lomize A, Fong T, Weinberg D, Nargund R, et al. Interactions of human melanocortin 4 receptor with nonpeptide and peptide agonists. Biochemistry. 2005;44:11329-41 pubmed
  8. Bauer F, Elbers C, Adan R, Loos R, Onland Moret N, Grobbee D, et al. Obesity genes identified in genome-wide association studies are associated with adiposity measures and potentially with nutrient-specific food preference. Am J Clin Nutr. 2009;90:951-9 pubmed publisher
    ..Our results suggest that these loci are not specifically associated with abdominal adiposity but more generally with obesity. We also found that some of the SNPs were associated with macronutrient-specific food intake. ..
  9. Zechner J, Mirshahi U, Satapati S, Berglund E, Rossi J, Scott M, et al. Weight-independent effects of roux-en-Y gastric bypass on glucose homeostasis via melanocortin-4 receptors in mice and humans. Gastroenterology. 2013;144:580-590.e7 pubmed publisher
    ..MC4Rs in autonomic neurons mediate beneficial effects of RYGB, including weight-independent improved glucose homeostasis, in mice and humans. ..
  10. Lubrano Berthelier C, Cavazos M, Le Stunff C, Haas K, Shapiro A, Zhang S, et al. The human MC4R promoter: characterization and role in obesity. Diabetes. 2003;52:2996-3000 pubmed
    Heterozygous mutations in the coding sequence of the serpentine melanocortin 4 receptor (MC4R) are the most frequent genetic cause of severe human obesity...
  11. Valli Jaakola K, Palvimo J, Lipsanen Nyman M, Salomaa V, Peltonen L, Kontula K, et al. A two-base deletion -439delGC in the melanocortin-4 receptor promoter associated with early-onset obesity. Horm Res. 2006;66:61-9 pubmed
    ..We report an MC4R promoter mutation, -439delGC, associated with early-onset obesity and show that transcription factor Nhlh2 recognises this site in vitro. Nhlh2 mutations unlikely underlie severe human obesity. ..
  12. Meyre D, Delplanque J, Chevre J, Lecoeur C, Lobbens S, Gallina S, et al. Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations. Nat Genet. 2009;41:157-9 pubmed publisher
    ..9 x 10(-7)), near MAF (encoding the transcription factor c-MAF, P = 3.8 x 10(-13)) and near PTER (phosphotriesterase-related gene, P = 2.1 x 10(-7)). ..
  13. Timpson N, Sayers A, Davey Smith G, Tobias J. How does body fat influence bone mass in childhood? A Mendelian randomization approach. J Bone Miner Res. 2009;24:522-33 pubmed publisher
  14. Hinney A, Schmidt A, Nottebom K, Heibült O, Becker I, Ziegler A, et al. Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans. J Clin Endocrinol Metab. 1999;84:1483-6 pubmed
    ..Whereas our data support the evidence for dominantly inherited obesity as revealed by the three obese probands with haplo-insufficiency, the functional significance of the missense mutations remains to be determined. ..
  15. Challis B, Pritchard L, Creemers J, Delplanque J, Keogh J, Luan J, et al. A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism. Hum Mol Genet. 2002;11:1997-2004 pubmed
    ..These results suggest that the R236G mutation may confer an inherited susceptibility to obesity through the production of an aberrant fusion protein that has the capacity to interfere with central melanocortin signalling. ..
  16. Srinivasan S, Lubrano Berthelier C, Govaerts C, Picard F, Santiago P, Conklin B, et al. Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans. J Clin Invest. 2004;114:1158-64 pubmed
    ..Our results also suggest that the tonic satiety signal provided by the constitutive activity of MC4R may be required for maintaining long-term energy homeostasis in humans. ..
  17. Li S, Zhao J, Luan J, Luben R, Rodwell S, Khaw K, et al. Cumulative effects and predictive value of common obesity-susceptibility variants identified by genome-wide association studies. Am J Clin Nutr. 2010;91:184-90 pubmed publisher
    ..These variants have cumulative effects, yet their predictive value for obesity risk is limited. ..
  18. Shi J, Long J, Gao Y, Lu W, Cai Q, Wen W, et al. Evaluation of genetic susceptibility loci for obesity in Chinese women. Am J Epidemiol. 2010;172:244-54 pubmed publisher
    ..Results from this study extend some previous GWA findings to Chinese women and show the need for additional studies to identify susceptibility loci in Chinese and other Asian populations. ..
  19. Ortega Azorín C, Sorli J, Asensio E, Coltell O, Martinez Gonzalez M, Salas Salvado J, et al. Associations of the FTO rs9939609 and the MC4R rs17782313 polymorphisms with type 2 diabetes are modulated by diet, being higher when adherence to the Mediterranean diet pattern is low. Cardiovasc Diabetol. 2012;11:137 pubmed publisher
    ..These novel results suggest that the association of the FTO-rs9939609 and the MC4R-rs17782313 polymorphisms with type 2 diabetes depends on diet and that a high adherence to the MedDiet counteracts the genetic predisposition. ..
  20. Granell S, Mohammad S, Ramanagoudr Bhojappa R, Baldini G. Obesity-linked variants of melanocortin-4 receptor are misfolded in the endoplasmic reticulum and can be rescued to the cell surface by a chemical chaperone. Mol Endocrinol. 2010;24:1805-21 pubmed publisher
    ..These data offer a cell-based rationale that drugs that improve MC4R folding or decrease ER-associated degradation of the receptor may function to treat some forms of hereditary obesity. ..
  21. Horstmann A, Kovacs P, Kabisch S, Boettcher Y, Schloegl H, Tonjes A, et al. Common genetic variation near MC4R has a sex-specific impact on human brain structure and eating behavior. PLoS ONE. 2013;8:e74362 pubmed publisher
    ..These findings suggest that rs17782313's effect on eating behavior is mediated by central mechanisms and that these effects are sex-specific. ..
  22. Farooqi I, Keogh J, Yeo G, Lank E, Cheetham T, O Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003;348:1085-95 pubmed
    b>Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form of obesity...
  23. Tarnow P, Schoneberg T, Krude H, Gruters A, Biebermann H. Mutationally induced disulfide bond formation within the third extracellular loop causes melanocortin 4 receptor inactivation in patients with obesity. J Biol Chem. 2003;278:48666-73 pubmed
    By screening patients with severe early onset obesity for mutations within the melanocortin 4 receptor (MC4R) gene, we have identified a missense mutation (C271R) that occurs homozygous in two siblings with obesity...
  24. Ho G, MacKenzie R. Functional characterization of mutations in melanocortin-4 receptor associated with human obesity. J Biol Chem. 1999;274:35816-22 pubmed
    ..Thus, unlike the obesity-associated MC4R truncation mutants, the polymorphisms of MC4R are unlikely to be contributors to human obesity. ..
  25. Tao Y, Segaloff D. Functional characterization of melanocortin-4 receptor mutations associated with childhood obesity. Endocrinology. 2003;144:4544-51 pubmed
    ..Our data, therefore, stress the importance of characterizing the properties of MC4R variants associated with early-onset severe obesity. We further propose a classification scheme for mutant MC4Rs based upon their properties. ..
  26. Dempfle A, Hinney A, Heinzel Gutenbrunner M, Raab M, Geller F, Gudermann T, et al. Large quantitative effect of melanocortin-4 receptor gene mutations on body mass index. J Med Genet. 2004;41:795-800 pubmed
  27. Loos R, Lindgren C, Li S, Wheeler E, Zhao J, Prokopenko I, et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet. 2008;40:768-75 pubmed publisher
  28. Greenfield J, Miller J, Keogh J, Henning E, Satterwhite J, Cameron G, et al. Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med. 2009;360:44-52 pubmed publisher overweight or obese subjects with a loss-of-function mutation in MC4R, the gene encoding the melanocortin 4 receptor, and in equally overweight control subjects...
  29. Fan Z, Tao Y. Functional characterization and pharmacological rescue of melanocortin-4 receptor mutations identified from obese patients. J Cell Mol Med. 2009;13:3268-82 pubmed publisher
    ..In conclusion, of 10 mutants we studied, 6 had decreased cell surface expression. Pharmacological chaperone is a potential approach for treating obesity caused by MC4R mutations that result in intracellular retention. ..
  30. Fleck B, Ling N, Chen C. Substituted NDP-MSH peptides paired with mutant melanocortin-4 receptors demonstrate the role of transmembrane 6 in receptor activation. Biochemistry. 2007;46:10473-83 pubmed
    ..51) and F284(7.35). These findings refine the molecular basis for the mechanism of ligand-stimulated hMC4R activation and will be useful for the development of hMC4R agonists and antagonists. ..
  31. Grant S, Bradfield J, Zhang H, Wang K, Kim C, Annaiah K, et al. Investigation of the locus near MC4R with childhood obesity in Americans of European and African ancestry. Obesity (Silver Spring). 2009;17:1461-5 pubmed publisher
    ..As such, variants 3' to the MC4R locus present on the genotyping platform utilized confer a similar magnitude of risk of obesity in white children as to their adult white counterparts but this observation did not extend to AAs. ..
  32. Kim C, Lee S, Kim R, Kim B, Li S, Lee I, et al. Identification of domains directing specificity of coupling to G-proteins for the melanocortin MC3 and MC4 receptors. J Biol Chem. 2002;277:31310-7 pubmed
    ..Overall, this study demonstrated that MC3R and MC4R have distinct signaling in either the cAMP- or the inositol phospholipid-mediated pathway with different conformational requirements. ..
  33. Tabara Y, Osawa H, Guo H, Kawamoto R, Onuma H, Shimizu I, et al. Prognostic significance of FTO genotype in the development of obesity in Japanese: the J-SHIPP study. Int J Obes (Lond). 2009;33:1243-8 pubmed publisher
    ..Polymorphisms in the melanocortin 4 receptor (MC4R) gene were recently explored as another susceptible locus...
  34. Cecil J, Dalton M, Finlayson G, Blundell J, Hetherington M, Palmer C. Obesity and eating behaviour in children and adolescents: contribution of common gene polymorphisms. Int Rev Psychiatry. 2012;24:200-10 pubmed publisher
    ..variants of fat mass and obesity associated (FTO), peroxisome proliferator-activated receptor (PPARG) and melanocortin 4 receptor (MC4R) which contribute to variance in BMI also influence the variance in appetite factors such as ..
  35. Kvaløy K, Kulle B, Romundstad P, Holmen T. Sex-specific effects of weight-affecting gene variants in a life course perspective--The HUNT Study, Norway. Int J Obes (Lond). 2013;37:1221-9 pubmed publisher
    ..Some variants less known for obesity-susceptibility such as OPRD1 were found to be associated to weight with strongest effects in males. ..
  36. Yang Y, Chen M, Lai Y, Gantz I, Georgeson K, Harmon C. Molecular determinants of human melanocortin-4 receptor responsible for antagonist SHU9119 selective activity. J Biol Chem. 2002;277:20328-35 pubmed
    ..This report provides the details of the molecular recognition of SHU9119 antagonism at hMC4R and shows that amino acid Leu(133) of hMC4R plays a key role in melanocortin receptor subtype specificity. ..
  37. Willer C, Speliotes E, Loos R, Li S, Lindgren C, Heid I, et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet. 2009;41:25-34 pubmed publisher
    ..Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity. ..
  38. Santini F, Maffei M, Pelosini C, Salvetti G, Scartabelli G, Pinchera A. Melanocortin-4 receptor mutations in obesity. Adv Clin Chem. 2009;48:95-109 pubmed
  39. Liu G, Zhu H, Lagou V, Gutin B, Barbeau P, Treiber F, et al. Common variants near melanocortin 4 receptor are associated with general and visceral adiposity in European- and African-American youth. J Pediatr. 2010;156:598-605.e1 pubmed publisher
    Recent genome-wide association studies found common variants near the melanocortin 4 receptor gene associated with obesity...
  40. Liu G, Zhu H, Dong Y, Podolsky R, Treiber F, Snieder H. Influence of common variants in FTO and near INSIG2 and MC4R on growth curves for adiposity in African- and European-American youth. Eur J Epidemiol. 2011;26:463-73 pubmed publisher
    ..Common variants for obesity identified in GWA studies have detectable but modest effects on growth curves for adiposity in EA and AA youth. ..
  41. Timpson N, Harbord R, Davey Smith G, Zacho J, Tybjaerg Hansen A, Nordestgaard B. Does greater adiposity increase blood pressure and hypertension risk?: Mendelian randomization using the FTO/MC4R genotype. Hypertension. 2009;54:84-90 pubmed publisher
    ..002). Observed associations are large and illustrate the considerable benefits in terms of reductions in blood pressure-related morbidity that could be achieved through a reduction in body mass index. ..
  42. Okada Y, Kubo M, Ohmiya H, Takahashi A, Kumasaka N, Hosono N, et al. Common variants at CDKAL1 and KLF9 are associated with body mass index in east Asian populations. Nat Genet. 2012;44:302-6 pubmed publisher
    ..0 × 10(-8)) between a SNP in the KLF9 locus (rs11142387) and one in the MSTN (also known as GDF8) locus at 2q32 (rs13034723). These findings should provide useful insights into the etiology of obesity. ..
  43. Rong R, Tao Y, Cheung B, Xu A, Cheung G, Lam K. Identification and functional characterization of three novel human melanocortin-4 receptor gene variants in an obese Chinese population. Clin Endocrinol (Oxf). 2006;65:198-205 pubmed
    ..Two known polymorphisms and three novel variants of the MC4R were identified. No overt functional defects were observed for the three novel MC4R variants, suggesting that they might not be the cause of obesity in variant carriers. ..
  44. Tao Y. Mutations in melanocortin-4 receptor and human obesity. Prog Mol Biol Transl Sci. 2009;88:173-204 pubmed publisher
    ..Potential therapeutic implications from the analyses of the naturally occurring MC4R mutations, such as novel ligands and pharmacological chaperones, are highlighted. ..
  45. Mirshahi U, Still C, Masker K, Gerhard G, Carey D, Mirshahi T. The MC4R(I251L) allele is associated with better metabolic status and more weight loss after gastric bypass surgery. J Clin Endocrinol Metab. 2011;96:E2088-96 pubmed publisher
    ..Diabetic status has only a small, short-term effect on weight loss after RYGB. ..
  46. Tan K, Pogozheva I, Yeo G, Hadaschik D, Keogh J, Haskell Leuvano C, et al. Functional characterization and structural modeling of obesity associated mutations in the melanocortin 4 receptor. Endocrinology. 2009;150:114-25 pubmed publisher
    Mutations in the melanocortin 4 receptor (MC4R) gene are the most common known cause of monogenic human obesity. The MC4R gene was sequenced in 2000 subjects with severe early-onset obesity...
  47. Scherag A, Dina C, Hinney A, Vatin V, Scherag S, Vogel C, et al. Two new Loci for body-weight regulation identified in a joint analysis of genome-wide association studies for early-onset extreme obesity in French and german study groups. PLoS Genet. 2010;6:e1000916 pubmed publisher
    ..We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults. ..
  48. Yeo G, Lank E, Farooqi I, Keogh J, Challis B, O Rahilly S. Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms. Hum Mol Genet. 2003;12:561-74 pubmed
  49. Kim D, Shin S, Baik J. Role of third intracellular loop of the melanocortin 4 receptor in the regulation of constitutive activity. Biochem Biophys Res Commun. 2008;365:439-45 pubmed
    The melanocortin 4 receptor (MC4R) has been reported to display constitutive activity, which is probably relevant to the maintenance of a normal energy balance...
  50. Sayk F, Heutling D, Dodt C, Iwen K, Wellhoner J, Scherag S, et al. Sympathetic function in human carriers of melanocortin-4 receptor gene mutations. J Clin Endocrinol Metab. 2010;95:1998-2002 pubmed publisher
    ..Their dysfunction could explain reduced sympathoexcitability, lower sympathetic nerve-induced lipolysis, and the fact that blood pressure is rarely elevated in this type of obesity. ..
  51. Huang H, Zeng Z, Zhang L, Liu R, Li X, Qiang O, et al. Implication of genetic variants near TMEM18, BCDIN3D/FAIM2, and MC4R with coronary artery disease and obesity in Chinese: a angiography-based study. Mol Biol Rep. 2012;39:1739-44 pubmed publisher
    ..001, OR = 2.96, 95% CI 2.01-3.73; and P = 0.003, OR = 2.59, 95% CI 1.86-3.19, respectively). Our observations suggest that the polymorphism rs12970134 near MC4R may be associated to the risk of obesity in Han Chinese population. ..
  52. Branson R, Potoczna N, Kral J, Lentes K, Hoehe M, Horber F. Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. N Engl J Med. 2003;348:1096-103 pubmed
    ..A few mutations in these genes, such as in the leptin receptor (LEPR) gene and melanocortin 4 receptor (MC4R) gene, have been identified as causes of monogenic obesity...
  53. Ma L, Tataranni P, Bogardus C, Baier L. Melanocortin 4 receptor gene variation is associated with severe obesity in Pima Indians. Diabetes. 2004;53:2696-9 pubmed
    Heterozygous coding mutations in the melanocortin 4 receptor gene (MC4R) are the most common genetic causes of severe human obesity identified to date...
  54. Proneth B, Xiang Z, Pogozheva I, Litherland S, Gorbatyuk O, Shaw A, et al. Molecular mechanism of the constitutive activation of the L250Q human melanocortin-4 receptor polymorphism. Chem Biol Drug Des. 2006;67:215-29 pubmed
  55. Kang S, Chiang C, Palmer C, Tayo B, Lettre G, Butler J, et al. Genome-wide association of anthropometric traits in African- and African-derived populations. Hum Mol Genet. 2010;19:2725-38 pubmed publisher
    ..Meta-analysis of this data set with additional studies in African-ancestry populations will be helpful to improve power to detect novel associations. ..
  56. Shinyama H, Masuzaki H, Fang H, Flier J. Regulation of melanocortin-4 receptor signaling: agonist-mediated desensitization and internalization. Endocrinology. 2003;144:1301-14 pubmed
    ..Our data demonstrate that, through PKA-, GRK-, beta-arrestin-, and dynamin-dependent processes, MC4R undergoes internalization in response to agonist, thereby providing novel insights into the regulation of MC4R signaling. ..
  57. Hebebrand J, Geller F, Dempfle A, Heinzel Gutenbrunner M, Raab M, Gerber G, et al. Binge-eating episodes are not characteristic of carriers of melanocortin-4 receptor gene mutations. Mol Psychiatry. 2004;9:796-800 pubmed
    ..In particular, we found no evidence for an increased rate of binge-eating behavior in obese carriers of MC4R variants. Our findings do not support the strong association between BED and MC4R carrier status. ..
  58. Valli Jaakola K, Suviolahti E, Schalin Jantti C, Ripatti S, Silander K, Oksanen L, et al. Further evidence for the role of ENPP1 in obesity: association with morbid obesity in Finns. Obesity (Silver Spring). 2008;16:2113-9 pubmed publisher
    ..In this study, we did not find association between the frequently studied ENPP1 K121Q variant, nor SNPs in the MCR or POMC genes and obesity or type 2 diabetes. ..
  59. Stutzmann F, Vatin V, Cauchi S, Morandi A, Jouret B, Landt O, et al. Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene. Hum Mol Genet. 2007;16:1837-44 pubmed
    ..These results also emphasize the importance of the MC4R signalling tonus to prevent obesity, even in the context of our current obesogenic environment. ..
  60. Roth C, Ludwig M, Woelfle J, Fan Z, Brumm H, Biebermann H, et al. A novel melanocortin-4 receptor gene mutation in a female patient with severe childhood obesity. Endocrine. 2009;36:52-9 pubmed publisher
    ..These results add to the growing list of loss-of-function MC4R mutations in early onset obese patients and suggest an orexigenic effect of novel Y302F mutation. ..
  61. Chai B, Li J, Zhang W, Wang H, Mulholland M. Melanocortin-4 receptor activation inhibits c-Jun N-terminal kinase activity and promotes insulin signaling. Peptides. 2009;30:1098-104 pubmed publisher
    ..NDP-MSH increased insulin-stimulated glucose uptake in hypothalamic GT1-1 cells. The current study shows that the melanocortinergic system interacts with insulin signaling via novel effects on JNK activity. ..
  62. Razquin C, Marti A, Martinez J. Evidences on three relevant obesogenes: MC4R, FTO and PPAR?. Approaches for personalized nutrition. Mol Nutr Food Res. 2011;55:136-49 pubmed publisher
    ..This review is specifically focused on the study of the effects of melanocortin 4 receptor, Peroxisome proliferator-activated receptor ? and fat mass and obesity associated (FTO) gene variants and ..
  63. Wang Z, Tao Y. Functional studies on twenty novel naturally occurring melanocortin-4 receptor mutations. Biochim Biophys Acta. 2011;1812:1190-9 pubmed publisher
    ..Five mutants had normal functions. In summary, we provided detailed functional data for further studies on identifying therapeutic approaches for personalized medicine to treat patients harboring these mutations. ..
  64. Hotta K, Nakamura M, Nakamura T, Matsuo T, Nakata Y, Kamohara S, et al. Association between obesity and polymorphisms in SEC16B, TMEM18, GNPDA2, BDNF, FAIM2 and MC4R in a Japanese population. J Hum Genet. 2009;54:727-31 pubmed publisher
    ..v-maf musculoaponeurotic fibrosarcoma oncogene homolog (MAF), Niemann-Pick disease, type C1 (NPC1), melanocortin 4 receptor (MC4R) and potassium channel tetramerisation domain containing 15 (KCTD15)...
  65. Reinehr T, Hebebrand J, Friedel S, Toschke A, Brumm H, Biebermann H, et al. Lifestyle intervention in obese children with variations in the melanocortin 4 receptor gene. Obesity (Silver Spring). 2009;17:382-9 pubmed publisher
    Because information on weight changes after lifestyle intervention in children with mutations in the melanocortin 4 receptor (MC4R) gene is scarce, we compared weight changes after lifestyle intervention between children with and without ..
  66. Wang D, Ma J, Zhang S, Hinney A, Hebebrand J, Wang Y, et al. Association of the MC4R V103I polymorphism with obesity: a Chinese case-control study and meta-analysis in 55,195 individuals. Obesity (Silver Spring). 2010;18:573-9 pubmed publisher
    ..It provides significant evidence for the association in East Asian populations. Further large-scaled studies in East Asian populations are needed to validate the association. ..
  67. Ewens K, Jones M, Ankener W, Stewart D, Urbanek M, Dunaif A, et al. FTO and MC4R gene variants are associated with obesity in polycystic ovary syndrome. PLoS ONE. 2011;6:e16390 pubmed publisher
    ..These findings support the notion that PCOS phenotypes are a consequence of an oligogenic/polygenic mechanism. ..
  68. Mo X, Yang R, Tao Y. Functions of transmembrane domain 3 of human melanocortin-4 receptor. J Mol Endocrinol. 2012;49:221-35 pubmed publisher
    ..Moreover, L140 was critical for locking MC4R in inactive conformation and several mutants showed biased signaling in cAMP and ERK1/2 signaling pathways. ..
  69. Aslan I, Campos G, Calton M, Evans D, Merriman R, Vaisse C. Weight loss after Roux-en-Y gastric bypass in obese patients heterozygous for MC4R mutations. Obes Surg. 2011;21:930-4 pubmed publisher
    ..This study suggests that patients with heterozygous MC4R mutations also benefit from RYGB and that weight loss may be independent of the presence of such mutations. ..
  70. Heid I, Vollmert C, Hinney A, Doring A, Geller F, Lowel H, et al. Association of the 103I MC4R allele with decreased body mass in 7937 participants of two population based surveys. J Med Genet. 2005;42:e21 pubmed
  71. Zobel D, Andreasen C, Grarup N, Eiberg H, Sørensen T, Sandbaek A, et al. Variants near MC4R are associated with obesity and influence obesity-related quantitative traits in a population of middle-aged people: studies of 14,940 Danes. Diabetes. 2009;58:757-64 pubmed publisher
    ..08, P = 0.08 and 1.08, P = 0.06, respectively); however, these borderline associations were abolished after adjustment for BMI. rs17782313, rs17700633, and rs12970134 near MC4R associate with measures of obesity in Danish individuals. ..
  72. Valladares M, Dominguez Vásquez P, Obregon A, Weisstaub G, Burrows R, Maiz A, et al. Melanocortin-4 receptor gene variants in Chilean families: association with childhood obesity and eating behavior. Nutr Neurosci. 2010;13:71-8 pubmed publisher
    ..The rs17782313 variant is possibly associated with satiety responsiveness (P = 0.01) and enjoyment of food scores (P = 0.03). The rs17782313 variant may influence eating behavior in obese children. ..
  73. Elks C, Loos R, Sharp S, Langenberg C, Ring S, Timpson N, et al. Genetic markers of adult obesity risk are associated with greater early infancy weight gain and growth. PLoS Med. 2010;7:e1000284 pubmed publisher
    ..92 per allele; 0.86-0.98; p = 0.009). The use of robust genetic markers identified greater early infancy gains in weight and length as being on the pathway to adult obesity risk in a contemporary birth cohort. ..
  74. Yang Y, Fong T, Dickinson C, Mao C, Li J, Tota M, et al. Molecular determinants of ligand binding to the human melanocortin-4 receptor. Biochemistry. 2000;39:14900-11 pubmed
    ..In addition, mutation of TM3 residue D122 or D126 decreased the binding affinity of hMC4R antagonist SHU 9119. These results provide further insight into the molecular determinants of hMC4R ligand binding. ..
  75. Jacobson P, Ukkola O, Rankinen T, Snyder E, Leon A, Rao D, et al. Melanocortin 4 receptor sequence variations are seldom a cause of human obesity: the Swedish Obese Subjects, the HERITAGE Family Study, and a Memphis cohort. J Clin Endocrinol Metab. 2002;87:4442-6 pubmed
    The prevalence of mutations within and in the flanking regions of the gene encoding the melanocortin 4 receptor was investigated in severely obese and normal-weight subjects from the Swedish Obese Subjects study, the Health, Risk Factors,..
  76. Nijenhuis W, Garner K, van Rozen R, Adan R. Poor cell surface expression of human melanocortin-4 receptor mutations associated with obesity. J Biol Chem. 2003;278:22939-45 pubmed
    ..Hemagglutinin-tagged mutant receptors were retained in the intracellular environment. These pharmacological data provide a basis to estimate the quantitative effect of MC4R mutations for the development of obesity. ..
  77. Buono P, Pasanisi F, Nardelli C, Ieno L, Capone S, Liguori R, et al. Six novel mutations in the proopiomelanocortin and melanocortin receptor 4 genes in severely obese adults living in southern Italy. Clin Chem. 2005;51:1358-64 pubmed
    ..Here we report variants of the proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) genes detected in severely obese adults living in southern Italy...
  78. Patten C, Daniels D, Suzuki A, Fluharty S, Yee D. Structural and signaling requirements of the human melanocortin 4 receptor for MAP kinase activation. Regul Pept. 2007;142:111-22 pubmed
    ..Taken together, these data indicate that cAMP is required, but not sufficient for p44/42 MAPK activation and suggest structural elements required for hMC4 receptor signaling. ..
  79. Cole S, Butte N, Voruganti V, Cai G, Haack K, Kent J, et al. Evidence that multiple genetic variants of MC4R play a functional role in the regulation of energy expenditure and appetite in Hispanic children. Am J Clin Nutr. 2010;91:191-9 pubmed publisher
    ..81. This comprehensive investigation provides strong evidence that MC4R genetic variants are likely to play a functional role in the regulation of weight, not only through energy intake but through energy expenditure. ..
  80. Hasselbalch A, Angquist L, Christiansen L, Heitmann B, Kyvik K, Sørensen T. A variant in the fat mass and obesity-associated gene (FTO) and variants near the melanocortin-4 receptor gene (MC4R) do not influence dietary intake. J Nutr. 2010;140:831-4 pubmed publisher
    ..The outcome of this study indicates that polymorphisms in the FTO gene and near the MC4R gene do not have a role in regulating food intake and preference for specific food items. ..
  81. Ng M, Tam C, So W, Ho J, Chan A, Lee H, et al. Implication of genetic variants near NEGR1, SEC16B, TMEM18, ETV5/DGKG, GNPDA2, LIN7C/BDNF, MTCH2, BCDIN3D/FAIM2, SH2B1, FTO, MC4R, and KCTD15 with obesity and type 2 diabetes in 7705 Chinese. J Clin Endocrinol Metab. 2010;95:2418-25 pubmed publisher
    ..2 x 10(-12)). Our findings support the important contribution of GNPDA2, BCDIN3D/FAIM2, SH2B1, FTO, and KCTD15 in the regulation of adiposity, which in turn affects T2D risk in Chinese. ..
  82. Moore B, Mirshahi U, Yost E, Stepanchick A, Bedrin M, Styer A, et al. Long-term weight-loss in gastric bypass patients carrying melanocortin 4 receptor variants. PLoS ONE. 2014;9:e93629 pubmed publisher
    The melanocortin 4 receptor (MC4R) critically regulates feeding and satiety. Rare variants in MC4R are predominantly found in obese individuals...
  83. Vaisse C, Clement K, Guy Grand B, Froguel P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet. 1998;20:113-4 pubmed
  84. Valli Jaakola K, Lipsanen Nyman M, Oksanen L, Hollenberg A, Kontula K, Bjørbaek C, et al. Identification and characterization of melanocortin-4 receptor gene mutations in morbidly obese finnish children and adults. J Clin Endocrinol Metab. 2004;89:940-5 pubmed
    ..Impaired function of the S127L receptor was due to reduced activation, not a defect of protein transport to the cell membrane. ..
  85. Krakoff J, Ma L, Kobes S, Knowler W, Hanson R, Bogardus C, et al. Lower metabolic rate in individuals heterozygous for either a frameshift or a functional missense MC4R variant. Diabetes. 2008;57:3267-72 pubmed publisher
    Humans with functional variants in the melanocortin 4 receptor (MC4R) are obese, hyperphagic, and hyperinsulinemic but have been reported to have no difference in energy expenditure...
  86. Stutzmann F, Cauchi S, Durand E, Calvacanti Proença C, Pigeyre M, Hartikainen A, et al. Common genetic variation near MC4R is associated with eating behaviour patterns in European populations. Int J Obes (Lond). 2009;33:373-8 pubmed publisher
    ..The potential effect of the obesity-associated FTO gene on eating behaviour deserves additional investigation. ..
  87. Tan S, Scherag A, Janssen O, Hahn S, Lahner H, Dietz T, et al. Large effects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS). BMC Med Genet. 2010;11:12 pubmed publisher
    ..associated gene (FTO), insulin-induced gene-2 (INSIG2), transcription factor 7-like 2 gene (TCF7L2) and melanocortin 4 receptor gene (MC4R)...
  88. Holzapfel C, Grallert H, Huth C, Wahl S, Fischer B, Doring A, et al. Genes and lifestyle factors in obesity: results from 12,462 subjects from MONICA/KORA. Int J Obes (Lond). 2010;34:1538-45 pubmed publisher
    ..Our data first confirm the findings for TMEM18 with BMI in a single study on adults and also confirm the findings for FTO and SH2B1. There was no evidence for a direct SNP-lifestyle association. ..
  89. Wu L, Xi B, Zhang M, Shen Y, Zhao X, Cheng H, et al. Associations of six single nucleotide polymorphisms in obesity-related genes with BMI and risk of obesity in Chinese children. Diabetes. 2010;59:3085-9 pubmed publisher
    ..Results of this study support obesity-related genes in adults as important genes for BMI variation in children and suggest that some SNPs identified by GWA studies in Caucasians also confer risk for obesity in Chinese children. ..
  90. van den Berg L, Van Beekum O, Heutink P, Felius B, van de Heijning M, Strijbis S, et al. Melanocortin-4 receptor gene mutations in a Dutch cohort of obese children. Obesity (Silver Spring). 2011;19:604-11 pubmed publisher
    ..These patients are difficult to recognize in a clinical setting. We generated a list of all MC4R variants that were described in the literature so far, which can aid the interpretation of mutations found in a diagnostic setting. ..
  91. Huang H, Tao Y. Pleiotropic functions of the transmembrane domain 6 of human melanocortin-4 receptor. J Mol Endocrinol. 2012;49:237-48 pubmed publisher
    ..We also reported constitutive activation of the MAPK pathway and biased signaling. These data will be useful for rationally designing MC4R agonists and antagonists for treatment of eating disorders. ..
  92. Xi B, Chandak G, Shen Y, Wang Q, Zhou D. Association between common polymorphism near the MC4R gene and obesity risk: a systematic review and meta-analysis. PLoS ONE. 2012;7:e45731 pubmed publisher
    ..association studies on Europeans have shown that two polymorphisms (rs17782313, rs12970134) near the melanocortin 4 receptor (MC4R) gene were associated with increased risk of obesity...