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Cited by 284Regulation of Appetite and ObesityReceptor Mechanisms and SignalingGenetic Associations and Epidemiology

Human gain-of-function MC4R variants show signaling bias and protect against obesity

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Lotta, Luca A., Mokrosiński, Jacek, Mendes de Oliveira, Edson, Li, Chen, Sharp, Stephen J., Luan, Jian’an, Brouwers, Bas, Ayinampudi, Vikram +11 more·2019·Cell
DOI 10.1016/j.cell.2019.03.044PMC PMC6476272
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Abstract

The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor whose disruption causes obesity. We functionally characterized 61 MC4R variants identified in 0.5 million people from UK Biobank and examined their associations with body mass index (BMI) and obesity-related cardiometabolic diseases. We found that the maximal efficacy of β-arrestin recruitment to MC4R, rather than canonical Gα s -mediated cyclic adenosine-monophosphate production, explained 88% of the variance in the association of MC4R variants with BMI. While most MC4R variants caused loss of function, a subset caused gain of function; these variants were associated with significantly lower BMI and lower odds of obesity, type 2 diabetes, and coronary artery disease. Protective associations were driven by MC4R variants exhibiting signaling bias toward β-arrestin recruitment and increased mitogen-activated protein kinase pathway activation. Harnessing β-arrestin-biased MC4R signaling may represent an effective strategy for weight loss and the treatment of obesity-related cardiometabolic diseases.

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  • MC4R signalling involves multiple G-protein-mediated pathways, including Gsα/cAMP and Gαq/PLC signalling.

    “MC4R signalling involves multiple G-protein-mediated pathways, including Gsα/cAMP and Gαq/PLC signalling, and different patterns of signalling bias among different pathways are associated with distinct phenotypes and treatment responses (111, 112).”

    From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [111]

    The Introduction and Results identify MC4R as a Gαs-coupled receptor and measure Gαs-mediated cAMP signaling. The paper also examines β-arrestin signaling, but the passages from our copy do not identify Gαq/PLC as an MC4R pathway; searches for Gαq, PLC, and phospholipase C did not establish that part of the claim. No page numbers were provided. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Different patterns of signalling bias among MC4R pathways are associated with distinct phenotypes and treatment responses.

    “MC4R signalling involves multiple G-protein-mediated pathways, including Gsα/cAMP and Gαq/PLC signalling, and different patterns of signalling bias among different pathways are associated with distinct phenotypes and treatment responses (111, 112).”

    From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [111]

    The Results section reports that MC4R variants biased toward β-arrestin recruitment, rather than cAMP production, were associated with differences in BMI and obesity risk. The Discussion proposes that these genetic findings could guide pathway-selective treatments, but does not report distinct treatment responses to MC4R therapies. Page numbers are unavailable in our copy. (LLM, conf=0.86)

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Research works printed but not linked: 56

  1. Bray G.A. Frühbeck G. Ryan D.H. Wilding J.P. Management of obesity Lancet 387 2016 1947 1956 26868660
  2. Burgess S. Butterworth A. Thompson S.G. Mendelian randomization analysis with multiple genetic variants using summarized data Genet. Epidemiol. 37 2013 658 665 24114802 PMC4377079
  3. Bycroft C. Freeman C. Petkova D. Band G. Elliott L.T. Sharp K. Motyer A. Vukcevic D. Delaneau O. O’Connell J. The UK Biobank resource with deep phenotyping and genomic data Nature 562 2018 203 209 30305743 PMC6786975
  4. Clarke R. Peden J.F. Hopewell J.C. Kyriakou T. Goel A. Heath S.C. Parish S. Barlera S. Franzosi M.G. Rust S. PROCARDIS Consortium Genetic variants associated with Lp(a) lipoprotein level and coronary disease N. Engl. J. Med. 361 2009 2518 2528 20032323
  5. Clément K. Biebermann H. Farooqi I.S. Van der Ploeg L. Wolters B. Poitou C. Puder L. Fiedorek F. Gottesdiener K. Kleinau G. MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency Nat. Med. 24 2018 551 555 29736023
  6. Cohen J.C. Boerwinkle E. Mosley T.H. Jr. Hobbs H.H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease N. Engl. J. Med. 354 2006 1264 1272 16554528
  7. Cowley M.A. Smart J.L. Rubinstein M. Cerdán M.G. Diano S. Horvath T.L. Cone R.D. Low M.J. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus Nature 411 2001 480 484 11373681
  8. Dewey F.E. Gusarova V. Dunbar R.L. O’Dushlaine C. Schurmann C. Gottesman O. McCarthy S. Van Hout C.V. Bruse S. Dansky H.M. Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease N. Engl. J. Med. 377 2017 211 221 28538136 PMC5800308
  9. Fan W. Boston B.A. Kesterson R.A. Hruby V.J. Cone R.D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome Nature 385 1997 165 168 8990120
  10. Farooqi I.S. Yeo G.S. Keogh J.M. Aminian S. Jebb S.A. Butler G. Cheetham T. O’Rahilly S. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency J. Clin. Invest. 106 2000 271 279 10903343 PMC314308
  11. Farooqi I.S. Keogh J.M. Yeo G.S. Lank E.J. Cheetham T. O’Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene N. Engl. J. Med. 348 2003 1085 1095 12646665
  12. Ference B.A. Majeed F. Penumetcha R. Flack J.M. Brook R.D. Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 × 2 factorial Mendelian randomization study J. Am. Coll. Cardiol. 65 2015 1552 1561 25770315 PMC6101243
  13. Friend S.H. Schadt E.E. Translational genomics. Clues from the resilient Science 344 2014 970 972 24876479
  14. Geller F. Reichwald K. Dempfle A. Illig T. Vollmert C. Herpertz S. Siffert W. Platzer M. Hess C. Gudermann T. Melanocortin-4 receptor gene variant I103 is negatively associated with obesity Am. J. Hum. Genet. 74 2004 572 581 14973783 PMC1193776
  15. Goate A. Segregation of a missense mutation in the amyloid beta-protein precursor gene with familial Alzheimer’s disease J. Alzheimers Dis. 9 3, Suppl 2006 341 347 16914872
  16. Govindaraju D. Atzmon G. Barzilai N. Genetics, lifestyle and longevity: Lessons from centenarians Appl. Transl. Genomics 4 2015 23 32 PMC4745363 26937346
  17. Gu W. Tu Z. Kleyn P.W. Kissebah A. Duprat L. Lee J. Chin W. Maruti S. Deng N. Fisher S.L. Identification and functional analysis of novel human melanocortin-4 receptor variants Diabetes 48 1999 635 639 10078568
  18. Gundry J. Glenn R. Alagesan P. Rajagopal S. A Practical Guide to Approaching Biased Agonism at G Protein Coupled Receptors Front. Neurosci. 11 2017 17 28174517 PMC5258729
  19. Harper A.R. Nayee S. Topol E.J. Protective alleles and modifier variants in human health and disease Nat. Rev. Genet. 16 2015 689 701 26503796
  20. Hauser A.S. Attwood M.M. Rask-Andersen M. Schiöth H.B. Gloriam D.E. Trends in GPCR drug discovery: new agents, targets and indications Nat. Rev. Drug Discov. 16 2017 829 842 29075003 PMC6882681
  21. Hauser A.S. Chavali S. Masuho I. Jahn L.J. Martemyanov K.A. Gloriam D.E. Babu M.M. Pharmacogenomics of GPCR Drug Targets Cell 172 2018 41 54 e19 29249361 PMC5766829
  22. Heid I.M. Vollmert C. Hinney A. Döring A. Geller F. Löwel H. Wichmann H.E. Illig T. Hebebrand J. Kronenberg F. KORA Group Association of the 103I MC4R allele with decreased body mass in 7937 participants of two population based surveys J. Med. Genet. 42 2005 e21 15805150 PMC1736034
  23. Hinney A. Bettecken T. Tarnow P. Brumm H. Reichwald K. Lichtner P. Scherag A. Nguyen T.T. Schlumberger P. Rief W. Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany J. Clin. Endocrinol. Metab. 91 2006 1761 1769 16492696
  24. 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. Targeted disruption of the melanocortin-4 receptor results in obesity in mice Cell 88 1997 131 141 9019399
  25. Kishi T. Aschkenasi C.J. Lee C.E. Mountjoy K.G. Saper C.B. Elmquist J.K. Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat J. Comp. Neurol. 457 2003 213 235 12541307
  26. Kühnen P. Clément K. Wiegand S. Blankenstein O. Gottesdiener K. Martini L.L. Mai K. Blume-Peytavi U. Grüters A. Krude H. Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist N. Engl. J. Med. 375 2016 240 246 27468060
  27. Liu R. Paxton W.A. Choe S. Ceradini D. Martin S.R. Horuk R. MacDonald M.E. Stuhlmann H. Koup R.A. Landau N.R. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection Cell 86 1996 367 377 8756719
  28. Locke A.E. Kahali B. Berndt S.I. Justice A.E. Pers T.H. Day F.R. Powell C. Vedantam S. Buchkovich M.L. Yang J. LifeLines Cohort Study ADIPOGen Consortium AGEN-BMI Working Group CARDIOGRAMplusC4D Consortium CKDGen Consortium GLGC ICBP MAGIC Investigators MuTHER Consortium MIGen Consortium PAGE Consortium ReproGen Consortium GENIE Consortium International Endogene Consortium Genetic studies of body mass index yield new insights for obesity biology Nature 518 2015 197 206 25673413 PMC4382211
  29. Loh P.R. Tucker G. Bulik-Sullivan B.K. Vilhjálmsson B.J. Finucane H.K. Salem R.M. Chasman D.I. Ridker P.M. Neale B.M. Berger B. Efficient Bayesian mixed-model analysis increases association power in large cohorts Nat. Genet. 47 2015 284 290 25642633 PMC4342297
  30. Lotta L.A. Wittemans L.B.L. Zuber V. Stewart I.D. Sharp S.J. Luan J. Day F.R. Li C. Bowker N. Cai L. Association of Genetic Variants Related to Gluteofemoral vs Abdominal Fat Distribution With Type 2 Diabetes, Coronary Disease, and Cardiovascular Risk Factors JAMA 320 2018 2553 2563 30575882 PMC6583513
  31. Morris A.P. Voight B.F. Teslovich T.M. Ferreira T. Segrè A.V. Steinthorsdottir V. Strawbridge R.J. Khan H. Grallert H. Mahajan A. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes Nat. Genet. 44 2012 981 990 22885922 PMC3442244
  32. Mountjoy K.G. Mortrud M.T. Low M.J. Simerly R.B. Cone R.D. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain Mol. Endocrinol. 8 1994 1298 1308 7854347
  33. Musunuru K. Pirruccello J.P. Do R. Peloso G.M. Guiducci C. Sougnez C. Garimella K.V. Fisher S. Abreu J. Barry A.J. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia N. Engl. J. Med. 363 2010 2220 2227 20942659 PMC3008575
  34. Ollmann M.M. Wilson B.D. Yang Y.K. Kerns J.A. Chen Y. Gantz I. Barsh G.S. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein Science 278 1997 135 138 9311920
  35. Plenge R.M. Scolnick E.M. Altshuler D. Validating therapeutic targets through human genetics Nat. Rev. Drug Discov. 12 2013 581 594 23868113
  36. Povsic T.J. Scott R. Mahaffey K.W. Blaustein R. Edelberg J.M. Lefkowitz M.P. Solomon S.D. Fox J.C. Healy K.E. Khakoo A.Y. Navigating the Future of Cardiovascular Drug Development-Leveraging Novel Approaches to Drive Innovation and Drug Discovery: Summary of Findings from the Novel Cardiovascular Therapeutics Conference. Cardiovasc Drugs Ther. 31 2017 445 458 28735360
  37. Rajagopal S. Shenoy S.K. GPCR desensitization: Acute and prolonged phases Cell. Signal. 41 2018 9 16 28137506 PMC5533627
  38. Rajagopal S. Ahn S. Rominger D.H. Gowen-MacDonald W. Lam C.M. Dewire S.M. Violin J.D. Lefkowitz R.J. Quantifying ligand bias at seven-transmembrane receptors Mol. Pharmacol. 80 2011 367 377 21610196 PMC3164332
  39. Santos R. Ursu O. Gaulton A. Bento A.P. Donadi R.S. Bologa C.G. Karlsson A. Al-Lazikani B. Hersey A. Oprea T.I. Overington J.P. A comprehensive map of molecular drug targets Nat. Rev. Drug Discov. 16 2017 19 34 27910877 PMC6314433
  40. Sayk F. Heutling D. Dodt C. Iwen K.A. Wellhoner J.P. Scherag S. Hinney A. Hebebrand J. Lehnert H. Sympathetic function in human carriers of melanocortin-4 receptor gene mutations J. Clin. Endocrinol. Metab. 95 2010 1998 2002 20147580
  41. Shenoy S.K. Lefkowitz R.J. β-Arrestin-mediated receptor trafficking and signal transduction Trends Pharmacol. Sci. 32 2011 521 533 21680031 PMC3159699
  42. Shinyama H. Masuzaki H. Fang H. Flier J.S. Regulation of melanocortin-4 receptor signaling: agonist-mediated desensitization and internalization Endocrinology 144 2003 1301 1314 12639913
  43. Simonds S.E. Pryor J.T. Ravussin E. Greenway F.L. Dileone R. Allen A.M. Bassi J. Elmquist J.K. Keogh J.M. Henning E. Leptin mediates the increase in blood pressure associated with obesity Cell 159 2014 1404 1416 25480301 PMC4259491
  44. Smith J.S. Lefkowitz R.J. Rajagopal S. Biased signalling: from simple switches to allosteric microprocessors Nat. Rev. Drug Discov. 17 2018 243 260 29302067 PMC5936084
  45. Stutzmann F. Vatin V. Cauchi S. Morandi A. Jouret B. Landt O. Tounian P. Levy-Marchal C. Buzzetti R. Pinelli L. Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene Hum. Mol. Genet. 16 2007 1837 1844 17519222
  46. Stutzmann F. Tan K. Vatin V. Dina C. Jouret B. Tichet J. Balkau B. Potoczna N. Horber F. O’Rahilly S. Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees Diabetes 57 2008 2511 2518 18559663 PMC2518504
  47. Sudlow C. Gallacher J. Allen N. Beral V. Burton P. Danesh J. Downey P. Elliott P. Green J. Landray M. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age PLoS Med. 12 2015 e1001779 25826379 PMC4380465
  48. Tallam L.S. Stec D.E. Willis M.A. da Silva A.A. Hall J.E. Melanocortin-4 receptor-deficient mice are not hypertensive or salt-sensitive despite obesity, hyperinsulinemia, and hyperleptinemia Hypertension 46 2005 326 332 16027245
  49. Turcot V. Lu Y. Highland H.M. Schurmann C. Justice A.E. Fine R.S. Bradfield J.P. Esko T. Giri A. Graff M. CHD Exome+ Consortium EPIC-CVD Consortium ExomeBP Consortium Global Lipids Genetic Consortium GoT2D Genes Consortium EPIC InterAct Consortium INTERVAL Study ReproGen Consortium T2D-Genes Consortium MAGIC Investigators Understanding Society Scientific Group Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity Nat. Genet. 50 2018 26 41 29273807 PMC5945951
  50. 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. 20 1998 113 114 9771699
  51. Wadman M. ‘Biased’ opioids could yield safer pain relief Science 358 2017 847 848 29146784
  52. Whalen E.J. Rajagopal S. Lefkowitz R.J. Therapeutic potential of β-arrestin- and G protein-biased agonists Trends Mol. Med. 17 2011 126 139 21183406 PMC3628754
  53. Wormser D. Kaptoge S. Di Angelantonio E. Wood A.M. Pennells L. Thompson A. Sarwar N. Kizer J.R. Lawlor D.A. Nordestgaard B.G. Emerging Risk Factors Collaboration Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies Lancet 377 2011 1085 1095 21397319 PMC3145074
  54. Wright C.F. West B. Tuke M. Jones S.E. Patel K. Laver T.W. Beaumont R.N. Tyrrell J. Wood A.R. Frayling T.M. Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting Am. J. Hum. Genet. 104 2019 275 286 30665703 PMC6369448
  55. Yeo G.S. Farooqi I.S. Aminian S. Halsall D.J. Stanhope R.G. O’Rahilly S. A frameshift mutation in MC4R associated with dominantly inherited human obesity Nat. Genet. 20 1998 111 112 9771698
  56. Young E.H. Wareham N.J. Farooqi S. Hinney A. Hebebrand J. Scherag A. O’rahilly S. Barroso I. Sandhu M.S. The V103I polymorphism of the MC4R gene and obesity: population based studies and meta-analysis of 29 563 individuals Int. J. Obes. 31 2007 1437 1441 PMC2683751 17356525

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Authors
Lotta, L. A., Mokrosiński, J., Mendes de Oliveira, E., Li, C., Sharp, S. J., Luan, J., Brouwers, B., Ayinampudi, V., Bowker, N., Kerrison, N., Kaimakis, V., Hoult, D., Stewart, I. D., Wheeler, E., Day, F. R., Perry, J. R. B., Langenberg, C., Wareham, N. J., & Farooqi, I. S.
Affiliations
University of Cambridge (GB)
Corresponding author
  • Lotta, Luca A.
  • Farooqi, I. Sadaf
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2019-04
Volume
177
Issue
3
Pages
597-607.e9
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2019.03.044
PMC
PMC6476272
OpenAlex
W2940057741
Cited by
284
References
14
Citations by year
2026: 32 · 2025: 36 · 2024: 33 · 2023: 41 · 2022: 40 · 2021: 49 · 2020: 39 · 2019: 14
FWCI
19.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
  • Apollo
Funders
Wellcome Trust
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
melanocortin-4 receptor, gain-of-function mutations, β-arrestin recruitment, signaling bias, body mass index, obesity, type 2 diabetes, coronary artery disease, cardiometabolic disease, MAPK signaling, G protein-coupled receptor signaling, weight loss
MeSH terms
beta-Arrestins, Gain of Function Mutation, Cyclic AMP, Adult, Aged, Coronary Artery Disease, Diabetes Mellitus, Type 2, Female, Genotype, Humans, Male, Middle Aged, Obesity, Signal Transduction, Body Mass Index, Databases, Factual, GTP-Binding Protein alpha Subunits, Gs, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Receptor, Melanocortin, Type 4

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