Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect Against Obesity

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2019 Apr 20

PMID 31002796

Citations 119

Authors

Luca A Lotta

Jacek Mokrosinski

Edson Mendes de Oliveira

Chen Li

Stephen J Sharp

Jianan Luan

Bas Brouwers

Vikram Ayinampudi

Nicholas Bowker

Nicola Kerrison

Vasileios Kaimakis

Diana Hoult

Isobel D Stewart

Eleanor Wheeler

Felix R Day

John R B Perry

Claudia Langenberg

Nicholas J Wareham

I Sadaf Farooqi

Affiliations

Soon will be listed here.

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-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.

Citing Articles

Trans-ancestral rare variant association study with machine learning-based phenotyping for metabolic dysfunction-associated steatotic liver disease.

Chen R, Petrazzini B, Duffy A, Rocheleau G, Jordan D, Bansal M Genome Biol. 2025; 26(1):50.

PMID: 40065360 PMC: 11892324. DOI: 10.1186/s13059-025-03518-5.

Rare MTNR1B variants causing diminished MT2 signalling associate with elevated HbA levels but not with type 2 diabetes.

Sorensen K, Justesen J, Angquist L, Bork-Jensen J, Hartmann B, Jorgensen N Diabetologia. 2025; .

PMID: 40064676 DOI: 10.1007/s00125-025-06381-y.

Tonic ubiquitination of the central body weight regulator melanocortin receptor 4 (MC4R) promotes its constitutive exit from cilia.

Ojeda-Naharros I, Das T, Castro R, Bazan J, Vaisse C, Nachury M PLoS Biol. 2025; 23(2):e3003025.

PMID: 39899600 PMC: 11825094. DOI: 10.1371/journal.pbio.3003025.

regulates melanocortin 4 receptor transcription and energy homeostasis.

Xu B, Lawler K, Wyler S, Li L, Swati , Keogh J Sci Transl Med. 2025; 17(781):eadr6459.

PMID: 39813316 PMC: 11797978. DOI: 10.1126/scitranslmed.adr6459.

Obesity-associated MRAP2 variants impair multiple MC4R-mediated signaling pathways.

Wyatt R, Jamaluddin A, Mistry V, Quinn C, Gorvin C Hum Mol Genet. 2025; 34(6):533-546.

PMID: 39807633 PMC: 11891872. DOI: 10.1093/hmg/ddaf005.

References

Burgess S, Butterworth A, Thompson S . Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013; 37(7):658-65. PMC: 4377079. DOI: 10.1002/gepi.21758. View

Loh P, Tucker G, Bulik-Sullivan B, Vilhjalmsson B, Finucane H, Salem R . Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat Genet. 2015; 47(3):284-90. PMC: 4342297. DOI: 10.1038/ng.3190. View

Cohen J, Boerwinkle E, Mosley Jr T, Hobbs H . Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006; 354(12):1264-72. DOI: 10.1056/NEJMoa054013. View

Kuhnen P, Clement K, Wiegand S, Blankenstein O, Gottesdiener K, Martini L . Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist. N Engl J Med. 2016; 375(3):240-6. DOI: 10.1056/NEJMoa1512693. View

Bray G, Fruhbeck G, Ryan D, Wilding J . Management of obesity. Lancet. 2016; 387(10031):1947-56. DOI: 10.1016/S0140-6736(16)00271-3. View

Ollmann M, Wilson B, Yang Y, Kerns J, Chen Y, Gantz I . Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science. 1997; 278(5335):135-8. DOI: 10.1126/science.278.5335.135. View

Clarke R, Peden J, Hopewell J, Kyriakou T, Goel A, Heath S . Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009; 361(26):2518-28. DOI: 10.1056/NEJMoa0902604. View

Clement K, Biebermann H, Farooqi I, van der Ploeg L, Wolters B, Poitou C . MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nat Med. 2018; 24(5):551-555. DOI: 10.1038/s41591-018-0015-9. View

Collet T, Dubern B, Mokrosinski J, Connors H, Keogh J, Mendes de Oliveira E . Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. Mol Metab. 2017; 6(10):1321-1329. PMC: 5641599. DOI: 10.1016/j.molmet.2017.06.015. View

10.

Goate A . Segregation of a missense mutation in the amyloid beta-protein precursor gene with familial Alzheimer's disease. J Alzheimers Dis. 2006; 9(3 Suppl):341-7. DOI: 10.3233/jad-2006-9s338. View

11.

Shenoy S, Lefkowitz R . β-Arrestin-mediated receptor trafficking and signal transduction. Trends Pharmacol Sci. 2011; 32(9):521-33. PMC: 3159699. DOI: 10.1016/j.tips.2011.05.002. View

12.

Geller F, Reichwald K, Dempfle A, Illig T, Vollmert C, Herpertz S . Melanocortin-4 receptor gene variant I103 is negatively associated with obesity. Am J Hum Genet. 2004; 74(3):572-81. PMC: 1193776. DOI: 10.1086/382490. View

13.

Gundry J, Glenn R, Alagesan P, Rajagopal S . A Practical Guide to Approaching Biased Agonism at G Protein Coupled Receptors. Front Neurosci. 2017; 11:17. PMC: 5258729. DOI: 10.3389/fnins.2017.00017. View

14.

Fan W, Dinulescu D, Butler A, Zhou J, Marks D, Cone R . The central melanocortin system can directly regulate serum insulin levels. Endocrinology. 2000; 141(9):3072-9. DOI: 10.1210/endo.141.9.7665. View

15.

Morris A, Voight B, Teslovich T, Ferreira T, V Segre A, Steinthorsdottir V . Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet. 2012; 44(9):981-90. PMC: 3442244. DOI: 10.1038/ng.2383. View

16.

Flannick J, Thorleifsson G, Beer N, Jacobs S, Grarup N, Burtt N . Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat Genet. 2014; 46(4):357-63. PMC: 4051628. DOI: 10.1038/ng.2915. View

17.

Kievit P, Halem H, Marks D, Dong J, Glavas M, Sinnayah P . Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes. 2012; 62(2):490-7. PMC: 3554387. DOI: 10.2337/db12-0598. View

18.

Young E, Wareham N, Farooqi S, Hinney A, Hebebrand J, Scherag A . The V103I polymorphism of the MC4R gene and obesity: population based studies and meta-analysis of 29 563 individuals. Int J Obes (Lond). 2007; 31(9):1437-41. PMC: 2683751. DOI: 10.1038/sj.ijo.0803609. View

19.

Shinyama H, Masuzaki H, Fang H, Flier J . Regulation of melanocortin-4 receptor signaling: agonist-mediated desensitization and internalization. Endocrinology. 2003; 144(4):1301-14. DOI: 10.1210/en.2002-220931. View

20.

Turcot V, Lu Y, Highland H, Schurmann C, Justice A, Fine R . Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat Genet. 2017; 50(1):26-41. PMC: 5945951. DOI: 10.1038/s41588-017-0011-x. View