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

被引：200

作者：

Lotta, Luca A. ^{[1
]}

Mokrosinski, Jacek ^{[2
,3
]}

de Oliveira, Edson Mendes ^{[2
,3
]}

Li, Chen ^{[1
]}

Sharp, Stephen J. ^{[1
]}

Luan, Jian'an ^{[1
]}

Brouwers, Bas ^{[2
,3
]}

Ayinampudi, Vikram ^{[2
,3
]}

Bowker, Nicholas ^{[1
]}

Kerrison, Nicola ^{[1
]}

Kaimakis, Vasileios ^{[1
]}

Hoult, Diana ^{[1
]}

Stewart, Isobel D. ^{[1
]}

Wheeler, Eleanor ^{[1
]}

Day, Felix R. ^{[1
]}

Perry, John R. B. ^{[1
]}

Langenberg, Claudia ^{[1
]}

Wareham, Nicholas J. ^{[1
]}

Farooqi, I. Sadaf ^{[2
,3
]}

机构：

[1] Univ Cambridge, MRC Epidemiol Unit, Wellcome Trust MRC, Inst Metab Sci,Addenbrookes Hosp, Cambridge CB2 0QQ, England

[2] Univ Cambridge, Metab Res Labs, Wellcome Trust MRC, Inst Metab Sci,Addenbrookes Hosp, Cambridge CB2 0QQ, England

[3] Univ Cambridge, NIHR Cambridge Biomed Res Ctr, Wellcome Trust MRC, Inst Metab Sci,Addenbrookes Hosp, Cambridge CB2 0QQ, England

来源：

CELL | 2019年 / 177卷 / 03期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

BODY-MASS INDEX; FUNCTION MUTATIONS; FRAMESHIFT MUTATION; BLOOD-PRESSURE; LIFE-STYLE; RECEPTOR; ASSOCIATION; AGONIST; GENE; DISEASE;

D O I：

10.1016/j.cell.2019.03.044

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 their associations with body mass index (BMI) and obesity-related cardiometabolic diseases. We found that the maximal efficacy of beta-arrestin recruitment to MC4R, rather than canonical G(alpha 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 beta-arrestin recruitment and increased mitogen-activated protein kinase pathway activation. Harnessing beta-arrestinbiased MC4R signaling may represent an effective strategy for weight loss and the treatment of obesity-related cardiometabolic diseases.

引用

页码：597 / +

页数：20

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