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Publication

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

Cell | 2019

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 Gαs-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.

Pubmed ID: 31002796 RIS Download

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Associated grants

Agency: Department of Health, United Kingdom
Agency: Medical Research Council, United Kingdom
Id: MC_UU_12015/1
Agency: Wellcome Trust, United Kingdom
Id: 098497/Z/12/Z
Agency: Medical Research Council, United Kingdom
Id: MR/L00002/1
Agency: Medical Research Council, United Kingdom
Id: MC_UU_00014/1
Agency: Wellcome Trust, United Kingdom
Id: 208363/Z/17/Z
Agency: Medical Research Council, United Kingdom
Id: MC_PC_13048
Agency: Medical Research Council, United Kingdom
Id: MC_PC_13046
Agency: Medical Research Council, United Kingdom
Id: MC_UU_12015/2

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