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

Summary 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 Biobankand examined their associations with body mass index (BMI) and obesity-related cardiometabolic diseases. We found that the maximal efficacy of β- arrestinrecruitment to MC4R, rather than canonical Gα s -mediated cyclic adenosine-monophosphateproduction, 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- arrestinrecruitment 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.