University of Cambridge MRC Epidemiology Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
Cell. 2019 Apr 18;177(3):597-607.e9. doi: 10.1016/j.cell.2019.03.044.
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.
黑皮质素 4 受体（MC4R）是一种 G 蛋白偶联受体，其功能丧失会导致肥胖。我们对来自英国生物库的 50 万人中的 61 种 MC4R 变体进行了功能表征，并研究了它们与体重指数（BMI）和肥胖相关的心血管代谢疾病的关联。我们发现，β-arrestin 对 MC4R 的募集最大功效，而不是经典的 Gα 介导的环磷酸腺苷产生，解释了 MC4R 变体与 BMI 关联的 88%的变异性。虽然大多数 MC4R 变体导致功能丧失，但一部分变体导致功能获得；这些变体与 BMI 显著降低以及肥胖、2 型糖尿病和冠心病的患病风险降低相关。保护性关联是由对 β-arrestin 募集具有信号偏向性的 MC4R 变体和丝裂原激活蛋白激酶途径激活增加驱动的。利用偏向β-arrestin 的 MC4R 信号可能是减肥和治疗肥胖相关心血管代谢疾病的有效策略。
