期刊
CELL
卷 177, 期 3, 页码 597-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2019.03.044
关键词
-
资金
- United Kingdom's Medical Research Council [MC_UU_12015/1, MC_PC_13046, MC_PC_13048, MR/L00002/1]
- Cambridge NIHR Biomedical Research Centre
- EU FP6 program [LSHM_CT_2006_037197]
- Wellcome Trust [098497/Z/12/Z]
- NIHR Cambridge Biomedical Research Centre
- Botnar Foundation
- Bernard Wolfe Health Neuroscience Endowment
- Wellcome Trust Major Award [208363/Z/17/Z]
- Wellcome Trust [098497/Z/12/Z] Funding Source: Wellcome Trust
- MRC [1950385, MC_UU_12015/2, MC_UU_12015/1, MC_UU_00014/1] Funding Source: UKRI
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据