| Title: | Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity |
| Journal: | Cell |
| Published: | 1 Apr 2019 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/31002796/ |
| DOI: | https://doi.org/10.1016/j.cell.2019.03.044 |
| URL: | http://www.cell.com/article/S0092867419303459/pdf |
Publication 3183
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Abstract
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.</p>
19 Authors
- Luca A. Lotta
- Jacek Mokrosiński
- Edson Mendes de Oliveira
- Chen Li
- Stephen J. Sharp
- Jian'an Luan
- Bas Brouwers
- Vikram Ayinampudi
- Nicholas Bowker
- Nicola Kerrison
- Vasileios Kaimakis
- Diana Hoult
- Isobel D. Stewart
- Eleanor Wheeler
- Felix R. Day
- John R.B. Perry
- Claudia Langenberg
- Nicholas J. Wareham
- I. Sadaf Farooqi
1 Application
| Application ID | Title |
|---|---|
| 12885 | Genetic determinants of objective physical activity levels and fitness in the UK Biobank |
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