Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity.
Mendes de Oliveira, Edson
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Lotta, L., Mokrosiński, J., Mendes de Oliveira, E., Li, C., Sharp, S., Luan, J., Brouwers, B., et al. (2019). Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity.. Cell, 177 (3), 597-607.e9. https://doi.org/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 Gαs-mediated cyclic adenosine-monophosphate production, explained 88% of the variance in the association of MC4R variants with BMI. Whilst 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 towards 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.
Humans, Diabetes Mellitus, Type 2, Obesity, Genetic Predisposition to Disease, GTP-Binding Protein alpha Subunits, Gs, Receptor, Melanocortin, Type 4, Cyclic AMP, Body Mass Index, Signal Transduction, Genotype, Polymorphism, Single Nucleotide, Databases, Factual, Adult, Aged, Middle Aged, Female, Male, Coronary Artery Disease, beta-Arrestins, Gain of Function Mutation
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Wellcome Trust (207462/Z/17/Z)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0617-10149)
WELLCOME TRUST (098497/Z/12/Z)
Wellcome Trust (208363/Z/17/Z)
External DOI: https://doi.org/10.1016/j.cell.2019.03.044
This record's URL: https://www.repository.cam.ac.uk/handle/1810/291605
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/