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Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity
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....
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476272/ https://www.ncbi.nlm.nih.gov/pubmed/31002796 http://dx.doi.org/10.1016/j.cell.2019.03.044 |
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author | Lotta, Luca A. Mokrosiński, Jacek Mendes de Oliveira, Edson Li, Chen Sharp, Stephen J. Luan, Jian’an Brouwers, Bas Ayinampudi, Vikram Bowker, Nicholas Kerrison, Nicola Kaimakis, Vasileios Hoult, Diana Stewart, Isobel D. Wheeler, Eleanor Day, Felix R. Perry, John R.B. Langenberg, Claudia Wareham, Nicholas J. Farooqi, I. Sadaf |
author_facet | Lotta, Luca A. Mokrosiński, Jacek Mendes de Oliveira, Edson Li, Chen Sharp, Stephen J. Luan, Jian’an Brouwers, Bas Ayinampudi, Vikram Bowker, Nicholas Kerrison, Nicola Kaimakis, Vasileios Hoult, Diana Stewart, Isobel D. Wheeler, Eleanor Day, Felix R. Perry, John R.B. Langenberg, Claudia Wareham, Nicholas J. Farooqi, I. Sadaf |
author_sort | Lotta, Luca A. |
collection | PubMed |
description | 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(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 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. |
format | Online Article Text |
id | pubmed-6476272 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-64762722019-04-25 Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity Lotta, Luca A. Mokrosiński, Jacek Mendes de Oliveira, Edson Li, Chen Sharp, Stephen J. Luan, Jian’an Brouwers, Bas Ayinampudi, Vikram Bowker, Nicholas Kerrison, Nicola Kaimakis, Vasileios Hoult, Diana Stewart, Isobel D. Wheeler, Eleanor Day, Felix R. Perry, John R.B. Langenberg, Claudia Wareham, Nicholas J. Farooqi, I. Sadaf Cell Article 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(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 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. Cell Press 2019-04-18 /pmc/articles/PMC6476272/ /pubmed/31002796 http://dx.doi.org/10.1016/j.cell.2019.03.044 Text en © 2019 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lotta, Luca A. Mokrosiński, Jacek Mendes de Oliveira, Edson Li, Chen Sharp, Stephen J. Luan, Jian’an Brouwers, Bas Ayinampudi, Vikram Bowker, Nicholas Kerrison, Nicola Kaimakis, Vasileios Hoult, Diana Stewart, Isobel D. Wheeler, Eleanor Day, Felix R. Perry, John R.B. Langenberg, Claudia Wareham, Nicholas J. Farooqi, I. Sadaf Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity |
title | Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity |
title_full | Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity |
title_fullStr | Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity |
title_full_unstemmed | Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity |
title_short | Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity |
title_sort | human gain-of-function mc4r variants show signaling bias and protect against obesity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476272/ https://www.ncbi.nlm.nih.gov/pubmed/31002796 http://dx.doi.org/10.1016/j.cell.2019.03.044 |
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