Year: 2019
Type: article
Study design: Observational Study
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 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.
Source: Cell
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
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,200
Awards: Aetiology of type 2 diabetes and related metabolic disorders, High Throughput Science - Investigating pathways to metabolic disease using "omic" approaches, Mechanisms in Disorders of Energy Balance, High Throughput Science - Investigating the genetic determinants of healthy ageing: the MRC EPIC-Norfolk study, NIHR Senior Investigator Award, G2892497062, G339059223, G3652455175, G3812975344, The University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Cambridge, G5787426001, Fundamental mechanisms controlling human energy homeostasis, Employing multi-omic approaches to the investigation of the causation of cardio-metabolic disease., Molecular and neural basis of obesity, G8585681489, NIHR Senior Investigator Award, Child Growth and development, G8975348055
OpenAlex ID: W2940057741