Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity

Cell. 2019 Apr 18;177(3):597-607.e9. doi: 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. 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.

Keywords: GPCRs; MC4R; UK Biobank; biased signaling; genetics; melanocortin; obesity; β-arrestin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Body Mass Index
  • Coronary Artery Disease / complications
  • Coronary Artery Disease / metabolism
  • Coronary Artery Disease / pathology
  • Cyclic AMP / metabolism
  • Databases, Factual
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Female
  • GTP-Binding Protein alpha Subunits, Gs / metabolism
  • Gain of Function Mutation / genetics*
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Obesity / complications
  • Obesity / metabolism
  • Obesity / pathology*
  • Polymorphism, Single Nucleotide
  • Receptor, Melanocortin, Type 4 / chemistry
  • Receptor, Melanocortin, Type 4 / genetics*
  • Receptor, Melanocortin, Type 4 / metabolism
  • Signal Transduction*
  • beta-Arrestins / metabolism


  • MC4R protein, human
  • Receptor, Melanocortin, Type 4
  • beta-Arrestins
  • Cyclic AMP
  • GTP-Binding Protein alpha Subunits, Gs