Gene of the Month – April: MC4R
The melanocortin-4 receptor (MC4R) belongs to the family of G protein-coupled receptors, which play essential roles in signal processing and transduction in our cells. MC4R is expressed primarily in the central nervous system and is found in high concentration in the hypothalamus, for example. It has been shown that MC4R acts as an important factor in the regulation of appetite and energy homeostasis, by processing leptin-mediated signals in the brain. Leptin, a hormone produced by fat cells, has inhibitory effects on food intake. MC4R deficiency is the most common monogenic cause of obesity identified so far. In affected children, it manifests as accelerated growth, hyperphagia and heavily increased plasma insulin levels.
A UK study recently published in Cell provides new insights into the role of MC4R in the protection against obesity and its related complications such as type 2 diabetes and cardiovascular disease. Researchers performed genetic association studies on 0.5 million participants in the UK biobank cohort and identified 61 genetic variants of MC4R. While most of them were loss-of-function variants, a small proportion (6%) caused an increase in protein function. The latter variants were associated significantly with a lower body mass index and up to 50 % lower risk of obesity, type 2 diabetes and coronary heart disease. MC4R activates multiple signaling pathways, and functional analyses revealed that the MC4R variants associated with protection against obesity exhibited signaling bias towards effective recruitment of beta arrestin rather than activation of the canonical signaling cascade via cAMP formation. The researchers therefore suggest that preferential activation of the beta-arrestin-dependent MAPK signaling pathway might be a promising strategy for weight loss and for treating obesity-related cardiometabolic diseases.
Lotta LA, Mokrosiński J, Mendes de Oliveira E, […] Farooqi IS. 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.