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- TL;DR Summary
- Variants of the gene MC4R protect against obesity and point to MC4R as a potential target for anti-obesity drugs.
Published this week in the journal Cell, researchers report discovering variants of the human gene MC4R that protect against obesity by helping to make people full. These new findings, combined with previous work on other MC4R variants that contribute to obesity, suggest the potential for new anti-obesity therapies that target MC4R.
Citation to the paper discussed:
Lotta et al. Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity. Cell 177: 597 (2019)
https://doi.org/10.1016/j.cell.2019.03.044
Abstract:
https://www.nytimes.com/2019/04/18/health/genetics-weight-obesity.htmlIn the new study, Dr. Farooqi and her colleagues found that in some thin people, the MC4R gene is always turned on, instead of always off, because of different mutations involving a previously unknown metabolic pathway.
These people continually feel satiated. About 6 percent of the population carries such protective mutations.
“This proves that MC4R is an important, if not the most important, controller of weight,” Dr. Farooqi said. And the new pathway provides an obvious target for drugs to protect against obesity.
Researchers increasingly are finding that appetite and satiety determine who gains excess weight and who does not
Citation to the paper discussed:
Lotta et al. Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity. Cell 177: 597 (2019)
https://doi.org/10.1016/j.cell.2019.03.044
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 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.