Obesity: a new target
Rare genetic variants that protect against obesity have been identified
A group of researchers has identified rare gene variants that protect their happy carriers from being overweight.
At least 2.8 million people die each year from being overweight or clinically obese. Obesity increases the risk of type 2 diabetes, heart disease, certain cancers, and even severe COVID-19. Diet and physical activity can help obese people lose weight, but genetics also greatly affects whether a person develops the disease. Previously, studies focused on people with extreme obesity have identified gene variants that increase the likelihood of overweight in humans, for example, a "broken" copy of the MC4R gene associated with appetite regulation. Other work has found thousands of genetic variants, each of which slightly affects body weight, but together they can significantly increase the likelihood of obesity.
The new study sequenced the genomes of more than 640,000 people from Mexico, the US and the UK. Only the exome, the part of the genome that encodes proteins, was studied in the work. The researchers then looked at mutations in genes that were associated with a lower or higher body mass index (BMI). Of the 16 genes associated with BMI, five encode transmembrane proteins known as G-protein coupled receptors. In addition to proving that these genes affect weight, the scientists found that all five genes are expressed in the hypothalamus, the area of the brain that regulates hunger and metabolism.
Variants of one of these genes – GPR75 – had the greatest impact on BMI. People carrying mutations that inactivated one copy of this gene weighed an average of 5.3 kilograms less and had half the chance of obesity compared to people with both working versions of the gene. To demonstrate how GPR75 affects weight gain, the researchers created genetically modified mice deprived of a working copy of the gene. On a high-fat diet, these mice gained 44% less weight compared to control mice. The modified mice also had better blood sugar control and were more sensitive to insulin.
Unfortunately, GPR75 variants that inactivate this gene are rare: only one person out of three thousand has them. But GPR75 could be a potential drug target. Two molecules that activate the GPR75 receptor are already known. If you find drugs that turn it off, scientists can offer new treatment options for obesity.
Article by Akbari et al. Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity is published in the journal Science – VM.
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