Genetic variants protect against obesity, could lead to new weight loss medicine
Researchers have shown that other genetic variants in the MC4R gene that increase the activity of this brain receptor can protect people from becoming overweight, a finding that could lead to the development of new medicines that “copy” the protective effect of these genetic variants to achieve or maintain weight-loss, according to a new study published in the journal Cell.
Scientists have known for several years that genes can influence a person's weight. One of the genes that is known to play a key role in regulating weight is MC4R, which codes for the melanocortin 4 receptor. This receptor acts like a switch in the brain to suppress appetite. People who have genetic variants that disrupt this receptor gain weight easily.
A team at the Institute of Metabolic Science in Cambridge, England looked at the MC4R gene in half a million volunteers from the U.K. population who have taken part in the U.K. Biobank study, finding 61 distinct naturally-occurring genetic variants. While some of these genetic variants predisposed people to become obese, other variants provided protection against obesity and some of its major complications, such as type 2 diabetes and heart disease.
Previous research has shown that MC4R works in the brain as a switch to tell us to stop eating after a meal, studied the function of these genetic variants in several laboratory experiments. They found that MC4R gene variants linked to higher obesity risk stopped the gene from working, whereas variants that offered protection against obesity kept the gene switched on.
About six percent of study participants carried genetic variants that caused the receptor to remain switched on. People with these variants would eat less, which could explain their lower weight. People with two copies of these variants, one in over 1,000 people, were on average 2.5 kilograms lighter than people without the variants and had a 50 percent lower risk of type 2 diabetes and heart disease.
The discovery adds to recent work by the team which showed that some slim people have a genetic advantage when it comes to maintaining their weight. When the researchers looked in detail at the genetic variants in laboratory experiments, they found that MC4R can send signals through a pathway, known as the beta-arrestin pathway, that had not previously been linked to weight regulation. Genetic variants that sent signals preferentially through this pathway were the ones driving the association with protection against obesity and its complications and, importantly, were also associated with lower blood pressure.
Researchers say designing drugs that mimic the effect of the protective variants in MC4R could provide new, safer weight loss therapies.