Discovery of genetic variants that protect against obesity and type 2 diabetes could lead to new weight loss medicines

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 new discovery could lead to the development of new drugs that help people lose weight. Photo: i yunmai/Unsplash

Now, 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.

A team had find 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.

To investigate the reasons for this mystery, the team who previously showed 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 a number of 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’.

Around six per cent 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 particular variants (1 in over 1,000 people) were on average 2.5 kg lighter than people without the variants and had a 50% lower risk of type 2 diabetes and heart disease.

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.

Designing drugs that mimic the effect of the protective variants in MC4R could provide new, safer weight loss therapies. (University of Cambridge)

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