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.
Now, in a study published in the journal Cell, 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 led by Professors Sadaf Farooqi and Nick Wareham and Dr Claudia Langenberg at the Wellcome Trust-MRC Institute of Metabolic Science in Cambridge looked at the MC4R gene in half a million volunteers from the UK population who have taken part in the UK 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.
To investigate the reasons for this mystery, Professor Farooqi’s 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 6% 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 (one in over 1,000 people) were on average 2.5kg lighter than people without the variants and had a 50% lower risk of type 2 diabetes and heart disease.
Professor Farooqi said: “This study drives home the fact that genetics plays a major role in why some people are obese – and that some people are fortunate enough to have genes that protect them from obesity. It doesn’t mean that we can’t influence our weight by watching what we eat, but it does mean the odds are stacked against some people and in favour of others.”
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.
Joint lead author Dr Luca Lotta, of the Medical Research Council Epidemiology Unit, said: “A powerful emerging concept is that genetic variants that protect against disease can be used as models for the development of medicines that are more effective and safer. Our findings may pave the way for a new generation of weight loss therapies that activate MC4R preferentially via the beta-arrestin pathway.”
The work was funded by the MRC and Wellcome, with support from the NIHR Cambridge Biomedical Research Centre.