The MC4R gene promotes gain of fat tissue (pictured, artificially coloured fat cells) but suppresses cholesterol levels.Credit: Steve Gschmeissner/SPL
A gene that causes obesity is paradoxically linked to a reduced risk of having heart disease and high cholesterol, according to an analysis of thousands of people with obesity.
Obesity is often associated with high levels of low-density lipoprotein (LDL) or ‘bad’ cholesterol, and an increased risk of cardiovascular disease. But the new results, published on 16 October in Nature Medicine1, reveal that people with obesity due to relatively rare forms of a gene called MC4R have lower levels of LDL cholesterol and reduced rates of heart disease than do peers with a similar body-mass-index.
“Although the obesity is quite severe in mutation carriers, their risk of these additional complications of obesity is reduced,” says Anke Hinney, a geneticist at the University of Duisburg-Essen in Germany, who was not involved with the study. “This is really good news.”
The results could also point drug developers to new targets for treating high cholesterol, she says.
A weighty paradox
The study emerged from an effort to understand the fundamental mechanisms that regulate body weight — and why some people with obesity maintain good heart health, says study author Sadaf Farooqi, who studies metabolism at the University of Cambridge, UK.
These brain cells could influence how fast you eat — and when you stop
To learn more, Farooqi and her colleagues turned to MC4R, which encodes a pivotal protein in the brain that acts as a brake on hunger. “Its activation tells you to reduce food intake,” she says. “If that doesn’t work due to loss-of-function mutations, then you don’t have the brake on and you gain weight.”
As a result, people who carry such mutations are prone to obesity: about 1% of people with obesity — and up to 5% of children with obesity — carry mutations that impair MC4R. That amounts to roughly 1 in 300 people in the United Kingdom.
Heart healthy
Farooqi and her team identified hundreds of people with these mutations by analysing genetic sequences from participants in two research projects: the Genetics of Obesity Study and the UK Biobank.
