Mutated gene thought to exist in just 4% of people could ‘help tackle obesity’

A gene variant that helps regulate body weight could aid in tackling obesity, scientists have said.

The ZFHX3 gene mutation – thought to exist in just 4% of people – has been found to control parts of the brain responsible for appetite.

Scientists at Nottingham Trent University and MRC Harwell have uncovered the mechanism which allows the mutated gene to play a key role in regulating appetite, weight and the insulin hormone – which helps keep blood sugar under control and prevents diabetes complications – in mice.

The team found that it can affect a region of the brain known as the hypothalamus – which controls appetite, food intake, hunger and thirst – by switching on and off the function of other genes there.

The researchers said understanding this pathway, which has been reported in the journal FASEB (Federation of American Societies for Experimental Biology, could pave the way for new targeted weight loss therapies.

Dr Rebecca Dumbell, a researcher in Nottingham Trent University’s School of Science and Technology, said: “For the first time, we have demonstrated a role for this gene to alter growth and energy balance with a protein altering mutation similar to a variant found at low frequency in the human population.

“There is a big genetic component related to our appetite and growth but it’s not fully understood.

“Understanding what is happening in those who have the mutation paves the way to exploring potential new weight loss intervention targets for all people.”

For the first time, we have demonstrated a role for this gene to alter growth and energy balance with a protein altering mutation similar to a variant found at low frequency in the human population

Dr Dumbell believes the ZFHX3 mutation, which plays a similar role in mice and people, may “explain a way in which some people have a smaller appetite, and so tend not to gain as much weight as others”.

While everyone has the ZFHX3 gene, the specific mutation to be driving this mechanism is thought to exist in just 4% of people.

Dr Dumbell said: “It is likely one of many different mutations that make people different in their natural ability to stick to a diet in the first place.”

For the study, the researchers monitored the food intake of mice with the mutated ZFHX3 gene alongside those who did not have the gene variation.

They found those with the mutation had a lower food intake, a shorter body length, and lower levels of insulin and another hormone known as leptin, which helps to regulate body weight.

They mice also ate about 12% less, and at age one, and weighed about 20% less than those without the mutation.

The researchers said the lower insulin levels suggest that the mice with less body fat have healthier blood sugar regulation and, therefore, are less likely to be at risk from conditions such as type 2 diabetes and heart disease.

Dr Dumbell, who received £100,000 funding from the Academy of Medical Sciences as part of a two-year project to further explore the role of the gene, said: “Our future work will look at how the ZFHX3 gene acts in key parts of the brain, this will help narrow down exactly how it works to change how much the mice eat, or how fast their metabolism is.

“The current work tells us that it does this, but doesn’t tell us how – that’s what the planned work will do.

“Understanding how this works will (also) allow us to understand how different people might struggle more to maintain a ‘healthy’ weight.”