Discovery of 'fat gene' raises hopes for fighting obesity

Science Editor,Steve Connor
Monday 15 November 2010 01:00

The mystery of why some people stay thin without effort while others have continually to fight off the fat has come significantly closer to being solved with a study showing that a single gene can affect appetite.

Scientists have found convincing evidence to support the idea that the "fat gene" affects how hungry someone feels, which has a direct effect on how much food is eaten and how much fat is accumulated in the body.

The study was carried out on genetically modified mice with several copies of the fat gene added to their DNA. The scientists said the findings support the idea that the gene in humans plays a direct role in determining whether someone is likely to become obese.

In Britain, about one in five people are classed as clinically obese. Women are affected more than men, with a third of women and half of men classified as overweight, which carries an increased risk of heart disease, cancer and diabetes.

Three years ago, scientists found that variants of the FTO gene are linked with a 70 per cent increased risk of developing obesity, with people carrying two copies of one gene variant being on average 3kg (6.6lb) heavier than people carrying alternative variants of the gene.

However, scientists were unsure at the time whether the gene was merely associated with obesity or whether it was actually responsible for it, and, if so, how it was causing the problem. The latest study demonstrates that the gene is indeed directly influencing the risk of obesity, probably by increasing a person's appetite for food.

"This work makes us confident that FTO is an important gene that contributes to obesity. Too much activity of this gene can lead to putting on weight by overeating," said Professor Frances Ashcroft of Oxford University.

"We see an increase in actual fat mass [in the laboratory mice], which demonstrates that this gene is regulating body weight and regulating it by appetite – the mice eat more and put on more weight as a result," Professor Ashcroft said.

Female mice with two extra copies of the FTO gene became 22 per cent heavier when fed a standard diet, while male mice became 10 per cent heavier. The scientists demonstrated that the weight gain was the result of the mice eating more.

The researchers do not yet know exactly how the FTO gene influences weight gain in mice or humans but one possible route is by affecting the levels of a hormone called leptin in the body, which is known to affect appetite. One suggestion is that more active variants of the FTO gene lower the levels of leptin, which works as an appetite suppressor in the brain, and therefore increase food intake and levels of fat deposited under the skin.

"We're confident that this is a gene that influences food intake and therefore body mass and it looks as if it works through appetite regulation," Professor Ashcroft said.

"We can now think about developing drugs that turn down the activity of the FTO gene as potential anti-obesity pills. That's a long way off and there's no certainty of success, but it's an enticing prospect," she said.

The development of anti-obesity drugs will be a valuable weapon in the battle against obesity, Professor Ashcroft added. "It is easy to say to someone that they should eat less and exercise more, but for many people that is unbelievably difficult," she said.

The study, published in the journal Nature Genetics, was carried out with the help of mice genetically engineered with extra copies of the FTO gene, which were created by scientists at MRC Harwell in Oxfordshire led by Professor Roger Cox. "This gene is novel to obesity research and it is going to be exciting to find out how it works. We have the mouse models now to address these questions," Professor Cox said.

Chris Church, a PhD student at Harwell who created the GM mice, said that further work should lead to a better understanding of how the FTO gene directly influences weight gain and obesity.

"For the first time we have provided convincing proof that the FTO gene causes obesity. The next step is to understand how it does this, for instance whether it increases appetite by influencing our brain or alters messages from our fat stores and other tissues," Mr Church said.

"Once we know how FTO causes obesity we have the potential to look at developing drugs to treat it," he said.

Professor Ashcroft said that the FTO gene is not the only gene that influences a person's genetic predisposition to obesity, but it is the most important genetic factor so far identified. "It's probably one of many but the one that is of the greatest importance in the human population. It looks as if it works through appetite regulation," she said.

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