Study confirms gene link to obesity
16 November 2010
The research team from the University of Oxford and the Medical Research Council (MRC) Harwell, with funding from the Wellcome Trust and the MRC, published their results yesterday in the journal 'Nature Genetics'.
"This work makes us confident that FTO is an important gene that contributes to obesity," says Professor Frances Ashcroft of the Department of Physiology, Anatomy and Genetics at the University of Oxford, and one of the leaders of the research. "Too much activity of this gene can lead to putting on weight by over-eating.
"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 adds.
In 2007, the results of a large genome-wide association study revealed the first genetic variant that could be linked to increased likelihood of obesity.
The variant was a single change in DNA sequence that lay within the FTO gene. People with two copies of this genetic variant, around 16 per cent of people of European descent, were 3 kg heavier on average than those without.
While this was an important result, genome-wide association studies are often first steps that enable detailed research to pin down the mechanisms behind the observed connection, in this case to obesity.
In particular, genome-wide studies cannot be certain that the genetic variation identified directly increases obesity risk. The DNA change could show that the important gene lies nearby, or the DNA change could lie within a control element that regulates a different gene some distance away.
The researchers in the current study, led by Professor Roger Cox at MRC Harwell and Professor Ashcroft, set out to determine if it was differences in the activity of the FTO gene itself that were directly causing the increase in body weight.
Female mice with two extra copies of the FTO gene, when fed a standard diet, became 22 per cent heavier than normal female mice after 20 weeks. The difference in weight for male mice was 10 per cent. The researchers also showed that the difference came because mice with FTO over-activity consumed more food. There is no suggestion that weight differences in humans with FTO variants are, or would be, nearly as large, or would necessarily affect the sexes in a similar proportion.
Chris Church, a PhD student from MRC Harwell and first author of the study, said: "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. Once we know how FTO causes obesity we have the potential to look at developing drugs to treat it.
"Genome-wide association studies have done a fantastic job narrowing down the areas responsible for obesity. They've provided signposts of where to look, but these areas still need pinning down to a precise gene, as we have done here for the first time with FTO. The mouse model has enabled us to achieve this in just a few years, and we hope the same process will now be applied to the other gene areas implicated in obesity, enabling scientists to confirm precisely which other genes predispose us to become overweight."
Almost one in three people in the UK are overweight or obese. Obesity predisposes people to numerous diseases, including heart disease, type 2 diabetes and cancer. The estimated cost of obesity to the NHS is approximately £1 billion a year, with an additional £2.3 to £2.6bn per year to the economy as a whole.
"This gene is novel to obesity research and it is going to be exciting to find out how it works,' says Professor Cox. 'We have the mouse models now to address these questions."
Image: Man eating a burger. Credit: Anthea Sieveking , Wellcome Images.
Reference
Church C et al. Overexpression of Fto leads to increased food intake and results in obesity. Nat Gen 2010 [Epub ahead of print]