An international team of researchers has shown why people with a variation of the FTO gene affecting one in six of the population are 70 per cent more likely to become obese.
A new study led by BRC-supported researcher Dr Rachel Batterham, and including scientists from UCL, the Medical Research Council (MRC) and King’s College London Institute of Psychiatry, shows that people with the obesity-risk FTO variant have higher circulating levels of the ‘hunger hormone’, ghrelin, in their blood. This means they start to feel hungry again soon after eating a meal. The findings paved the way for researchers to find new ways of fighting obesity.
The number of people who are overweight or obese has markedly increased over the last 30 years such that two thirds of the UK population are overweight and one quarter are obese with all the associated health risks.
Researchers suggest that although changes to the environment are the main driver for this increase in obesity, genetic make-up also plays a part.
Professor Bryan Williams, Director of the National Institute for Health Research University College London Hospitals Biomedical Research Centre (BRC), said: “We are delighted to have supported Dr Batterham and her team in conducting this important work. It reveals another piece of the jigsaw as to why some people are more prone to gain weight than others and may in future help us develop better ways to identify and help people who more likely to develop obesity ".
In 2007 the FTO gene was identified as a widespread genetic contributor to people becoming overweight. Studies have shown that adults and children with the obesity-risk gene variant have increased appetite and a preference for high-calorie foods.
However, it was not known how this gene variant led to these tendencies. This study has shown that people with the FTO variant have higher levels of ghrelin, which is released by cells in the stomach and stimulates appetite. In addition, Dr Batterham and her team used real-time brain imaging to show that the FTO variant also changes the way the brain responds to images of food in the regions linked with the control of eating and reward.
Together these findings explain for the first time why people with the obesity-risk variant of the FTO gene eat more and prefer higher calorie foods compared with those with the low-risk version, even before they become overweight. The research, funded by the MRC and the Rosetrees Trust, is published today in the Journal of Clinical Investigation.
Using a unique study design, 359 healthy male volunteers were recruited to examine the ‘real life’ effects of the FTO variation in humans. The researchers studied two groups of participants – those with two copies of the high obesity-risk FTO variant (AA group) and those with the low obesity-risk version (TT group). They matched the volunteers perfectly for body weight, fat distribution and social factors such as educational level to ensure that any differences they saw were linked to FTO, and not to other physical or psychological characteristics.
A group of 20 participants (10 AA and 10 TT) were asked to rate their hunger before and after a standard meal, while blood samples were taken to test levels of ghrelin. Normally ghrelin levels rise before meals and fall after eating, but in this study men with the AA variation had much higher circulating ghrelin levels and felt hungrier after the meal than the TT group. This suggests that the obesity-risk variant (AA) group do not suppress ghrelin in a normal way after a meal.
BRC-supported Dr Batterham, from the UCL Centre for Obesity Research, said: “We've known for a while that variations in the FTO gene are strongly linked with obesity, but until now we didn’t know why. What this study shows us is that individuals with two copies of the obesity-risk FTO variant are biologically programmed to eat more. Not only do these people have higher ghrelin levels and therefore feel hungrier, their brains respond differently to ghrelin and to pictures of food – it’s a double hit.
“At a therapeutic level this arms us with some important new insights to help in the fight against the obesity pandemic. For example, we know that ghrelin (and therefore hunger) can be reduced by exercise like running and cycling, or by eating a high-protein diet. There are also some drugs in the pipeline that suppress ghrelin, which might be particularly effective if they are targeted to patients with the obesity-risk variant of the FTO gene.”
Professor David Lomas, Chair of the MRC’s Population and Systems Medicine Board, said: “This work will contribute to more targeted treatments and better outcomes for obese patients in the future.”
Richard Ross, Chairman of the Rosetrees Trust, said: “Rosetrees is delighted to be able to support cutting-edge research carried out by outstanding researchers such as Dr Batterham, which has such a direct human impact. Rosetrees supports over 200 projects, helping researchers to make breakthroughs across all the major illnesses.”
The research programme was undertaken at Imperial College London and Kings College London where PIs were Professor Dominic Withers (MRC Clinical Sciences Centre at Imperial College London) and Dr Fernando Zelaya (King’s College London Institute of Psychiatry) in collaboration with a host of international partners. It was funded by the BRC, MRC, Rosetrees Trust and the Wellcome Trust.
