Researchers reveal how 'obesity gene' triggers weight gain
An international team of researchers has discovered why people with a variation of the FTO gene that affects one in six of the population are 70 per cent more likely to become obese.
A new study led by scientists at King’s College London, UCL (University College London), and the Medical Research Council (MRC) 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.
Real-time brain imaging reveals that FTO gene variation also changes the way the brain responds to ghrelin, and 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.
Dr Rachel Batterham from UCL and University College London Hospitals, who led the research along with Dr Fernando Zelaya from the Department of Neuroimaging at King's College London, 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.
Conventional genome-wide association studies have required much larger numbers of subjects to reveal statistically significant results. This study on the other hand used two carefully matched groups of participants, that differed only in their FTO profile. Combined with neuroimaging, it has enabled us to gain a clearer insight into how FTO interacts with ghrelin in order to modify the way in which brain controls appetite in these two populations.
“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.”
A quarter of all adults in the UK are now obese (have a BMI greater than 30) and it is expected that this will rise to 60 per cent of men, 50 per cent of women and 25 per cent of children by 2050.
Previous studies have revealed that single ‘letter’ variations in the genetic code of the FTO gene are linked with an increased risk of obesity, and this behaviour is present even in preschool children.
Using a unique study design, scientists recruited 359 healthy male volunteers to examine the ‘real life’ effects of the FTO variation in humans. They 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 (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 - a hormone released by cells in the stomach that stimulates appetite. 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.
The scientists then used functional magnetic resonance imaging (fMRI) in a different group of 24 participants to measure how the brain responds to pictures of high-calorie and low-calorie food images and non-food items, before and after a meal. Again they took blood samples and asked the participants to rate on a scale how appealing the images were.
Individuals with the obesity-risk FTO variant rated pictures of high-calorie foods as more appealing after a meal than the normal group. In addition, the fMRI study results revealed that the brains of the two groups responded differently to food images (before and after a meal) and to circulating levels of ghrelin. The differences were most pronounced in the brain’s reward regions (known to respond to alcohol and recreational drugs) and in the hypothalamus – a non-conscious part of the brain that controls appetite.
Finally, the scientists looked at mouse and human cells to uncover what causes increased ghrelin production at a molecular level. They found that over-expression of the FTO gene altered the chemical make-up of ghrelin mRNA (the template for the ghrelin protein) and leading to higher levels of ghrelin itself. Blood cells taken from the obesity-risk group also had higher levels of FTO gene expression and more ghrelin mRNA than the low-risk group.
Professor David Lomas, Chair of the MRC’s Population and Systems Medicine Board said:
“Large scale population studies have done an excellent job at highlighting FTO as a key obesity gene. Here scientists have used an innovative combination of human studies and more basic biology to finally give us the ‘smoking gun’ linking FTO variations, hunger and weight gain. The brain imaging adds a fascinating insight into the role of the nervous system in obesity, which is becoming increasingly clear. This work will undoubtedly contribute to more targeted treatments and better outcomes for obese patients in the future.”
The research was funded by the MRC, Rosetrees Trust and the National Institute for Health Research Biomedical Research Centres and Wellcome Trust.
Paper reference: ‘A link between FTO, ghrelin and impaired brain food‐cue responsivity’ by Karra et al, is published in the Journal of Clinical Investigation. http://www.jci.org/articles/view/44403
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