How 'obesity gene' triggers weight gain

FTO picture no labels

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 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.

Real-time brain imaging
reveals that the 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.

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.

Dr Rachel Batterham, UCL metabolism Experimental Therapeutics

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
led by Dr Rachel Batterham (UCL Metabolism and Experimental Therapeutics) 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 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.

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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 researchers 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

Individuals with the obesity-risk
FTO variant rated pictures of high-calorie foods as more appealing after a meal
than the low-risk 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 over-expressed the FTO gene and found that this altered
the chemical make-up of ghrelin mRNA (the template for the ghrelin protein) 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.

Dr Rachel Batterham from UCL
and University College London Hospitals, who led the study, 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.

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“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: ““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 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 was led by UCL, Professor
Dominic Withers in the MRC Clinical Sciences Centre at Imperial College London,
and Dr Fernando Zelaya at King’s College London Institute of Psychiatry in
collaboration with a host of international partners.

It was funded by the MRC,
Rosetrees Trust, the National Institute for Health Research University College
London Hospitals Biomedical Research Centre (NIHR BRC) and the Wellcome Trust.


Media contact: David Weston

Image caption: Key brain regions that
regulate eating, reward and motivation show altered response to the hunger
hormone ghrelin in subjects with the obesity-risk FTO variant. (Credit: UCL)