How Obesity Gene May Be Driving Overeating

Date: Jul-16-2013Researchers believe they have uncovered a biological mechanism through which a common version of an obesity gene drives
overeating and weight gain. It appears that the flawed gene, which affects 1 in 6 people, influences production of a hormone that
is closely linked to feelings of fullness and how the body deals with food.

Rachel Batterham and colleagues at the UK's University College London, describe how they found a connection between the FTO gene
and the hunger hormone ghrelin in the July 15th issue of the Journal of Clinical Investigation.

Individuals who carry a particular variant of the "obesity" gene FTO, are more likely to be obese, overeat, and to show a
preference for high-fat, energy-dense foods. They are also more likely to lack a feeling of fulness after eating.

However, until this study, the mechanism through which this particular gene flaw regulates obesity-prone behavior has not been
clear.
Researchers' hormone hunch

The team had a hunch that the missing link between FTO and obesity-prone behavior was something to do with the hormones in the gut
that affect digestion and reaction to food.

One of these is ghrelin, a hunger-stimulating hormone made in gut cells.

Higher levels of ghrelin are associated with feelings of hunger and increase the incentive for humans to eat high-calorie foods,
even on a full stomach. If you always have room for dessert, then the
culprit could be ghrelin.
Researchers studied human samples instead of using mouse models

Animal studies in mice have already found a direct connection between the FTO gene and obesity. For example in 2010, scientists
at the Medical Research Council (MRC) in the UK produced convincing evidence that overactivity of the FTO gene leads to overeating and obesity in
mice.

An important difference about this new study is that the researchers used blood samples and brain scans from
humans to study the FTO gene and ghrelin instead of using mouse models.

The team measured ghrelin levels in blood samples of normal-weight men with two versions of the FTO gene: one
version is linked to a 70% higher risk of obesity (the high-risk gene) while the other version is not (the low-risk gene).

They found that the men with the low-risk FTO gene had higher levels of ghrelin before a meal and these levels dropped after the
meal.

But in the men with the high-risk gene, levels of ghrelin did not fall so far after the meal. Plus, brain scans of the men
with the high-risk gene showed that motivation and reward centers were active both before and after the meal when they were shown
pictures of food.

The researchers suggest this means that by not dropping after the meal, the persistently high levels of ghrelin in the high-risk
gene group were continuing to activate the brain as if the men were still hungry.

This seemed to be confirmed in a separate series of tests where the men with the high-risk gene reported feeling hungry after a
meal much sooner than the men with the low-risk gene.
FTO tweaks the ghrelin gene to produce more hormone

Even after finding all this, there was still the possibility that the link between the high-risk FTO gene and persistently high
ghrelin levels was just a coincidence or due to some other effect.

So the researchers then did further tests on cells from the men's blood samples and showed that higher levels of FTO protein
caused more ghrelin to be produced.

And they also showed that the FTO protein is able to directly influence how much ghrelin is produced by tweaking the gene that
codes for ghrelin.

The high-risk version of FTO is able to remove more methyl groups from the ghrelin gene, which in turn causes it to produce more
ghrelin.

"Our findings show that FTO regulates ghrelin, a key mediator of ingestive behavior, and offer insight into how FTO obesity-risk
alleles [versions] predispose to increased energy intake and obesity in humans," write the authors.

They also note that while further studies now need to confirm these results, and they also need to look for other possible mechanisms, these findings may already help them better investigate what happens in the brain to make people prone to obesity, and
thus offer new ideas for treatment.

One possible avenue to explore could be whether people with the high-risk version of the FTO gene might benefit from treatments
that target the ghrelin system to change the way it affects the reward response in the brain.

The high-risk version of the FTO gene has also been implicated in
Alzheimer's disease. In 2010, researchers reported that they found people who carry the high-risk variant (known as the AA version)
had a 58% increased risk for developing Alzheimer's and a 48% percent increased risk for developing dementia compared with non-
carriers.

Written by Catharine Paddock PhD

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