THE COLOUR IS GRAY: British scientists find obesity gene link

THE COLOUR IS GRAY

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British scientists have made a breakthrough in understanding why some people are more likely to become obese than others.

Earlier this year they reported more than half of the population carries a variant of a gene called FTO that makes them more likely to pile on the pounds.

Today a large team of Oxford, Cambridge and London scientists reports in the journal Science the first clues regarding what this gene does and how it might affect body weight; findings which could pave the way for developing new treatments for obesity within a few years.

FTO forges a very common genetic link with mild obesity, boosting weight by up to seven pounds, rather than a rare genetic link with extreme obesity, as had previously been found. When the discovery was made, scientists speculated that it could eventually lead to treatments to help people lose the excess weight they carry simply because of their genetic make-up.

First they had to work out what the gene does. Today, the team led by Prof Chris Schofield of Oxford University reports that the protein corresponding to the FTO is an enzyme, or biological catalyst, that modifies DNA.

Prof Schofield said: "Because enzymes are the targets more many of our most important pharmaceuticals, such as aspirin and penicillin, it should be possible to artificially alter FTO activity using small molecules". However, he added: "there's a long way to go before the work could be applied medicinally."

FTO is most closely related to a family of enzymes that repair DNA that is damaged by chemicals.

The team showed how purified FTO acts on DNA, and is driven by oxygen. Prof Chris Ponting, one of the key scientists involved, commented: '"This is an astonishing finding. We never expected this first 'obesity gene' to have such a direct effect on DNA'.

However, he added that it is unclear whether FTO is acting to "repair" DNA or instead regulating how other genes are turned on and off.

The Cambridge group led by Prof Steve O'Rahilly discovered that the FTO gene is used in regions of the brain concerned with regulating hunger and appetite, notably one called the hypothalamus, so that FTO levels decrease following fasting. "Because FTO is an enzyme, it is susceptible to activation or inhibition by small molecules such as drugs, so it is possible that tests of such drugs could begin soon," said Prof O'Rahilly.

"But there is much work to do as we don't know yet whether turning up or turning down FTO would be the appropriate strategy," he added. " Even if an agent that worked in model systems it would be several years from now before any potentially appropriate drug could be safely tested in humans."

Prof Frances Ashcroft, a member of the Oxford team, said: "We are very excited by these findings.

Obesity is a rapidly growing problem worldwide that significantly enhances the risk of diabetes, cardiac disease, high blood pressure and cancer.

This breakthrough provides new leads for investigations into how chemical changes to our DNA cause an increase in fat mass and may ultimately help in the development of new drugs."

Remarkably, the team found that the FTO protein resembles enzymes that produce the penicillin antibiotics in bacteria and others that enable humans to sense and respond to changes in oxygen levels, for instance at high altitude.

And it is common in other creatures, suggesting it could have helped our ancestors survive starvation but, in modern society, makes it easier to put on weight.

The team of 42 scientists that made the original discovery of FTO found that if people carry one copy of a particular FTO variant, as half of the general population does, it will lead to a gain in weight of 2.6lb or put just over half an inch on their waists and raise their risk of being obese by one third.

If people have two copies of this variant in the FTO gene, which is the case in one sixth of the population, then they will gain almost 7lb more than those who lack the variation and are at a 70 per cent higher risk of obesity.

In the UK it is estimated that 20 per cent of men and 25 per cent of women are obese, and that as many as 30,000 people die prematurely from obesity-related conditions every year. At the current rate of increase, three-quarters of the UK population could be overweight by 2025.

Obesity-related conditions are expensive to treat and cost the NHS at least £500m a year.