'Obesity gene' probed further

reposted from: http://www.nhs.uk/news/2010/11November/Pages/obesity-overeating-fto-gene.aspx

crabsallover says: Fto gene (wikipedia) - Fat mass and obesity associated, also known as FTO, is a gene on human chromosome 16 in which certain variants appear to be correlated with obesity in humans. This study provides the first direct evidence that increased Fto expression causes obesity in mice.

'Obesity gene' probed further 

NHS Choices Mon Nov 15 2010 11:26:00 GMT+0000 (GMT Standard Time) Share

Research into a “fat gene” may lead to a new anti-obesity pill, The Daily Telegraph has reported. The newspaper said mice that carried extra copies of a gene called Fto“ate more and became fatter than normal mice”.

Researchers were prompted to look at the Fto gene because variations in this gene have previously been linked to obesity in human studies. Both genetic and environmental factors are likely to have an effect on obesity, and studies such as this may partially explain why some people are more prone to gaining weight than others.

However, this study does not suggest that people carrying the ‘at risk’ genetic variations in the human form of the Fto gene cannot maintain a healthy weight or that they cannot lose weight by reducing food intake or increasing physical activity. It is too early to say whether this research may contribute to the development of new anti-obesity drugs in the future.

Where did the story come from?

The study was carried out by researchers from Medical Research Council Harwell and other research centres in the UK and Germany, and was funded by the Wellcome Trust. It was published in the peer-reviewed scientific journal Nature Genetics.

The Daily Telegraph, The Independent, and Daily Mail have all covered this study. All of the papers mention the possibility of new anti-obesity drugs in a measured way. The study does not support the Daily Mail’s headline that suggests your diet may be “doomed before you even start”.

What kind of research was this?

This was animal research looking at the effects of the Fto gene on weight and appetite in mice. Genome-wide association studies in humans have found that single ‘letter’ variations in the genetic code within the DNA of the Fto gene are associated with an increased risk of obesity. Humans who carry two copies of the ‘at risk’ form of one of the variations, called rs9939609, on average weigh 3kg more than people who carry two copies of the ‘low risk’ variation. Previous human and animal studies have suggested that this form of the gene may be more active, which may be the cause of this extra weight.

To investigate this, the researchers wanted to test whether making the Fto gene more active in mice might cause them to become obese.

The methods used in this study were an appropriate way to investigate whether the genetic variations identified in human studies could cause obesity. Ethical and safety issues mean such research would obviously not be possible in humans.

What did the research involve?

The researchers genetically engineered mice to carry one or two extra copies of the Fto gene. Carrying these extra copies of the gene would mean that these mice could produce more of the Fto protein than a normal mouse.

The researchers compared the weight, fat mass, activity levels, and food consumption of genetically engineered and normal mice over time. They also looked at the effects of feeding the mice using different diets – a normal diet and a high-fat diet.

What were the basic results?

The researchers found that in the genetically engineered mice carrying one or two extra copies of the Fto gene, these genes were sending more ‘messages’ to the cell to produce Fto protein than in normal mice.

Mice carrying extra copies of the Fto gene also weighed more than normal mice. At 20 weeks of age, female mice carrying one extra copy of Fto weighed 11% more than their normal littermates, and those carrying two extra copies of Fto weighed 22% more than their littermates. Both normal and genetically engineered mice put on weight if fed a high fat diet, but the effect was greater in mice carrying extra copies of Fto. For example, after 20 weeks, female mice carrying one extra copy of Fto weighed 9% more than their littermates, and those carrying two extra copies of Fto weighed 18% more than their littermates.

Mice carrying extra copies of Fto showed greater fat mass than normal mice. At 20 weeks of age, compared to their normal littermates, female mice carrying one extra copy of Fto had 42% higher fat mass, and those carrying two extra copies had 85% higher fat mass. Similar results were found for male mice.

Mice carrying extra copies of Fto ate more than the normal mice, when fed either a normal diet or a high fat diet. There was no difference in the level of activity of the normal mice and the mice carrying extra copies of Fto.

How did the researchers interpret the results?

The researchers conclude that over activity of the Fto gene leads to obesity in mice fed either a standard or a high fat diet, mainly due to increased food intake. They suggest the variants of this gene that have been linked to obesity in humans may have a similar effect, and that this mechanism could potentially be targeted by anti-obesity drugs.

Conclusion

This research has provided an insight into the effects of Fto gene activity, food intake and obesity in mice. The fact that variations in this gene have also been linked to human obesity suggests the results may also apply to humans.

It is important to note that the single letter variations linked to obesity in humans may not have as great an effect on weight as carrying extra copies of the gene. To illustrate this fact, humans carrying two copies of the ‘at risk’ form of a variant in this gene only weigh on average about 3.4% more than people who do not, as opposed to the genetically engineered mice in this study which weighed up to 22% more than normal mice.

Future studies could look specifically at the whether the variations linked to obesity in humans do in fact increase activity of the Fto gene and have similar effects on appetite and weight to those seen in mice.

Although the results suggest that over activity of the Fto gene may influence appetite in humans, much more research would be needed to identify compounds that could potentially target this gene’s effects to reduce the risk of obesity. These compounds would then need to be thoroughly tested in animals before reaching human testing, and then undergo thorough human testing before they could be marketed for human use. This process takes a long time and many compounds fail to complete this process, either because they are not effective or because they are not safe.

Obesity is a serious problem and studies such as these help scientists to understand what genetic factors might influence whether a person becomes obese or not. However, this study does not suggest that people carrying the ‘at risk’ genetic variations in Fto cannot maintain a healthy weight or that they cannot lose weight by reducing food intake or increasing physical activity.

Links To The Headlines

'Fat gene' may lead to a thin pill. The Daily Telegraph, November 15 2010

Discovery of 'fat gene' raises hopes for fighting obesity. The Independent, November 15 2010

The reason your diet is doomed before you even start? You carry the greediness gene. Daily Mail, November 15 2010

Links To Science

Church C, Moir L,  McMurray F et al. Overexpression of Fto leads to increased food intake and results in obesity. Nature Genetics, 14 November 2010

Clear obesity gene link 'found'

Scientists have found a clear genetic link to obesity

Scientists say they have identified the clearest genetic link to obesity yet.

They found people with two copies of a "fat" version of a gene had a 70% higher risk of obesity than those with none, and weighed 3kg (6.5lb) more.

The work in Science by the Peninsula Medical School and Oxford University studied data from about 40,000 people.

The findings suggest that although improving lifestyle is key to reducing obesity, some people may find it harder to lose weight because of their genes.

The typical message has been that if you are overweight it is due to sloth and gluttony and it is your fault Professor Andrew Hattersley Send us your comments

Half of white Europeans carry one copy of the variant and one in six has two copies, experts estimate.

The authors say their work, funded by the Wellcome Trust, could improve understanding of obesity and eventually help prevent it, as well as an illness it is linked to.

Genome differences

Obesity is associated with an increased risk of type two diabetes, and the investigators first identified the FTO gene when looking for differences between the genomes of people with type two diabetes and people without diabetes.

People with type two diabetes were more likely to have a particular variant of the FTO gene, which was also shown to be linked to increased body weight.

The variant making people fatter differed from the other version of the FTO gene by a single mutation in the DNA sequence.

Sarah Collyer (pictured left) has no copies of the variant of FTO, while Rebecca Endicott (pictured right) has two copies I've always got a fridge full of chocolate or cakes and people ask how I can eat all that and still stay slim Sarah Collyer I've never been able to get off that last bit of weight, I've always been a bit heavier no matter what I eat Rebecca Endicott Both took part in the study

The team then looked at other studies involving 40,000 people searching for this FTO mutation, and confirmed that it was associated with body weight.

People carrying one copy of the "fat" FTO variant had a 30% increased risk of being obese compared to a person with no copies of that version.

Those carrying two copies of the variant had a 70% increased risk of being obese, and were on average 3kg (6.6lb) heavier than a similar person with no copies.

Professor Andrew Hattersley of the Peninsula Medical School said this could explain why two people can seem to eat the same things and do the same amount of exercise yet one may struggle to lose weight more than the other.

He said: "The typical message has been that if you are overweight it is due to sloth and gluttony and it is your fault.

"This work is suggesting that there is also a genetic component."

And he said although a 3kg difference in weight sounds relatively small, it is enough to make a big change in the risks of obesity.

Improving treatment

Dr Sadaf Farooqi of the Department of Clinical Biochemistry at the University of Cambridge said: "This study is important because it has yielded evidence for the first obesity susceptibility gene.

"Understanding the genetic susceptibility to weight gain will make an important contribution to the prevention and treatment of obesity."

The team does not yet know exactly what the FTO gene does or how the different variants work to influence body weight.

But they hope further research to understand the gene may lead to the unravelling of the basic biology of obesity.

Dr Mark Walport, director of the Wellcome Trust, said this could have very helpful consequences for public health as about one in six white Europeans carried two copies of the variant.

"Obesity is one of the most challenging problems for public health in the UK," he said.

"The discovery of a gene that influences the development of obesity in the general population provides a new tool for understanding how some people appear to gain weight more easily than others."

Obesity gene 'affects appetite'

Rates of obesity are on the rise

Children carrying the first gene that has been clearly linked to obesity find it harder than others to tell when they are full, London-based researchers say.

They studied over 3,000 children to see whether the FTO gene impacts on the ability to burn calories or appetite.

The researchers found those with copies of the gene's risky variant were less likely to have their appetite "switched off" when they should be full.

The study is published in the Journal of Clinical Endocrinology & Metabolism.

FTO is the first common gene to be linked to obesity in Caucasian populations.

Previous studies have shown that adults with two copies of the higher risk version of the gene are on average 3kg (6lb 10oz) heavier, and those with a single copy are on average 1.5kg heavier, than those without the gene.

We are looking at a thousand-piece jigsaw and we have shown how the first two pieces fit together Dr David Haslam National Obesity Forum

The researchers, from University College London and the Institute of Psychiatry, King's College London, set out to learn more about the way the gene works.

They tested whether children aged eight to 11 carrying the higher risk gene variation had an altered appetite through height, weight and waist circumference measurements, and a questionnaire which asked parents about their child's eating habits.

They found that children with the higher risk version of the gene tended to overeat and to struggle to recognise when they were full.

The effect of the gene on appetite was the same regardless of age, sex, socio-economic background and body mass index.

Other genes

Prof Jane Wardle explains the research into FTO and obesity

Lead researcher Professor Jane Wardle said: "It is not simply the case that people who carry the risky variant of this gene automatically become overweight, but they are more susceptible to overeating.

"This makes them significantly more vulnerable to the modern environment which confronts all of us with large portion sizes and limitless opportunities to eat."

However, Professor Wardle said the effect of the gene in isolation was relatively small.

She said it was likely that many genes contributed to obesity and appetite, each making a small contribution, but together creating a substantial effect.

Dr David Haslam, clinical director of the National Obesity Forum, said the research was "very interesting".

However, he said:

"We are looking at a thousand-piece jigsaw and we have shown how the first two pieces fit together.

"It is a step in the right direction, but what we don't want to say is 'we have got the gene for obesity, therefore we can cure it' - that is not going to happen for many years to come."