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Genetic variants at the FTO gene are associated with obesity in humans

Overexpression of Fto leads to increased food intake and results in obesity Chris Church, Lee Moir, Fiona McMurray, Christophe Girard, Gareth T Banks, Lydia Teboul, Sara Wells, Jens C Bruning, Patrick M Nolan, Frances M Ashcroft & Roger D Cox Published online Nature Genetics: 14 November 2010 | doi:10.1038/ng.713

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Now, Roger Cox and colleagues analyze mice globally overexpressing Fto and show that increased Fto expression leads to obesity in mice.

In lay terms, what is the main finding of your study?

Previous studies published by others in 2007 showed in humans that a chromosome region containing a gene called the Fat Mass and Obesity gene, FTO for short, was associated with increased body mass index. On average, measured across large populations of people,two copies of this version of the region made people 3kg heavier. The obvious question was which gene in this region, that contains a number of genes, causes this increase and how does it do that? Our study set out to answer this question and we found that the FTO gene does account for this difference in BMI and that this is because of increased food intake.

How significant are the findings?

The FTO gene was a candidate in the original studies because the DNA markers that showed the association with fat mass were within the FTO gene itself. However, these markers were within sequence that is not coding and that may be regulatory. These sorts of regulatory regions can have effects over long distances and therefore on other genes. Further, there is another gene right next door to the FTO gene that one might argue could be equally likely to be regulated by such a DNA element. The significance of our findings is that we know for sure that the FTO gene has a role in determining BMI. It is also significant that increasing the expression of FTO increases food intake and is consistent with a number of human studies that measured food intake against people's DNA marker genotype in this region. Because FTO is not an obvious candidate in the control of food intake our study and those that precede it open a new area of research.

In lay terms how did you conduct the experiment(s)?

We took the expressed FTO DNA sequence and introduced it into the mouse so that it was expressed in all cells in addition to the normal FTO gene that was already there. The result was increased expression of FTO with either one or two extra copies of the gene; thus we had mice that expressed two of their own copies that could be compared with mice that had one extra copy or two extra copies and consequently increasing expression of FTO. We measured the body weight of the mice, their body composition (fat and lean mass), the amount of food they ate, their metabolic rate and looked at glucose and lipids in their blood. We did this using normal mouse diet and a high fat version of the diet.

What are the clinical implications of your finding(s)?

Obesity is a major public health issue. The latest Health Survey for England shows that 1 in 4 adults and 1 in 10 children are obese, defined as a BMI (body weight in kg divided by the square of their height in meters) of 30 or higher. It is estimated that the cost of obesity to the NHS is around 1 billion pounds a year. Obesity is a key risk factor for Type 2 diabetes. This is the most common form of diabetes and is caused by problems with insulin resistance and insulin secretion. It is most common in people over the age of 40 although it is being increasingly observed in younger people because of obesity. The FTO gene increases the risk of Type 2 diabetes through its effect on BMI and specifically fat mass. Because the FTO gene has an enzyme activity we hope that it might be a good target for developing an anti-obesity therapy. However, there are a number of experiments that must be done to understand its physiological function, to prove whether the enzyme activity is required and to develop this gene further as a potential target before the long process of drug discovery can begin.

Does this study have implications for the treatment of diseases, disorders, and/or injuries?

Primarily in the treatment of obesity, food intake disorders and consequential conditions such as diabetes and diabetic complications.

Outside of the main finding(s), does this study suggest exciting ideas, concepts, etc.?

Food intake can at least partially be controlled or influenced by common variants in our genes.

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