BioWorld International Correspondent

LONDON - New understanding of the function of a mystery gene that can increase someone's risk of obesity by 70 percent could speed work toward potential new treatments for this condition.

There is a long way to go yet, however; researchers warn that, although they now know what the protein encoded by the gene, called FTO, does, they still have little idea of how its action leads to obesity. A team of researchers in the UK reported in April that people with two copies of a minor variant of FTO tend to weigh on average about 3 kilograms more than those without the variant, and that the extra weight is due to fat.

Now a team of scientists, led by Chris Schofield of the University of Oxford, have investigated the function of the protein encoded by FTO, and have shown that it plays a role in demethylating DNA. The report appears in Sciencexpress (Nov. 8, 2007, online publication) in a paper titled "The Obesity-Associated FTO Gene Encodes a 2-Oxoglutarate-Dependent Nucleic Acid Demethylase."

Frances Ashcroft, Royal Society Research Professor at the University of Oxford, and a senior co-author of the paper, told BioWorld International that "initially, the role of FTO was a mystery. Now we know what the protein does, we can think about designing drugs that would either increase or decrease its activity."

Schofield and his colleagues set out to discover what FTO does, using bioinformatics. They found that FTO shares sequence motifs with enzymes known as oxoglutarate-dependent oxygenases.

"Our search for proteins that the FTO gene product is related to showed that FTO had a particular fold that is conserved in a family of enzymes that is common to many organisms," Schofield told BioWorld International. "The one it was most closely related to was a bacterial protein called AlkB, which is known to be a DNA repair enzyme that demethylates DNA."

Enzymes from that same family also are involved in human fatty acid metabolism and the physiological response to low oxygen levels, such as at high altitude.

Experiments directed by Schofield's group confirmed that the FTO gene product does indeed have the ability to remove methyl groups from DNA, though "exactly how this demethylation is linked to obesity is unclear," Ashcroft said. "It may be that FTO is needed to repair your DNA, and if you don't have enough of it, and the DNA is not repaired, this could result in a problem that causes obesity. Alternatively, the presence or absence of methyl groups on the DNA might determine whether other genes are switched on or off, so demethylation might have a regulatory role. If the genes being switched on or off are involved in regulation of metabolism, you can see that there could be a relationship to obesity here."

Additional experiments, by Steve O'Rahilly of the University of Cambridge, reported in the Sciencexpress paper showed that the FTO gene is expressed in the brains of mice, particularly in the part of the hypothalamus that regulates feeding and fasting. The levels of FTO expression changed according to whether the mice were fed or fasted.

To take the work forward, the researchers hope to make direct links between the enzymatic activity of FTO and obesity. First, it will be important to make transgenic mice that either lack functional FTO or that make unnaturally high levels of it. "Mice are not humans, but this approach can sometimes give useful insights," Ashcroft said.

Secondly, it will be vital to find out what the FTO protein does in the cell. "We want to find out what happens to the metabolism or the expression of other genes in the cell when FTO is turned on or turned off," Ashcroft said. One major problem is that no one knows whether it is too much of FTO, or too little, that leads to obesity.

Thirdly, elucidating the 3-dimensional structure of FTO will help with structure-based design of compounds that will selectively inhibit or enhance the activity of FTO.