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Scientists home in on the real 'fat gene'

If you're a student of fat - and who isn't these days? - you know that the FTO gene is the gene thought to be most responsible for some people's inherited propensity to become obese. Well, forget that.

A multinational group of geneticists has discovered that, more likely, the real obesity gene is named IRX3, and it is very far from the FTO gene - or would be, if DNA were to be stretched out in linear fashion instead of coiled up like a skein of yarn.

In a letter posted Wednesday to the website of the journal Nature, University of Chicago geneticists Scott Smemo and Marcelo A. Nobrega, along with a team of Canadian and Spanish researchers, wrote that geneticists hunting for the obesity gene appear to have fallen into a trap: They assumed that genetic variations they could see have only local effects, and do not affect the workings of far-away genes.

Geneticists had designated the FTO gene the key obesity gene merely because it neighbored some oft-seen obesity-related genetic variations in the "intron," the 70% of DNA once thought to be "junk," because genes there don't code for protein production.

Instead, Smemo and Nobrega's team conducted a series of experiments that showed that the obesity-related "single nucleotide polymorphisms," or SNPs, seen in the intron may not even act on the FTO gene - or at least not only on the FTO gene. The SNPs that most often make mice and humans alike gain too much weight act on the IRX3 gene: When these genetic variations switch on the IRX3 gene, mice become chubby, have less "brown" fat (which helps burn up white fat) and have poorer metabolic function.

The group also discerned that IRX3 expressed itself in the brain's hypothalamus, a key node in the brain's hunger-and-satiety circuitry. It was also found in organs and fat cells, suggesting it may play a role in metabolism as well. When the IRX3 gene was activated, mice and people were likelier to be obese, and to have diabetes. When mice were bred without the IRX3 gene, they were lean, even when fed a high fat diet.

Nobrega said that scientists had begun to question whether FTO was the gene regulated by the SNPs they routinely found in the obese, in part because people born with a genetic deletion of the FTO gene have lots of problems, but obesity isn't one of them.

The discovery that genes in that thick forest of gene regulators known as the intron can act on genes very far away from them will make geneticists think twice before they make assumptions about the relationship of neighboring genes to one another.

As for what this finding means for the treatment of obesity, Nobrega said that the study of such genetic interactions would help illuminate how diseases such as obesity and type 2 diabetes take root and progress. Someday that may offer targets for the development of drugs or other therapies, "but this is way down the road," he said.

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