Researchers may have been focusing on the wrong gene

Obesity may be related to the gene IRX3, which is highly expressed in an area of the brain that regulates feeding behavior. Credit: Tony Alter/Flickr

Scientists studying what they thought was a fat gene seem to have been looking in the wrong place, according to research published today inNature. It suggests instead that the real culprit is another gene that the suspected obesity gene interacts with.

In 2007, several genome studies identified mutations in a gene called FTOthat were strongly associated with an increased risk of obesity and type 2 diabetes in humans. Subsequent studies in mice showed a link between the gene and body mass. So researchers, including Marcelo Nbrega, a geneticist at the University of Chicago, thought that they had found a promising candidate for a gene that helped cause obesity.

The mutations were located in non-coding portions ofFTOinvolved in regulating gene expression. But when Nbrega looked closer, he found that something was amiss. These regulatory regions contained some elements that are specific for the lungs, one of the few tissues in which FTOis not expressed. This made us pause, he says. Why are there regulatory elements that presumably regulateFTOin the tissue where it isnt expressed?

This was not the first red flag. Previous attempts to find a link between the presence of the obesity-associated mutations and the expression levels ofFTOhad been a miserable failure, he says. When Nbrega presented his new results at meetings, he adds that many people came to him to say I just knew there was something wrong here.

So Nbregas team cast the net wider, looking for genes in the broader neighborhood ofFTO whose expression matched that of the mutations, and foundIRX3, a gene about half a million base pairs away.IRX3encodes a transcription factor a type of protein involved in regulating the expression of other genes and is highly expressed in the brain, consistent with a role in regulating energy metabolism and eating behavior.

When they examined the looping three-dimensional structure of the chromosome on which both genes sit in mice, zebrafish and human cells, they found that the obesity-associated regions in FTOwere physically in contact with the promoter (the initial gene sequence which acts as an on/off switch) ofIRX3.So the switches that turn onIRX3are actually located far away fromIRX3itself, inside another gene.We think of the genome as a linear thing, but its really a complex 3D structure that coils back onto itself, he says.

Distant genes IRX3also appeared to be strongly linked with obesity. People with one of the obesity-associated mutations showed higher expression ofIRX3,but notFTO, in brain tissue samples, the team found. Nbrega and his colleagues also found that mice lacking the gene weighed 2530% less than mice with a functionalIRX3gene; did not gain weight on a high-fat diet; were resistant to metabolic disorders such as diabetes and had more of the energy-burning cells known as brown fat. The same results were seen in mice in which the expression ofIRX3was blocked in the hypothalamus, a brain region known to regulate feeding behavior and energy balance.

Ins Barroso, a geneticist at the Wellcome Trust Sanger Institute in Hinxton, UK, says that the work answers some of the questions around the biology of the link found in the genome-wide association studies (GWAS). Thats always the tricky thing; a GWAS gives you an association, but its just a marker on the genome, it doesnt actually say anything about which gene its affecting, she says. This strongly suggests that mediation of body mass is going to be throughIRX3rather thanFTO.

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