Scientists have identified a gene called IRX3 which is associated with obesity and may emerge as a serious contender as the most important 'fat gene' yet discovered.
The popular term 'fat gene' refers to genetic markers that are strongly linked to obesity, and they are mostly discovered thanks to genome-wide association studies (GWAS). To date, the strongest association has been found with markers in the FTO gene, and studies have sought to understand the role FTO plays in obesity.
Now a study in the journal Nature has shown that the genetic markers in the FTO gene actually regulate the expression of another gene, IRX3.
'Our data strongly suggest that IRX3 controls body mass and regulates body composition', said senior author Dr Marcelo Nobrega from the University of Chicago. 'Any association between FTO and obesity appears due to the influence of IRX3'.
It was already recognised that the genetic markers in the FTO gene are found in 'non-coding' regions of the gene and so not associated with the function of the gene itself.
Dr Nobrega's team were trying to understand why this should be so. This led to a hunt for other genes that could be regulated by the obesity-linked FTO markers and IRX3 emerged as the most likely candidate.
The researchers also investigated whether the IRX3 gene was directly related to obesity by genetically engineering mice without the IRX3 gene. These mice were leaner than mice with a functioning IRX3 gene, weighed 25 to 30 percent less and did not gain weight even on a high-fat diet.
'These mice are thin. They lose weight primarily through the loss of fat. But they are not runts', said co-author Dr Chin-Chung Hui, from the University of Toronto. 'They are also completely resistant to high-fat diet-induced obesity. They have much better ability to handle glucose, and seem protected against diabetes'.
The investigators saw similar results when IRX3 function was altered in the hypothalamus area of the brain, suggesting that area as important to how the gene influences body mass.
But fully understanding how IRX3 operates will be a complex task. IRX3 encodes a protein that regulates the expression of other genes and the next step for researchers will be to identify these.
'IRX3 is probably a master regulator of genetic programs in the cells where it is expressed', Dr Nobrega said. 'We're interested in what its targets are and what they alter. The goal is to identify downstream targets of IRX3 that become models for drug targeting'.
Discussing the study in Nature magazine, Dr Inês Barroso, head of human genetics at the Wellcome Trust Sanger Institute, who was not involved in the study, said: 'That's always the tricky thing; a GWAS gives you an association, but it's just a marker on the genome, it doesn't actually say anything about which gene it's affecting'.
'This [study] strongly suggests that mediation of body mass is going to be through IRX3 rather than FTO'.