New research suggests that the gene IRX3 is the driving genetic factor behind obesity, illuminating a potential drug target of the condition that currently affects a third of American adults.

Dr. Marcelo Nobrega, a researcher at the University of Chicago and senior author of the new study, said that the findings also refine the prevailing scientific understanding of the gene FTO — an earlier “fat gene” candidate. “Our data strongly suggest that IRX3 controls body mass and regulates body composition,” he explained. “Any association between FTO and obesity appears due to the influence of IRX3.”

The study, which is published in the journal Nature, used mouse models with the IRX3 gene knocked out. Nobrega and his colleagues found that these mice were significantly leaner compared to mice who had the gene, weighing about 30 percent less on average. The lower weight was mainly the result of less fat tissue.

Additionally, a more thorough analysis revealed that the knockout mice had smaller fat cells and increased levels of so-called brown fat — that is, fat tissue capable of burning calories. “These mice are thin,” co-author Chin-Chung Hui explained.  “They lose weight primarily through the loss of fat.

“They are also completely resistant to high-fat diet-induced obesity,” he added. “They have much better ability to handle glucose, and seem protected against diabetes.”

Fighting the Obesity Epidemic

The Centers for Disease Control and Prevention estimates that obesity now affects one-third of U.S. adults. The metabolic disease has been associated with a heightened risk of developing a range of other conditions, including heart disease, stroke, type 2 diabetes, and certain cancers. The agency estimates that the annual medical cost of the epidemic is $147 billion.

Nobrega’s study is the latest in an ever-growing series of attempts to identify a biological basis of obesity and excessive weight gain in general. Another example is a study from last year, in which researchers from Charité-University Medicine in Berlin linked the condition to a faulty "appetite hormone." Health experts hope that these efforts will lead to new, more effective treatments.

“IRX3 is probably a master regulator of genetic programs in the cells where it is expressed,” 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.”

 

Source: Nobrega M, Hui C, et al. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature. 2014.