Fat Gene Do You Have It?

Mutations within the gene FTO have been implicated as the strongest genetic determinant of obesity risk in humans, but the mechanism behind this link remained unknown. Now, an international team of scientists has discovered that the obesity-associated elements within FTO interact with IRX3, a distant gene on the genome that seems to be the functional obesity gene. The FTO gene itself appears to have only a peripheral effect on overweight.
The study appears online March 12 in Nature.
"Our data strongly suggest that IRX3 controls body mass and regulates body composition," said senior study author Marcelo Nobrega, PhD, associate professor of human genetics at the University of Chicago. "Any association between FTO and obesity appears due to the influence of IRX3."
Tests on mice showed IRX3 interacts with FTO even though its locality on the genome is a long way away.
An analysis of a human genetic database then found the same thing happens in people which was confirmed in experiments on human cells in the lab.
Using data from 153 brain samples of Europeans the researchers then discovered the mutations to FTO affecting body weight are associated with IRX3 expression.
Obesity-related FTO variants enhanced the expression of IRX3 but did not seem to play a direct role in this interaction themselves.
To verify the role of IRX3, the researchers engineered mice without the IRX3 gene. These mice were significantly Slimmer than their normal counterparts. They weighed about 30 percent less, primarily through reduced fat.
The decrease in weight gain occurred despite normal levels of calories intake and physical activity. When fed a high-fat diet, mice without IRX3 retained the same weight and fat levels as on normal diets. Normal mice fed a high-fat diet gained almost twice as much weight. Fat cells in IRX3-deficient mice were smaller, and increased levels of brown fat were observed. In addition, these mice were better able to process glucose.
"These mice are thin. They lose weight primarily through the loss of fat. But they are not runts," said co-author Chin-Chung Hui, PhD, professor of molecular genetics at 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."
IRX3 is  coding for a protein that regulates other genes and is present both in and outside the brain, in organs and cells such as fat cells.
Professor Nobrega and colleagues are currently investigating how IRX3 interacts with genes and molecules it regulates and hope to identify targets for the development of drugs against obesity and diabetes.
--------------------------------------------------------------------------------------------------------------------------

Story Source:

The above story is based on materials provided by University of Chicago Medical Center. Note: Materials may be edited for content and length.