IRX3 Made Me This Way

Aug. 1, 2014

By Medical Discovery News

IRX3 Made Me This Way

Obesity, which was once a purely clinical term, has become a household word, uttered in doctors’ offices, on media coverage, and in private conversations as it has become a growing concern for America. But what makes one person accumulate body fat more than another?

For years, scientists believed that the answer to that laid in human genes and their products, but until now, no one knew why or how. At first, they thought mutation of a gene called FTO was responsible. Yet, when they engineered mice with too little or too much FTO, it affected their whole body mass and composition, not just their body fat as is the case with obesity. But since then scientists have discovered that parts of the FTO gene interact with distant gene called IRX3.

While the parts of FTO that send signals to create products like proteins were doing their job, another part of FTO was sending signals to a different gene far, far away. When this gene, IRX3, received signals from FTO, its production was enhanced. As such, the products it encoded were amplified. It is this gene that appears to be the functional obesity gene, the one primarily responsible for instructing the body to hoard fat. This was found to be true in brain samples of 153 people of European ancestry, as well as in mice.

Researchers then engineered mice without IRX3 and found them to be significantly leaner than their normal counterparts. Both groups of mice consumed the same amounts of food and were equally physically active, but the engineered mice weighed about 30 percent less through reduced fat. Even when the engineered mice were fed a high-fat diet, they kept their lean figures while the normal mice gained twice as much weight.

Further research revealed that mice without IRX3 had smaller fat cells. They also had increased levels of brown fat, which is not the excess fat stored around our middles but the kind of fat used to generate body heat. Additionally, mice with no IRX3 were better able to process glucose, making them more resistant to diabetes.

Next, scientists deleted the IRX3 gene in just the hypothalamus of mice. The hypothalamus is an area in the brain that helps to maintain many basic physiological functions and regulate complex behaviors such a thirst, sleep, general arousal, reproductive behaviors, and appetite. These mice were just as lean as the mice that were missing IRX3 throughout their bodies. Therefore, the risk of obesity appears to be due to IRX3 control of body mass and composition from within the hypothalamus. 

So what is this product of the IRX3 gene anyway? It’s a protein that regulates other genes in the brain, fat cells, and elsewhere. The goal of continuing research is to identify the genes that IRX3 targets. The products of some of those genes are what actually cause obesity to develop. Once discovered, they could be used to create new drugs to control the development of obesity and even provide new approaches to weight control in humans. In the meantime, sadly the answer to curbing weight gain is still to eat well and exercise. 

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