A faulty gene may explain why some people gain excessive weight despite eating normally

A faulty gene may explain why some people gain excessive weight despite eating normally

A faulty gene, rather than a faulty diet, may explain why some people gain excessive weight even when they don't eat more than others, UT Southwestern researchers at the Center for the Genetics of Host Defense have found.

The findings, published in Cell Metabolism, describe how a defect in a gene called Ovol2 caused mice with normal activity and food intake to become obese when they reached adulthood due to problems producing body heat. If this also applies to people who share a nearly identical gene and its protein product, the results could eventually help identify potential treatments for obesity.

Most cases of obesity are caused by overeating or lack of physical activity, but our research has shown that a mutation of a little-studied gene called Ovol2 causes massive obesity - due solely to a defect in thermogenesis, or heat production."

Zhao Zhang, Ph.D., principal investigator, assistant professor of internal medicine, UT Southwestern

Zhao Zhang co-led this study with Nobel laureate Bruce Beutler, MD, professor of immunology and director of the Center for the Genetics of Host Defense.

About 42% of people in the United States are obese, a condition that increases the risk of many other health problems, including heart disease, stroke, type 2 diabetes and certain cancers. Although researchers agree that obesity arises from an interplay between a person's genes and their environment, the genes that play important roles in the most common forms of obesity are not well understood, and the most famous obesity mutations in mice and humans cause a voracious appetite.

To learn more about the basic mechanisms of obesity, Dr. Zhang and Beutler and their colleagues used a chemical to create random mutations in the DNA of mice. In a particular family of mice, obesity began around 10 weeks of age - young adulthood in the rodents - and continued until the animals were massively overweight. The researchers identified the responsible mutation in a gene called Ovol2.

“Nobody had previously linked this gene to obesity,” said Dr. Beutler, “because it is vital.

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The obese mice experienced a 556% increase in fat weight, accompanied by a 20% decrease in lean weight, compared to littermates that did not undergo mutagenesis. Experiments showed that the obese animals were unable to maintain their core body temperature when exposed to cold, apparently due to an inability to effectively use a type of tissue called brown fat, whose main function is to generate heat. Further testing suggested that the healthy Ovol2 gene suppresses the development of white fat, the main tissue responsible for energy storage.

When the researchers overexpressed the normal Ovol2 protein, they found that in mice fed a high-fat diet, the animals gained far less weight than wild-type controls. The authors said these results suggest that Ovol2 plays a key role in energy metabolism - which is likely true in humans as well, since the human Ovol2 protein is very similar to the mouse version. Finally, said Dr. Zhang, doctors may be able to treat obesity by giving patients drugs that increase Ovol2 function.

Dr. Beutler and Zhang are inventors on a patent related to these findings.

UT Southwestern is a Nutrition Obesity Research Center, one of 12 in the U.S. funded by the National Institutes of Health and the only one in Texas. The center supports the work of more than 150 UT Southwestern scientists to study the causes, prevention and treatments of obesity.

Dr. Beutler is a Regental Professor who holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research in honor of Laverne and Raymond Willie, Sr. He received the Nobel Prize in Physiology or Medicine in 2011 for his discovery of how the innate immune system is activated.

Other UTSW researchers who contributed to this study include Yiao Jiang, Lijing Su, Sara Ludwig, Xuechun Zhang, Miao Tang, Xiaohong Li, Priscilla Anderton, Xiaoming Zhan, Mihwa Choi, Jamie Russell, Chun-Hui Bu, Stephen Lyon, Darui Xu, Sara Hildebrand, Lindsay Scott, Jiexia Quan, Rochelle Simpson, Qihua Sun, Baifang Qin, Tiffany Collie, Meron Tadesse and Eva Marie Y. Moresco.

Source:

UT Southwestern Medical Center

Reference:

Zhang, Z., et al. (2022) Obesity caused by OVOL2 mutation reveals a dual role of OVOL2 in promoting thermogenesis and limiting white adipogenesis. Cell metabolism. doi.org/10.1016/j.cmet.2022.09.018.

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