UT Researchers at the Center for Host Defense Genetics at Southwestern University found that a defective gene, rather than a defective diet, may explain why some people can overweight even if they don’t eat more than others. The results of the study, published in Cell Metabolism, describe how a genetic defect called Ovol2 causes mice with normal activity levels and food intake to become obese after entering adulthood due to problems in producing body calories.
If this is the case in humans, it is likely that humans have a nearly identical gene and their protein product, then these findings could ultimately help identify potential treatments for obesity. "Most obesity is caused by overeating or lack of physical activity, but our study shows that a mutation in a rarely studied gene, Ovol2, can lead to mass obesity - entirely due to defects in heat-generating or heat-generating defects," said Dr. Zhang Zhao, assistant professor of internal medicine and assistant professor of internal medicine. "Most obesity is caused by overeating or lack of physical activity, but our study shows that mutations in a rarely studied gene Ovol2 can lead to mass obesity - entirely due to defects in heat-generating or heat-generating defects." In the United States, approximately 42% of people experience obesity problems, which drives an increase in the risk of many other health problems, including heart disease, stroke, type II diabetes and certain types of cancer. Although researchers agree that obesity appears to stem from the interaction between a person’s genes and his or her environment, genes that play an important role in the most common form of obesity are not known, with the most famous obesity mutations in mice and humans leading to greedy appetite.
To further understand the basic mechanisms of obesity, Dr. Zhang and Dr. Betler and colleagues used a chemical to produce random mutations in DNA in mice. In a particular family of mice, obesity begins at about 10 weeks of age - young adults in rodents and continues until these animals are severely overweight. The researchers found a related mutation in a gene called Ovol2.
Dr. Betler said: "No one has ever linked this gene to obesity because it is a necessity for life. The mutations our bodies create are gentle enough to allow people to continue to survive, but are destructive enough to show amazing metabolic defects."
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Compared with siblings who did not undergo mutagenesis, fat weight in obese mice increased by 556%, while lean meat weight decreased by 20%. Experiments show that obese animals are unable to maintain their core body temperature when exposed to cold, which appears to be due to the inability to effectively use a tissue called brown fat, whose main function is to generate calories. Further tests showed that the healthy Ovol2 gene inhibited the development of white fat , the main tissue responsible for energy storage.
When the researchers overexpressed normal Ovol2 protein, they found that animals gained much lower weight in mice fed a high-fat diet than in wild-type controls. The authors say these findings suggest that Ovol2 is a key player in energy metabolism, which may be the same for humans, because the Ovol2 protein in humans is very similar to the mouse version. Dr. Zhang said eventually doctors may be able to treat obesity by giving patients drugs that improve Ovol2 function.
Betler and Dr. Zhang are the inventors of a patent related to these findings.
Southwestern University is a nutritional and obesity research center, one of the 12 centers funded by the National Institutes of Health and the only center in Texas. The center supports more than 150 UT Southwestern scientists studying the causes, prevention and treatment options for obesity.
Dr. Beutler is Executive Professor of the Research Center and serves as the Distinguished Chair of Raymond and Allen Willy Cancer Research in honor of Mr. Lavern and Raymond Willy. He won the 2011 Nobel Prize in Physiology or Medicine for discovering how the innate immune system is activated.
This work was supported by National Institutes of Health (K99 DK115766, R00 DK115766, R01 AI125581 and U19 AI100627) and the Lyda Hill Foundation.
