The gene called SIRT3 is responsible for contributing to several of the most severe health problems across the U.S. today, according to one researcher at the Gladstone Institutes.
Gladstone Senior Investigator Eric Verdin, MD will be publishing a paper in Molecular Cell describing how the inactivity of the SIRT3 gene increases the rate at which fats are built up and stored throughout the human body. Among the effects of SIRT3’s inactivity are diabetes, high blood pressure, obesity, and a reduction in the body’s sugar-processing capabilities. These complications, commonly occurring together in individuals, are collectively called “metabolic syndrome;” the syndrome puts people at a dramatically higher risk of developing diabetes and heart disease.
Warner Greene, MD, PhD, director of virology and immunology research at Gladstone, says that metabolic syndrome is a serious problem on the rise. “Estimates indicate that one-third of Americans have the metabolic syndrome, and more develop it each year,” according to Greene. “By showing how the absence of SIRT3 can exacerbate obesity, Dr. Verdin’s group offers important clues concerning new ways to alleviate the symptoms of this American epidemic.”
Dr. Verdin and his colleagues performed the study by deactivating the SIRT3 gene in mice. The mice were then subjected to a high-fat diet and monitored for changes in their metabolisms.
When SIRT3 is active, it begins a process that signals the body to transform dietary fat into energy for cells to function. However, when the SIRT3 gene is gone, the process never begins and fat deposits are stored instead of being used for energy.
The study also showed that long-term intake of the high fat diet can reduce the activity of the SIRT3 gene, even in mice where the gene is still present. The reduced activity of SIRT3 causes increased buildup of fat in places such as the liver and bloodstream. Over time, the increased fat levels can lead to insulin resistance, higher blood pressure, and obesity.
In addition to their research on mice, Dr. Verdin’s team studied the SIRT genes of 8,000 Finnish men. They discovered a mutation in the gene that was present in 30% of the men; this mutation lowered SIRT3 activity levels and put the men at greater risk for developing metabolic syndrome.
“Finding a SIRT3 gene mutation linked to metabolic syndrome is a big step towards developing treatments for this increasingly common collection of obesity-related illnesses,” said Verdin. “In the future, we hope to examine whether increasing SIRT3 activity can help decrease the symptoms of metabolic syndrome. We are also working to identify new drugs that can enhance the SIRT3 enzyme. Such drugs could be used in the future to stem the tide of the metabolic syndrome and its many complications.” Verdin is hopeful that his research with mice will lead to medications that can treat reduced SIRT3 activity, thus mitigating or eliminating the risk of patients developing the severe complications that make up the metabolic syndrome.
In addition to being senior investigator at Gladstone, Dr. Eric Verdin is a professor of medicine at UCSF. The Gladstone lab is dedicated to researching proteins and the role they play in the regulation of biological systems.
Also participating in the study were Matthew D. Hirschey, Tadahiro Shimazu, Carrie A. Grueter, Amy M. Collins, Bjoern Schwer and Robert V. Farese, Jr. The research was funded by a variety of organizations, including the National Institute of Diabetes and Digestive and Kidney Diseases, the Sandler Foundation, and the Elison Medical Foundation.
