Joslin Scientists Help to Identify Novel Target for Obesity Drugs
C. Ronald Kahn, M.D.
Wednesday, March 03, 2010
A collaboration between scientists at Joslin and the Gladstone Institute (GI) has discovered a novel potential therapeutic target for controlling fat metabolism. The target is a protein from the mitochondria, or the “power plants” of every cell, which process oxygen and convert substances from the foods we eat into energy for essential cell functions.
“Many mitochondrial proteins undergo a small chemical modification known as acetylation, which varies during feeding and fasting conditions,” says GI’s Eric Verdin, M.D., senior investigator and senior author of the study, reported in the current edition of the journal Nature. “We knew that the enzyme SIRT3 is involved in removing these modifications, and we speculated that SIRT3 might have a role in regulating metabolism.”
In previous studies from the lab of Joslin’s C. Ronald Kahn, M.D., it had been shown that the levels of SIRT3 are reduced in tissues of animal models of diabetes. Therefore, to study the enzyme’s role in metabolism, these researchers teamed up to characterize mice in which both copies of the SIRT3 gene had been deleted.
They found that during fasting, the livers of these mice had higher levels of fat and triglycerides than normal mice, because the mice could not burn fat. Further investigation showed that in the mice, a mitochondrial enzyme called LCAD contained even more acetyl groups than usual and it showed reduced activity in burning fat. Conversely, mice with higher levels of SIRT3 expression increased the activity of this key enzyme.
The researchers concluded that acetylation aids in regulating the burning of fat and that SIRT3 helps to control this mechanism. “Coupled with our previous studies showing that SIRT3 levels are reduced in diabetes, finding drugs that restore SIRT3 levels or activity may have a beneficial effect in disorders such as diabetes or fatty liver disease,” says Dr. Kahn, coauthor of the study and Head of the Joslin Section on Integrative Physiology and Metabolism.
Enxuan Jing and Sudha Biddinger of the Kahn lab were among the authors of the paper. Other contributors include Robert Farese of the Gladstone Institute and Chris Newgard of Duke University Medical Center.
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