How Fat Is Produced And Stored: Sirtuin Protein Instrumental In Fat Production And Metabolism

The study examined the role of a protein called Sirt2, a member of the sirtuin family of seven cellular proteins. These proteins have recently been shown to be important in the control of aging and metabolism. Previous studies have focused on one member of this family, Sirt1, which is activated by high doses of resveratrol, a substance found in red grapes, which can prevent diabetes from developing and also prolong life. This finding generated tremendous attention, leading biotechnology and pharmaceutical companies to begin developing drugs and supplements to harness this effect. Joslin researchers have focused on other sirtuin proteins to find out what role they might play in fat and glucose metabolism and fat development.

This led to the discovery that Sirt2 is the most abundant of the sirtuins in fat cells, expressed in quantities five to ten times higher than the other sirtuin proteins. “We wanted to find out what would happen to the behavior of fat cells–in terms of metabolism or growth–if we changed the levels of Sirt2,” said lead investigator C. Ronald Kahn, M.D., an internationally recognized researcher who is head of the Joslin section on Obesity and Hormone Action and the Mary K. Iacocca Professor of Medicine at Harvard Medical School.

When a person gains weight, cells in connective tissue known as pre-adipocytes differentiate and fill with fat and form adipocytes, which are able to store fat as a potential energy source when food is not available. However, too much fat storage leads to obesity and to many obesity-related diseases, including type 2 diabetes.

Using genetically altered cells from mice, the Joslin researchers were able to manipulate Sirt2 levels in adipocytes.  They found that increasing Sirt2 levels in the cell would block the cell’s ability to undergo differentiation and store fat, while reducing Sirt2 would promote adiopogenesis, or fat production. They then went on to pinpoint exactly how Sirt2 produced these effects by interacting with and modifying one of the key transcription factors, or molecular switches, regulating fat differentiation and function, a molecule called FoxO1. FoxO1 is also an important target of insulin action in fat where it helps control the aging process.

Thus, when Sirt2 levels in pre-adipocytes are low, more fat cells develop, while when Sirt2 levels are high, this process is blocked. “So, to reduce the amount of fat in the body and help people stay thin, we need to find an activator of Sirt2,” said Kahn.

The discovery of Sirt2's role in fat production gives researchers a new avenue to pursue in preventing and treating obesity. “Since most of the diabetes epidemic is driven by obesity, Sirt2 may also play a role in preventing type 2 diabetes from developing and in treating people who have already developed the disease,” said Kahn.

This is an important goal since more than 60 percent of Americans are now overweight or obese, and obesity is a major factor driving the current epidemic of type 2 diabetes, which now affects more than 20 million people in the U.S. alone.

The next step in the research process will be to create an animal model to validate the results. Once they are confirmed, biotechnology companies can try to develop drugs that would activate Sirt2 in fat cells and provide another tool for combating overweight, obesity and diabetes.

This latest research appears in the August 2007 issue of Cell Metabolism. Funding for the study was provided by the National Institutes of Health.

Other researchers participating in this study include: Enxuan Jing, Ph.D., and Stephane Gesta, Ph.D. of the Joslin Diabetes Center