Sirtuin protein protects against the ravages of high-fat diets and obesity

A new study from the Massachusetts Institute of Technology (MIT) suggests that a protein called sirtuin, which slows the aging process in many animal species, protects against the damaging effects of a high-fat diet and obesity-related diseases, including diabetes.

MIT biology professor Leonard Guarente discovered SIRT1’s ability to extend lifespan in some animal species more than a decade ago and has since studied its role in many different tissues. In his latest study, published in the print edition of the journal Cell Metabolism, he shows what happens when SIRT1 is absent from adipocytes, the cells that make up fat tissue.

In the absence of this protein, mice fed a high-fat diet develop metabolic disorders much earlier than normal animals fed the same diet.

This discovery suggests that drugs that increase SIRT1 activity may protect against obesity-related diseases.

Professor Garente discovered the effects of SIRT1 and other sirtuins while studying yeast in the 1990s. Since then, scientists have shown the vital role these proteins play in coordinating various hormonal networks, regulatory proteins and other genes that help maintain cell health.

In recent years, Garente and his colleagues have focused on the effects of deleting the gene from brain and liver cells. Their previous work showed that SIRT1 protects the brain from the degeneration that characterizes Alzheimer's, Parkinson's, and Huntington's diseases.

The SIRT1 protein removes acetyl groups from other proteins, altering their activity. Many targets of this deacetylation are known, which likely explains the broad spectrum of protective effects of SIRT1.

MIT biology professor Leonard Guarente discovered the effects of SIRT1 and other sirtuins while studying yeast in the 1990s. His latest findings suggest that drugs that boost SIRT1 activity may protect against obesity-related diseases.

In the latest study, the researchers analyzed hundreds of genes turned on in mice lacking SIRT1 but fed a normal diet, and found that they were almost identical to those turned on in normal mice fed a high-fat diet.

This means that in normal mice, the development of metabolic disorders is a two-stage process. “Stage one is the inactivation of SIRT1 by high fat, and stage two is all the bad stuff that comes after the first,” Garente says of his findings.

The scientists studied how this happens and found that in normal mice fed a high-fat diet, the SIRT1 protein is broken down by the inflammation-induced enzyme caspase-1. It is known that high-fat diets can provoke the development of inflammation, although it is not yet clear how exactly.

"Our study shows that in fat cells, an inevitable consequence of the induced inflammatory response will be the cleavage of SIRT1," the scientist continues.

According to Anthony Suave, an associate professor of pharmacology at Weill Cornell Medical College who was not involved in the study, the discovery "offers a good molecular mechanism to explain how inflammatory signals in adipose tissue can rapidly lead to metabolic tissue dysfunction."

Drugs that target inflammation and increase sirtuin activity may have some therapeutic benefit for obesity-related diseases, says Dr. Swave.

The researchers also found that as normal mice age, they become more sensitive to the effects of a high-fat diet, suggesting that the protective effects of sirtuins are lost as we age. Aging is known to increase inflammation, and Professor Garente is now investigating whether the loss of SIRT1 also triggers this age-related inflammation.

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