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Adipose tissue

Turning white adipose tissue into brown adipose tissue

Sirtuins boost metabolism by promoting the browning of WAT
Study could have implications for how new treatment strategies
Domenico Accili

Researchers at the Columbia University Medical Center (CUMC) claim to have identified a mechanism that can give energy-storing white adipose tissue (WAT) some of the beneficial characteristics of energy-burning brown adipose tissue.

The study could have implications for how new treatment strategies for treating obesity and type 2 diabetes are developed. The study was published in the journal Cell.

“We have known for a long time that WAT stores excess energy as triglycerides, whilst BAT burns energy as heat,” said study leader Dr Domenico Accili, professor of medicine and the Russell Berrie Foundation Professor at CUMC. “Turning WAT into BAT is an appealing therapeutic approach to staunching the obesity epidemic, but it has been difficult to do so in a safe and effective way.”

Previous research has shown that by using thiazolidazines (TZDs) it is possible to turn WAT into BAT (a process called “browning”), as they activate a cell receptor called peroxisome proliferator-activated receptor-gamma (ppar-gamma). However, the exact mechanism had not been identified.

In addition, the use of TZDs has so far been limited due to their adverse effects including liver toxicity, bone loss and weight gain.

The Columbia University study was undertaken to learn more about the function of TZDs, with the ultimate goal of developing better ways to promote the browning of WAT.

Accili and his colleagues studied a group of enzymes called sirtuins, which are thought to affect various biological processes, including metabolism.

The researchers had previously shown in mice that when sirtuin activity increases, so does metabolic activity. In the present study, they found that sirtuins boost metabolism by promoting the browning of WAT.

Sirtuins work by severing the chemical bonds between acetyl groups and proteins, a process known as deacetylation.

“When we sought to identify how sirtuins promote browning, we observed many similarities between the effect of sirtuins and that of TZDs,” said lead author Dr Li Qiang, associate research scientist in Medicine at CUMC. “So the next question was whether sirtuins remove acetyl groups from ppar-gamma and, indeed, that was what we found.”

To confirm that the deacetylation of ppar-gamma is crucial to the browning of fat, the researchers created a mutant version of ppar-gamma, in effect mimicking the actions of sirtuins. The mutation promoted the development of BAT-like qualities in WAT.

“Our findings have two important implications,” said Accili. “First, they suggest that TZDs may not be so bad if you can find a way to tweak their activity. Second, one way to tweak their activity is by using sirtuin agonists, that is, drugs that promote sirtuin activity.”

"The truth is, making sirtuin agonists has proved to be a real bear, more promise than fact," he added. "But now, for the first time, we have a biomarker for good sirtuin activity: the deacetylation of ppar-gamma. In other words, any substance that deacetylates ppar-gamma should in turn promote the browning of white fat and have a beneficial metabolic effect."

The additional researchers were Ning Kon (CUMC), Wenhui Zhao (CUMC), Sangkyu Lee (University of Chicago), Yiying Zhang (CUMC), Michael Rosenbaum (CUMC), Yingming Zhao (University of Chicago), Wei Gu (CUMC), and Stephen R Farmer (Boston University School of Medicine).

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