Earlier this year, a team from UC San Francisco reported on the discovery that a class of commonly prescribed type-2 diabetes drugs, called TZDs (thiazolidinediones, such as Actos and Avandia), promoted the conversion of energy-storing white fat cells into energy-burning brown fat cells. Now researchers at Columbia University Medical Center (CUMC) have identified the mechanism that causes this change to take place, potentially leading to new treatments for obesity and type-2 diabetes.
While it was known that TZDs have the ability to change white fat cells to brown fat cells by activating a cell receptor called peroxisome proliferator-activated receptor–gamma (ppar-gamma), the exact mechanism behind this transformation was unclear. Because TZDs have numerous adverse side effects, including liver toxicity, bone loss and, surprisingly enough, weight gain, the CUMC researchers, led by Domenico Accili, MD, professor of Medicine and the Russell Berrie Foundation Professor at CUMC, were attempting to find a safer way to change white fat to brown fat.
Having previously shown that increasing the activity of a group of enzymes called sirtuins (or Sir2) in mice resulted in increased metabolic activity, the CUMC team has now shown that this boost in metabolism is a result of promoting the browning of white fat.
“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 Li Qiang, PhD, associate research scientist in Medicine at CUMC.
Knowing that sirtuins work by severing the chemical bonds between acetyl groups and proteins in a process known as deacetylation, the researchers wanted to uncover whether sirtuins remove acetyl groups from ppar-gamma and if this deacetylation of ppar-gamma is crucial to the browning of white fat. They confirmed this is the case by creating a mutant gene of ppar-gamma that, in effect, mimicked the actions of sirtuins and promoted the development of brown fat-like qualities in white fat cells in both mice and human fat tissue.
“Our findings have two important implications,” said Dr. 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 continued. “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 CUMC team’s findings appear in the online edition of the journal Cell.