July 18, 2011

A Way to Burn More Calories?

Photo of a yellow tape measure wrapped around a scale

Scientists have uncovered a pathway in mice that allows white fat — a contributor to obesity and type 2 diabetes — to burn calories as if it were brown fat or muscle.

The body uses white fat to store extra energy. Too much white fat (obesity) increases the risk of type 2 diabetes and other diseases. Brown fat, in contrast, generates heat to maintain body temperature and, like muscle, has lots of calorie-burning mitochondria.

Brown fat is found in small mammals like rodents throughout their lives. Humans have it at birth, but we lose it as we age. Researchers once thought that our brown fat was essentially nonexistent by adulthood. Recent studies found that not only do adults have brown fat but it also may play an important role in weight control. Boosting the activity of brown fat, or converting white fat to brown fat, could be potential strategies for fighting obesity.

A team of NIH researchers led by Dr. Sushil G. Rane of NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) were studying a protein called TGF-beta. TGF-beta and its related factors are known to control the development, growth and function of many different cell types. Blood levels of TGF-beta have been linked to obesity in both mice and humans. In previous work, the team found that the TGF-beta pathway plays an important role in regulating insulin genes. To further investigate, the researchers studied mice deficient in the protein Smad3, which regulates gene expression in response to TGF-beta signals.

The researchers reported in the July 6, 2011, edition of Cell Metabolism that Smad3-deficient mice developed significantly less fat mass. The mice also had enhanced glucose uptake in their white fat. This observation prompted the scientists to examine the mice’s white fat more closely. They discovered that, without the influence of TGF-beta, the white fat became browner with more mitochondria. The increased metabolic activity due to the mitochondria burned more calories, lessening obesity.

To test whether blocking TGF-beta might help combat obesity, the scientists tested an antibody that neutralizes TGF-beta. The antibody suppressed fat formation and weight gain in 2 well-characterized mouse models of obesity. Similar to the Smad3-deficient mice, the antibody-treated mice showed an increase in mitochondrial activity.

“We weren’t looking to have white fat acquire the properties of brown fat, but that’s what we found, with the fat getting browner from increased mitochondria and displaying genes typically expressed in muscle. It was a striking difference,” Rane says.

These findings suggest a potential new approach to treating obesity and type 2 diabetes. However, this research is a long way from being applicable to people. A TGF-beta blocking antibody is currently being tested as a cancer treatment in a clinical trial at NIH’s National Cancer Institute (NCI). Due to the potential side effects of the antibody, it hasn’t yet been tested for treatment of human obesity. The researchers are working to design a more targeted approach to transform the white fat of mice into a brown fat or muscle-like state.

“Efforts to reduce obesity by dieting are mostly unsuccessful in the long term, so finding ways to prevent excess fat storage is an urgent medical need,” Rane says. “Our discovery that white fat can be reduced by partially transforming it to brown fat and muscle opens up new avenues to combat the obesity epidemic.”

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