Researchers have identified a protein that, when absent, helps the body burn fat and prevents insulin resistance and obesity. The discovery could aid development of drugs that not only prevent obesity, but also spur weight loss in people who are already overweight, says Stephen Hsu, M.D., Ph.D., one of the study’s corresponding authors and a principal investigator with the University of Florida Sid Martin Biotechnology Development Institute.
The protein, cell-cycle transcriptional co-regulator TRIP-Br2, modulates fat storage in cells. To better understand its role, the researchers compared mice that lacked the gene responsible for production of the protein with normal mice that had the gene.
They discovered that mice missing the TRIP-Br2 gene did not gain weight no matter what they ate—even when placed on a high-fat diet—and were otherwise normal and healthy. On the other hand, the mice that still made TRIP-Br2 gained weight and developed associated problems such as insulin resistance, type 2 diabetes, and high cholesterol when placed on a high-fat diet. The normal and fat-resistant mice ate the same amount of food, ruling out differences in food intake as a reason why the mice lacking TRIP-Br2 were leaner.
“We had to explain why the animals eating so much fat were remaining lean and not getting high cholesterol. Where was this fat going?” Dr. Hsu said. “It turns out this protein is a master regulator. It coordinates expression of a lot of genes and controls the release of the fuel form of fat and how it is metabolized.”
When functioning normally, TRIP-Br2 restricts the amount of fat that cells burn as energy. But when TRIP-Br2 is absent, a fat-burning fury seems to occur in fat cells. Although other proteins have been linked to the storage and release of fat in cells, TRIP-Br2 is unique in that it regulates how cells burn fat in a few different ways, Dr. Hsu said. When TRIP-Br2 is absent, fat cells dramatically increase the release of free fatty acids and also burn fat to produce ATP. Cells lacking TRIP-Br2 also have higher energy expenditure because they begin using free fatty acids to generate thermal energy, which protects the body from exposure to cold.
“TRIP-Br2 is important for the accumulation of fat,” says Rohit N. Kulkarni, M.D., Ph.D., also a senior author of the paper and an associate professor of medicine at Harvard Medical School and the Joslin Diabetes Center. “When an animal lacks TRIP-Br2, it can’t accumulate fat.”
Because the studies were done mostly in mice, additional studies are still needed to see if the findings translate to humans.
“We are very optimistic about the translational promise of our findings because we showed that only human subjects who had the kind of fat (visceral) that becomes insulin-resistant also had high protein levels of TRIP-Br2,” Dr. Hsu said.
“Imagine you are able to develop drugs that pharmacologically mimic the complete absence of TRIP-Br2,” Dr. Hsu said. “If a patient started off fat, he or she would burn the weight off. If people are at risk of obesity and its associated conditions, such as type 2 diabetes, it would help keep them lean regardless of how much fat they ate. That is the ideal anti-obesity drug, one that prevents obesity and helps people burn off excess weight.”
The findings from the NIH-funded study were published online ahead of print on January 6 in the journal Nature Medicine. The paper is titled “Ablation of TRIP-Br2, a regulator of fat lipolysis, thermogenesis and oxidative metabolism, prevents diet-induced obesity and insulin resistance”.