Changing the color of fat to fight obesity and diabetes

Scientists at Penn are investigating methods for turning obesity-causing white fat into healthier brown fat.

Over the past decade, scientists have learned an important lesson about fat cells: Their color plays a vital role in metabolic health. White fat cells, or white adipocytes, get their color from triglycerides and other unhealthy substances, and their only function is to store energy. Too much white fat causes obesity and other complications, like diabetes and heart disease. Brown adipocytes, on the other hand, burn energy and protect against obesity.

But what if we could turn white fat cells brown? Scientists at the Perelman School of Medicine at the University of Pennsylvania have identified a signaling pathway that may offer a way to do just that. The pathway activates a "browning program" in white adipocytes that gives them the characteristics of energy-burning brown fat, according to a press release from the university.

"It's conceivable that one would be able to target this pathway with a drug, to push white fat to become brown fat and thereby treat obesity," said Zoltan Arany, an associate professor of cardiovascular medicine at Penn and the senior author of the study.

Arany’s team discovered that the protein FLCN, working in conjunction with a protein complex called mTOR, suppresses browning activity in white fat cells. When they deleted the gene that makes FLCN from mice, their white cells started to brown, producing visibly more mitochondria—the tiny oxygen reactors that convert energy into heat.

It’s the latest development in Penn’s ongoing effort to fight obesity by changing the color of fat. Earlier this year, the team published research suggesting that activating the mTORC1 and mTORC2 protein complexes could instigate the “beiging” of white fat in mice, which helped burn fat, and control blood sugar and cholesterol.

The quest to turn white fat brown hasn’t been easy, though. In 2015, Ember Therapeutics—which had been launched three years earlier with $34 million from Third Rock—quietly closed its doors after its efforts to use the protein BMP-7 to stimulate the production of brown fat failed.

But academic scientists haven’t abandoned the notion that changing the color of fat could help fight metabolic disease. In 2015, a team at UC Berkeley developed a scaffold containing stem cells programmed to transform into beige fat. When they put the scaffold into mice and fed them a high-fat diet, they discovered that the animals gained half as much weight as control mice. Their blood sugar and fatty acid levels were healthier, too.

The Penn team plans further studies focusing on FLCN and its role in regulating fat color. In this most recent study, published in the journal Genes & Development, they discovered that deleting the FLCN gene allows a protein called TFE3 to penetrate the cell nucleus, where it activates a key player in cell metabolism known as PGC-1β. "In principle, a drug that boosts the activity of PGC-1β or some of its target genes might serve as a therapeutic activator of the browning program to curb obesity and treat or prevent diabetes," Arany said in the release.