A PILL FOR OBESITY

Harvard Stem Cell Institute (HSCI) researchers have taken what they describe as "the first step toward a pill that can replace the treadmill" for the control of obesity, though that shift, of course, would not provide all of the many benefits of exercise.

HSCI principal faculty member Chad Cowan and his team members at Harvard University and Massachusetts General Hospital (MGH), a Harvard affiliate, say they have created a system using human stem cells to screen for compounds that have the potential to turn white, or "bad," fat cells into brown, or "good," fat cells, and have already identified two compounds that can accomplish that in human cells.

The path from these findings to a safe and effective medication may not be easy, and the findings will have to be replicated by other research groups, as well as refined, before they could lead to a clinical treatment.

However, Cowan said that the two compounds discovered so far "target the same molecule, and that molecule plays a role in the inflammatory response. So if you administered them for a long time, the person taking them could become immune-compromised," which argues against the use of these initial compounds without modifications. One, however, is already on the market, as a treatment approved by the U.S. Food and Drug Administration for rheumatoid arthritis.

White fat cells store energy as lipids and play a role in the development of obesity, type 2 diabetes, and related conditions, including heart disease, while brown fat has been shown in mice to lower triglyceride levels, reduce the insulin resistance associated with type 2 diabetes, and burn white fat.

When the body takes in excess energy, it is stored as lipids in white fat cells. When there are too many calories coming in and not enough burned, adult stem cells in the body produce more white fat cells, adding to a person's burden of fat.

Cowan's group has found two small molecules that convert fat stem cells, which normally would produce white fat, into brown-like fat cells. These brown-like fat cells burn excess energy and thereby reduce the size and numbers of white fat cells.

The report by Cowan, an associate professor in Harvard's Department of Stem Cell and Regenerative Biology, and colleagues was released online earlier today by the journalNature Cell Biology. Annie Moisan, a postdoctoral fellow in Cowan's lab, is the lead author of the study.

Cowan said that what "we were really impressed by is that there are some compounds that have this same kind of effect when they are administered to animals, but when you remove them, the effect goes away. But what we saw here was a stable conversion" of white fat cells to brown cells.

"You're constantly replenishing your fat tissue," Cowan explained, "so if you were on a medication to convert the cells, each new fat cell would be more metabolically active and would convert to brown fat over time," reducing the likelihood of developing type 2 diabetes or any of the other conditions related to a buildup of fat.

A former postdoctoral fellow in HSCI co-director Doug Melton's Harvard lab, Cowan began working with fat cells more than seven years ago, when he established his own lab, which originally was in the MGH Center for Regenerative Medicine. "I wanted to use stem cell-derived fat for this purpose and to understand aspects of type 2 diabetes and obesity, which my lab still does," Cowan said.

But the path to this point has been a long one. Cowan said that while there were reports in the literature of research groups producing fat cells from stem cells, "we couldn't get any of those protocols to work. So we had to spend the first three or four years perfecting the protocols to produce white and brown fat cells."

The current findings resulted from a sponsored research collaboration with drug giant Roche Pharmaceuticals, Cowan said, but "unfortunately, the collaboration with Roche has ended because the company decided, for unrelated reasons, to end its metabolic disease program."

"We found these two compounds by screening a library of about 1,000 compounds," Cowan said, "so we know that if we have access to the typical pharmaceutical company library of 1.5 to 2 million compounds, we will find others." Cowan is currently in discussion with several pharmaceutical companies about continuing the work. Additionally, a collaborator in Germany has been testing the first two compounds on mice. "We expect to have results fairly soon," Cowan said, adding that, "The compounds appear to work the same way in mice, but we don't know what the long-term metabolic or immune system effects are

"This is the kind of thing we expected the formation of HSCI" a decade ago to lead to, Cowan said. "The good news/bad news is that science is slow. Just establishing proof of concept takes an enormous amount of time. We thought that working with stem cells would lead to the discovery of new drugs and therapies, and now it's really starting to happen. A decade of hard basic scientific work is paying off."