Hormone triggers cells to turn to fat.

Two groups of investigators have discovered a natural hormone that triggers the production of fat cells. While the finding could provide new strategies for the battle of the bulge, understanding the hormone's activities may also lead to new antidiabetes drugs.

The hormone, a type of prostaglandin, stimulates the maturation of so-called stem cells, immature cells that can develop into various cell types. The hormone appears to act as a master fat switch, telling stem cells to become fat cells, or adipocytes, says Bruce M. Spiegelman of the Dana Farber Cancer Institute in Boston.

Two reports in the Dec. 1 Cell describe the new findings. One report comes from a collaboration led by Spiegelman and Ronald M. Evans of the Salk Institute for Biological Studies in La Jolla, Calif., the other from a group led by Steven A. Kliewer and Juergen M. Lehmann of the Glaxo Research Institute in Research Triangle Park, N..

The investigators found that the hormone passes through a cell's outer membrane, penetrates deep into the interior, and binds to molecules called PPAR-gamma receptors. These receptors reside in the cell's nucleus, the saclike structure that houses a cell's genetic material. By attaching to PPAR-gamma, the hormone appears to send signals into the nucleus, switching on or off the genes needed to turn a stem cell into a fat cell.

Spiegelman and his colleagues had identified the receptor last year but did not know which of the body's native chemicals activated it. They showed that they had a master switch of adipogenesis, says Spiegelman, but they didn't know how to flip it.

Kliewer suggests that compounds able to prevent the hormone from binding to PPAR-gamma may provide leads for obesity drugs that would stop the body from creating fat. Earlier this year, other investigators found another hormone, leptin, that plays a role in obesity (SN: 12/3/94, p.372).

"This is a nice addition to the obesity story," says C. Ronald Kahn of the Joslin Diabetes Center in Boston. "It is important in understanding and circumventing the pathway to obesity."

Both groups of investigators have also shown that, curiously, a new class of drugs designed to combat one form of diabetes also binds to the PPAR-gamma receptor. The drugs, known as thiazolidinediones, are being tested in clinical trials as a treatment for non-insulin-dependent diabetes mellitus (NIDDM).

In NIDDM, the body produces sufficient insulin, the substance that controls concentrations of glucose in the blood. The body's tissues, however, slowly become resistant to insulin, sending blood glucose concentrations soaring.

Thiazolidinediones have shown great promise in treating NIDDM, but their exact mode of action remains a mystery. "They sensitize the body to insulin, but people had no real idea how they work," says Spiegelman.

NIDDM is generally linked to obesity, so it appears paradoxical that a drug that stimulates the production of fat cells would prove useful in treating diabetes. "You don't treat diabetes by creating more fat cells," says Spiegelman.

Spiegelman suggests that the thiazolidinediones may change patterns of genetic activity in existing fat cells, causing the cells to produce proteins that ameliorate the body's insulin resistance.

Other cells besides adipocytes may also contain the PPAR-gamma receptor, he says. If so, thiazolidinediones may protect by influencing the function of those cells.

Spiegelman and Kliewer agree that having a molecular target for antidiabetes drugs will speed the development of new compounds. In addition, both groups intend to examine relationships between fat storage and glucose regulation.