Hormone may directly trim fat from cells.

Leptin, a hormone secreted by fat cells, burst into the spotlight in 1995, when investigators found that injections of it could dramatically slim obese and even normal mice (SN: 7/29/95, p. 68).

The simple model proposed at the time was that leptin circulates into the brain and helps regulate food intake. If an animal put on too many pounds, the theory went, its fat cells simply secreted more leptin to reduce the appetite.

Simplicity rarely lasts long in biology.

Leptin is now seen as a versatile hormone that probably has roles both inside and outside the brain. This week, scientists report that leptin may govern mechanisms that prevent cells from storing fat. As a result, the hormone may offer protection against some forms of diabetes.

The new findings emerged from studies of rats with unusually high concentrations of leptin in their blood, explains Roger H. Unger of the University of Texas Southwestern Medical Center in Dallas. To create the animals, he and his colleagues added the human leptin gene to rats.

Like other scientists, Unger's team noticed that almost all fat disappeared from the animals. The slimming was so dramatic that the group suspected more than appetite suppression was involved.

Following up on that suspicion, Unger and his colleagues found that cellular concentrations of triglycerides, commonly known as fat, are significantly lower in rats with extra leptin than in normal rats. Most cells synthesize triglycerides for long-term energy storage.

The researchers then conducted test tube studies in which they exposed rat pancreatic beta islet cells to leptin. The hormone significantly reduced the triglyceride content of these cells, they report in the April 29 Proceedings of the National Academy of Sciences.

Leptin seems to inhibit the conversion of free fatty acids to triglycerides, says Unger. The hormone also appears to trigger the breakdown of cells' existing triglycerides. "We want to know the mechanisms for this," says Unger.

These newly discovered actions of leptin may have implications for diabetes, particularly the adult forms that arise because of the body's increasing resistance to the action of insulin, the hormone that regulates glucose in the blood.

First, leptin's triglyceride trimming may improve the body's overall production of insulin by beta islet cells. Researchers have found that people with diabetes often have abnormally large amounts of triglycerides in such cells. "If you stuff an insulin-making beta cell with fat, it doesn't work as well," says Unger.

Second, if leptin keeps the triglyceride content of other cells low, it may increase insulin's impact. "When you reduce fat in tissues, you increase their sensitivity to insulin," notes Unger.

The new work shows convincingly that, in addition to leptin's indirect actions via the brain, the hormone has "direct effects, particularly on pancreatic islets, which is something that really hadn't been suspected," says Simeon I. Taylor of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md.