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Distributed August 2, 2004
Contact Wendy Lawton

Leptin and obesity
Two enzymes key to calorie-burning, Brown research shows

A Brown-led research team has discovered a pair of universal switches in the brain that tell the body to stop eating and start burning calories. Tripped by leptin, these essential enzymes activate other chemical messengers that send metabolism-boosting signals from the brain to the body. The discovery, highlighted in the current issue of The Journal of Clinical Investigation, can be used to create new treatments for obesity, one of the nation’s most pressing health problems.

PROVIDENCE, R.I. — Metabolism is regulated by a host of tiny peptides in the hypothalamus, the small segment of the brain controlling hunger. But those peptides can’t perform their fat-fighting function without the aid of PC1 and PC2 enzymes, according to new Brown University research.

Led by Eduardo Nillni, a research professor of medicine at Brown Medical School and Rhode Island Hospital investigator, the team found that PC1 and PC2 chop up the precursor of thyrotropin-releasing hormone (TRH), a process that sets the molecules in motion. The smaller TRH peptides go on to stimulate the pituitary gland and the thyroid through a complex chemical cascade.

The end result: Food intake is inhibited. The body burns more calories.

PC1 and PC2 perform their crucial protein-cutting function not only on the chemical forerunner of TRH, but on several metabolic brain messengers, researchers say. These include insulin, the hormone that controls blood sugar. This finding will aid in the understanding and treatment of obesity, which affects nearly 68 million adults, teen-agers and children in the United States.

“What we have is an important discovery of how leptin regulates specific enzymes,” Nillni said. “While scientists have known for about a decade that PC1 and PC2 play a role in peptide processing, we did not know their importance in activating neuropeptides so key to energy balance. It’s a thrilling finding.”

The National Institutes of Health funded the research in Nillni’s laboratory. It was conducted at Brown Medical School and Rhode Island Hospital in Providence and Harvard Medical School and Beth Israel Deaconess Medical Center in Boston.

Results are published in The Journal of Clinical Investigation, which highlights the paper in its current issue.

Nillni and many other endocrinologists are intensely interested in leptin, a hormone produced in fat tissue and a key player in eating and energy use.

Nillni and the team found that when leptin moves through the bloodstream to the brain, it travels a direct path to make more PC1 and PC2, which then process the TRH precursor. Other new research, conducted by the same team, shows that leptin also travels an indirect path through the brain, triggering production of a peptide that sends a fast, strong message to the hypothalamus to burn calories. Those results were published in last week’s online early edition of the Proceedings of the National Academy of Sciences.


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