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Obese mice provide clues to a natural system that puts brakes on obesity

A gene that gets switched on only in the fat cells of obese mice may be a key to preventing obesity in humans, according to new research at The Rockefeller University in New York City and the Joslin Diabetes Center in Boston.

The finding, reported in the August 1 issue of the Journal of Clinical Investigation, marks the first time a gene has been identified that is induced, or activated, in the fat cells of obese animals. According to Rockefeller University professor Markus Stoffel, M.D., Ph.D., lead investigator of the study, the gene, called Foxa-2, inhibits young body cells from becoming mature fat-producing cells called adipocytes. In addition, when this gene is switched on in mature adipocytes, it functions as a brake to slow down further fat production and storage.

"We know a lot about the various molecular pathways that stimulate or promote fat production, and the focus has been on trying to block these pathways to fight obesity," says Stoffel. "This pathway is one of only a few that we know of that naturally work to counteract obesity.

"We have shown that Foxa-2 has two beneficial effects in mice: it counterregulates the formation of fat and it increases the activity of genes important for insulin sensitivity," Stoffel continues. "This is the ideal combination for pharmacologically treating obese or type 2 diabetic patients, or people with a risk of developing obesity."

Foxa-2 was originally discovered in the 1980s by Rockefeller scientist James E. Darnell Jr., M.D., as an activator of genes in the liver. Subsequent research by Stoffel and colleagues at Rockefeller showed that Foxa-2 also activates genes in the insulin-producing islet cells in the pancreas and it is expressed in the gut and the lung. However, previous research by scientists could not provide evidence for its expression in fat cells. The reason, says Stoffel, is "that we did not look at fat cells from obese animals."

"We were only able to find Foxa-2
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Contact: Joseph Bonner
bonnerj@rockefeller.edu
212-327-8998
Rockefeller University
15-Jul-2003


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