Anti-Obesity Protein Hits Possible Snag

One of the hottest biotech properties--a potential drug to treat obesity--may have encountered a stumbling block. A protein that makes obese mice lose weight also interferes with insulin in cultured human liver cells, says a report in the 15 November issue of Science. The findings suggest that diabetes could be a potential side effect of a leptin-based drug.

In December 1994, Rockefeller University scientists announced that they had discovered a human gene similar to one that, when mutated, causes severe hereditary obesity in mice. The normal gene codes for a protein called leptin, and the finding suggests that leptin plays a critical role in weight regulation. The prospect of a potent weight-loss drug sparked a bidding war among biotech firms. The victor, biotech giant Amgen Corp. of Thousand Oaks, California, paid a whopping $20 million for exclusive rights to Rockefeller's patent to develop leptin-based products.

But now comes what may be a reality check from a team at the Weizmann Institute in Rehovot, Israel. They found that the protein interfered with the normal function of insulin receptors within cultured human liver cells (see diagram). Reduced receptor function in people harbingers the onset of adult diabetes.

Experts are having trouble interpreting the findings, however, because they conflict with earlier work showing that too little leptin can trigger the same effect in liver cells. It might be that leptin levels outside a relatively narrow range--too high or too low--are damaging to cells, says Jeffrey Flier, an endocrinologist at Beth Israel-Deaconess Medical Center in Boston. Or, Flier says, it may simply be that the Weizmann study found "a biochemical artifact of some kind."

Other scientists agree that the test tube findings may not reflect how whole tissues or organs respond to leptin. "It's a big jump to go from the tissue-cell situation to the human situation," says Simeon Taylor, a diabetes researcher at the National Institutes of Health. Weizmann geneticist Menachem Rubinstein urges researchers to pursue further long-term animal studies on leptin that could portend any cumulative effects in people.

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