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Researchers Seek Safer Obesity Drug

Alternatives sought for dangerous diet pills

December 1, 2008
The weight loss drug Fen-phen was banned more than a decade ago after research revealed its life-threatening side effects. But researchers say if a safe equivalent to Fen-phen could be found, it might be a powerful weapon against obesity.

Scientists at UT Southwestern Medical Center in Dallas are on the trail. They're trying to understand how Fen-phen behaves in the brain in order to develop safer anti-obesity drugs with fewer side effects.

In a study appearing in the Nov. 25 issue of Neuron, the researchers define a circuit in the brain that explains the ways fenfluramine, a component of Fen-phen, suppresses appetite.

"Our findings provide evidence that the neural circuit we've proposed is sufficient for the neurotransmitter serotonin to regulate food intake and body weight, " said Dr. Joel Elmquist, professor of internal medicine and pharmacology at UT Southwestern and senior author of the study. "Fen-phen works directly on this pathway. Unfortunately, that drug also adversely affects peripheral tissue such as the heart."

Previous work from the UT Southwestern group led to the hypothesis that Fen-phen worked by activating the serotonin 2c receptor in the body. The current work provides genetic proof supporting this model, the researchers say.

"Conventional wisdom is that fenfluramine increases serotonin release that then activates serotonin receptors in the brain to regulate food intake and body weight, but unfortunately, this drug also causes lesions in heart valves," Elmquist said. "If you could develop a drug that would travel to both the brain and the peripheral tissues, and then give a blocker to protect the heart, it's possible that you could prevent the harmful side effects and still aid weight loss. Admittedly, that's a bit farfetched, but this mouse model could be used to test that theory."

The team's next step is to determine whether they've identified the sole circuit required to suppress appetite and induce weight loss.

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