In Search of Fen-Phen's Jekyll Without the Hyde

Scientists find pathways in how diet drug works

THURSDAY, July 25, 2002 (HealthDayNews) -- The idea of the perfect diet pill is still alive.

That drug appeared to have arrived a decade ago, in the form of d-Fenfluramine. In a combination with phenteramine called fen-phen, it was prescribed for millions of Americans. However, it caused heart problems in a significant number of users and was banned by the U.S. Food and Drug Administration in 1997, leaving a raft of litigation in its wake.

Now scientists say they have identified the molecular pathway in the brain that gave d-Fenfluramine its weight-loss powers, opening the way to developing a medication that would have its good effects without its damaging side effects. Since that pathway governs appetite in general, a drug that helps overcome eating disorders such as anorexia nervosa is also possible.

Learning about the brain mechanisms that control appetite was a widespread effort, including researchers in Boston, San Francisco and Portland, Ore., says a report in tomorrow's issue of Science. They start with the knowledge that the appetite-suppressing effect of fen-phen is due to its effect on neurons -- brain cells -- that are part of a system using a well-known protein called serotonin.

The problem is that serotonin is involved in a large number of other physical functions, which is why it caused the bad side effects. What the researchers have discovered is that serotonin does not act directly on appetite. Instead, it works through another set of neurons that use a different signaling molecule, melanocortin.

Thus, says Dr. Joel Elmquist, an associate professor of endocrinology and medicine at Harvard Medical School and a member of the research team, finding a molecule that acts on the melanocortin pathway could suppress appetite without undesired side effects. One of his postdoctoral students, Lora Heisler, led the research effort.

Melanocortin "is one of the hottest target areas in obesity research," Elmquist says.

Another member of the research team, Roger Cone, a senior scientist at the Oregon Health and Science University, has played a major role in melanocortin research. In the current effort, he and his colleagues manipulated the genes of mice to create some with a specific set of melanocortin-using neurons that would give off light when they became active. "Then we can go in and make electrical recordings from those neurons," Cone says.

The neurons they tracked are in a region of the hypothalamus called the arcuate nucleus, which is known to be associated with feelings of fullness. "Mice that have a defect in the ability to receive signals from those neurons are unresponsive to the appetite-suppressing activity of [fen-phen]," Cone says.

"If you activate these melanocortin neurons, you get decreased food intake and increased body weight loss," says Elmquist. "If they are nonfunctional, you get obesity."

And so, says Cone, "this technique will provide pharmaceutical companies with specific tools to look for drugs that act on this neuronal circuit: "Lots of companies are making pretty good progress on a new generation of drugs."

Cone is on the advisory board of a biotechnology company working on new drugs, aimed not at obesity but at disorders that cause excessive thinness, such as anorexia. "Blockage of the receptors might prevent weight loss," he says.

Work with melanocortin could have much wider implications, Elmquist says. Serotonin is involved in several psychiatric disorders, including addiction and depression, and it appears to operate through the melanocortin pathway, he says.

What To Do

You can learn more about fen-phen and other diet drugs from the U.S. Food and Drug Administration or the American Heart Association.

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