Researchers identify brain pathway to explain how Fenfluramine causes weight loss

July 25, 2002

BOSTON - Scientists have identified the molecular pathway in the brain that helps explain how the once-popular diet drug d-Fenfluramine (d-FEN) works to promote weight loss, a discovery reported in the July 26 issue of Science that could provide an opportunity to develop a new anti-obesity treatment without d-FEN's cardiac side effects.

The study, led by a team of researchers at Beth Israel Deaconess Medical Center (BIDMC), also suggests this same brain pathway - the melanocortin system - is responsible for regulation of body weight at either end of the weight spectrum from obesity at one extreme to anorexia nervosa at the other.

D-FEN, used in combination with phenteramine and known as fen-phen, was banned by the U.S. Food and Drug Administration (FDA) in 1997 after a subset of patients taking the drug developed cardiac complications.

"This study helps close the circle on the role of the melanocortin pathway and adds the serotonin system to the growing list of metabolic signals - including leptin - that act on the brain's melanocortin neurons, regulating food intake and body weight," explains the study's senior author Joel Elmquist, D.V.M., Ph.D., a neuroscientist and endocrinologist at BIDMC and associate professor of endocrinology and medicine at Harvard Medical School.

The diet drug d-FEN, which is the "fen" part of the fen-phen combination, first came on the market in 1992, and within five years, had been prescribed to millions of individuals who were trying to lose weight. The drug works by increasing the brain's release of serotonin, a "chemical messenger" that, among other things, helps to suppress appetite. Serotonin acts as a neurotransmitter to convey nerve impulses in the brain, and anti-obesity drugs such as fenfluramine, as well as the popular antidepressant medications fluoxetine (Prozac) and sertraline (Zoloft) work by enhancing this effect.

However, as Elmquist explains, d-FEN's popularity was relatively brief: Because d-FEN targeted multiple serotonin pathways and receptors, for some patients the result was a serotonin surplus. Unfortunately, for some of these individuals, cardiac side effects developed and, consequently, the drug was removed from the market.

"Obesity is a growing problem in need of solutions," says Elmquist. "d-Fenfluramine worked very well to help patients reduce food intake and body weight. Therefore our group, headed by Lora Heisler, Ph.D., set out to identify the specific pathways and mechanisms through which d-FEN mediates its effect on food intake in the hope of more precisely understanding how appetite suppressant drugs exert their effects."

The researchers began by investigating which of the brain's neurons were being activated during d-FEN treatment and discovered activity in a region of the hypothalamus called the arcuate nucleus (ARC), the region of the brain associated with satiety or feelings of "fullness."

To determine which ARC cells were involved, coauthors Michael Cowley, Ph.D., Malcolm Low, M.D., Ph.D., and Roger Cone, Ph.D., of Oregon Health & Science University used electrophysiology methods in transgenic mice, and "tracked" d-FEN's effects in a subset of ARC cells that expressed pro-opiomelanocortin (POMC). They discovered that d-FEN significantly increased activity of these neurons.

"The technique we had earlier developed with Dr. Low for measuring the activity of the POMC neurons allowed us, for the first time, to test the direct effects of hormones, neurotransmitters and drugs on feeding circuits in the brain," explains Cone.

"In other research, we had shown that these neurons sense and respond to a variety of other signals of energy stores, including fat mass and nutrient digestion signals from the gut," adds Cowley. "This study shows how crucial these circuits are for the brain to integrate signals from the body, and shows how fenfluramine can change the interpretation of those signals."

On the basis of findings showing that the brain's central serotonin system was directly involved in activating the POMC neurons, the researchers hypothesized that d-FEN was stimulating the release of serotonin, which was binding to particular serotonin receptors called 5-HT 2C. Work by coauthor Larry Tecott, M.D., Ph.D., of the University of California, San Francisco, had demonstrated that action at these 5-HT 2C receptors contributes to d-FEN's anorexic effect, and is required for the normal regulation of body weight.

Describing how the researchers closed in on the melanocortin pathway as the source of d-FEN's anorexic effect, Elmquist explains, "We knew that activation of POMC neurons could stimulate the release of the alpha-melanocyte stimulating hormone." This hormone, he explains, acts on neurons expressing melanocortin 4 (MC4-R) and melanocortin 3 (MC3-R) receptors. MC4-Rs had previously been identified as being critical regulators of food intake, energy expenditure and neuroendocrine function, initially by Cone's laboratory.

Furthermore, notes Elmquist, melanocortin receptors are expressed widely in the central nervous system, including several regions of the brain implicated in addictive behaviors and depression, suggesting the potential for a more widespread interaction of the melanocortin and serotonin systems.

"The current findings suggest that the melanocortin pathway could act as a critical effector arm of central serotonin systems that have long been thought to be involved in several psychiatric disorders."

Finally, he notes, coupled with recent data from Cone's group at the Vollum Institute, Oregon Health & Science University, "An intriguing possibility emerges that the central melanocortin system is also involved in eating disorders including anorexia nervosa and 'wasting syndromes' often seen in cases of chronic illness."
In addition to Heisler, Elmquist, Cowley, Low, Cone and Tecott, study coauthors include BIDMC researchers Jacob Marcus, Henne Holstege, and Charlotte Lee, M.S.; Wei Fan, Ph.D., and James Smart, Ph.D., of the Oregon Health & Science University; Marcelo Rubenstein of Universidad de Buenos Aires in Argentina; and Jeffrey Tatro, Ph.D., of Tufts University School of Medicine in Boston.

This research was funded by grants from the National Institute of Mental Health, the National Institute of Diabetes and Digestive and Kidney Diseases, and support from the National Alliance for Research on Schizophrenia and Depression, and the International Scholar Program of the Howard Hughes Medical Institute and the Agencia Nacional de Promocion Cientifica y Technologia.

Beth Israel Deaconess Medical Center is a major patient care, research and teaching affiliate of Harvard Medical School and a founding member of CareGroup Healthcare System. Beth Israel Deaconess is the third largest recipient of National Institutes of Health research funding among independent U.S. teaching hospitals.

Beth Israel Deaconess Medical Center

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