Researchers identify brain pathway to explain how Fenfluramine causes weight loss

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."

Contact: Bonnie Prescott
Beth Israel Deaconess Medical Center

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