Portland, Ore.

Method may be useful for identification of new drugs

Researchers at Oregon Health & Science University have helped link a weight control mechanism in the brain to D-fenfluramine (d-FEN), half of the once popular fen-phen weight loss drug combination. The drug, which used to be prescribed along with phentermine, was banned by the Food and Drug Administration (FDA) in 1997 due to cardiac complications. This latest research provides a new understanding of the brain's weight loss control functions. In addition, with this new information, scientists are hopeful that new drugs might be developed to control obesity without causing serious side effects. Researchers in the OHSU Vollum Institute conducted this research in collaboration with numerous institutions led by Beth Israel Deaconess Medical Center at Harvard University. Results are printed in the July 26 edition of the journal Science.

Using mice models, OHSU researchers Roger Cone, Ph.D., Malcolm Low, M.D., Ph.D., and Michael Cowley, Ph.D., developed a method by which key neurons involved in the regulation of body weight give off a green fluorescence when viewed under a microscope. This allowed them to identify and record the activity of cells called pro-opiomelanocortin (POMC) neurons when exposed to drugs or hormones. The scientists found that d-FEN had the ability to make these neurons fire at twice their regular rate. They believe this firing stimulates the increased release of neuropeptides, which then trigger cells in the brain expressing MC3 and MC4 receptors designed to bind the neuropeptides.

Past research conducted in Cone's lab demonstrated that a lack of the MC3 or MC4 receptors in mice causes obesity. Mutations in the MC4 receptor are believed to be the most common genetic cause of obesity. In addition, OHSU researchers have also connected this same system to wasting syndromes connected to chronic illness, such as AIDS and certain forms of cancer.

"The new method of tagging specific varieties of rare neurons in the brain to study their regulation should allow scientists to make similar advances in many fields," said Cone, senior scientist at the Vollum Institute, and assistant professor of cell and developmental biology in the OHSU School of Medicine, and one of the paper's senior authors.

"In other research, we have recently 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," said paper co-author Cowley, previously a scientist in the Cone lab, now an assistant scientist in the Division of Neuroscience at the OHSU Oregon National Primate Research Center. "This study shows how crucial these circuits are for the brain to integrate signals from the body and that fenfluramine changed the interpretation of those signals."

Back in 1997 the FDA withdrew approval of d-FEN based on findings from physicians who evaluated patients taking these two drugs with echocardiograms, a special procedure that can test the functioning of heart valves. These findings indicated that approximately 30 percent of patients who were evaluated had abnormal echocardiograms, even though they had no symptoms. At that point, millions of Americans had been prescribed the drug combination after it first came to market in 1992.

"d-FEN works by increasing the level of the neurotransmitter serotonin ,and there happen to be serotonin receptors in the POMC neurons as well as in other weight-regulatory centers in the brain," added Cone. "While this increase causes weight loss, there are a large number of different types of serotonin receptors elsewhere, thus the elevated serotonin also likely caused the cardiac side effects witnessed by some fen-phen patients. This research gives us much more insight into the brain's weight control functions and may allow for a much more targeted approach to treating obesity by developing drugs that more specifically impact the POMC neurons or their target sites."

Particulars:
Roger D. Cone, Ph.D., assistant professor of cell and developmental biology in the OHSU School of Medicine, and a senior scientist in the Vollum Institute
Michael Cowley, Ph.D., assistant scientist in the Division of Neuroscience at the OHSU Oregon National Primate Research Center
Malcolm J. Low, M.D., Ph.D., professor of behavioral neuroscience in the OHSU School of Medicine; and a scientist in the Vollum Institute