July 26, 2002 Research conducted in animals has revealed that an appetite suppressant drug, D-fenfluramine (D-FEN), activates brain pathways that regulate food intake and body weight. The NIH-funded study suggests that drugs targeting central nervous system pathways affecting appetite, obesity, and anorexia may lead to selective, effective treatments for weight control. Results appear in the July 26, 2002, Science.
A study led by researchers at Beth Israel Deaconess Medical Center (BIDMC) found that anorexia induced by d-FEN in rodents activates melanocortin neurons in the central nervous system. The drug, once prescribed for losing weight and known as fen-phen when used with phentermine, was withdrawn by the Food and Drug Administration after reports of cardiac complications. The National Institute of Mental Health (NIMH) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) supported the research.
The scientists set out to identify ways that d-FEN, which increases the brain's release of serotonin, a neurotransmitter that relays nerve impulses and curbs appetite, boosts this effect. Using a dose of d-FEN that reduced feeding behavior, they correlated anorexic effects with activity patterns in a network of neurons in the brain. Researchers targeted the arcuate nucleus (ARC) region of the hypothalamus, where pro-opiomelanocortin (POMC) neurons receive serotonin directly and signal to regions associated with regulating energy.
"Our study has linked the serotonin system, a classic brain pathway thought to be involved with eating disorders like anorexia nervosa, to the melanocortin system, a brain pathway involved in obesity," explained 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.
Using electrophysiology studies of the hypothalamus in mice, scientists found that d-FEN doubles the firing rate in the POMC neurons, an effect reversed by drug washout. Morover, POMC neurons depolarized in response to receiving d-FEN, serotonin, or two serotonin receptor agonists.
The results support the notion that serotonin systems directly activate POMC neurons, causing them to increase their firing and release chemical messengers. Findings propose that d-FEN stimulates the release of serotonin in the ARC region of the hypothalamus. The neurotransmitter then binds to receptors in POMC neurons. These receptors in turn stimulate the release of a peptide molecule that acts on melanocortin receptors, critical regulators of energy, appetite, and various hormones in the brain.
Components of the anorexic effects of d-FEN are mediated through the central melanocortin system, which is now well established as a fundamental regulator of food intake and body weight in rodents and humans, reported the researchers in Science.
The melanocortin circuit is implicated in both anorexia and obesity. "Our work gives a mechanistic explanation of how drugs like D-FEN may inhibit food intake. Investigating the neurobiology of drug-caused anorexia may lead to the development of new drugs with fewer side effects to prevent and treat obesity," Elmquist stated.
Also participating were lead author Lora K. Heisler and Michael A. Cowley, Laurence H. Tecott, Wei Fan, Malcolm J. Low, James L. Smart, Marcelo Rubinstein, Jeffrey B. Tatro, Jacob N. Marcus, Henne Holstege, Charlotte E. Lee, and Roger D. Cone.
This research was funded by grants from the National Institute of Mental Health (NIMH) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) with support from the National Alliance for Research on Schizophrenia and Depression, the International Scholar Program of the Howard Hugest Medical Institute, and the Agencia Nacional de Promocion Cientifica y Technologia.
NIMH and NIDDK are part of the National Institutes of Health (NIH), the Federal Government's primary agency for biomedical and behavioral research. NIH is a component of the U.S. Department of Health and Human Services.
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