Abstract
D-fenfluramine (d-FEN) was once widely prescribed and was among the most effective weight loss drugs, but was withdrawn from clinical use because of reports of cardiac complications in a subset of patients. Discerning the neurobiology underlying the anorexic action of d-FEN may facilitate the development of new drugs to prevent and treat obesity. Through a combination of functional neuroanatomy, feeding, and electrophysiology studies in rodents, we show that d-FEN-induced anorexia requires activation of central nervous system melanocortin pathways. These results provide a mechanistic explanation of d-FEN's anorexic actions and indicate that drugs targeting these downstream melanocortin pathways may prove to be effective and more selective anti-obesity treatments.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Appetite Depressants / pharmacology*
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Arcuate Nucleus of Hypothalamus / drug effects*
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Arcuate Nucleus of Hypothalamus / metabolism
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Feeding Behavior / drug effects*
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Fenfluramine / pharmacology*
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Male
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Melanocyte-Stimulating Hormones / pharmacology
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Mice
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Mice, Obese
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Mice, Transgenic
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Neurons / drug effects
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Neurons / metabolism
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Paraventricular Hypothalamic Nucleus / drug effects
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Paraventricular Hypothalamic Nucleus / metabolism
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Patch-Clamp Techniques
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Pro-Opiomelanocortin / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptor, Melanocortin, Type 3
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Receptor, Melanocortin, Type 4
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Receptor, Serotonin, 5-HT2C
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Receptors, Corticotropin / metabolism
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Receptors, Serotonin / metabolism
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Serotonin / metabolism
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Serotonin Agents / pharmacology
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alpha-MSH / metabolism*
Substances
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Appetite Depressants
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Receptor, Melanocortin, Type 3
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Receptor, Melanocortin, Type 4
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Receptor, Serotonin, 5-HT2C
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Receptors, Corticotropin
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Receptors, Serotonin
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Serotonin Agents
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SHU 9119
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Fenfluramine
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Serotonin
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alpha-MSH
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Pro-Opiomelanocortin
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Melanocyte-Stimulating Hormones