A serotonin and melanocortin circuit mediates D-fenfluramine anorexia

D-Fenfluramine (D-Fen) increases serotonin (5-HT) content in the synaptic cleft and exerts anorexigenic effects in animals and humans. However, the neural circuits that mediate these effects are not fully identified. To address this issue, we assessed the efficacy of D-Fen-induced hypophagia in mous...

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Bibliographic Details
Published in:The Journal of neuroscience 2010-11, Vol.30 (44), p.14630-14634
Main Authors: Xu, Yong, Jones, Juli E, Lauzon, Danielle A, Anderson, Jason G, Balthasar, Nina, Heisler, Lora K, Zinn, Andrew R, Lowell, Bradford B, Elmquist, Joel K
Format: Article
Language:English
Subjects:
Animals
Anorexia - chemically induced
Anorexia - metabolism
Anorexia - physiopathology
Brief Communications
Fenfluramine - pharmacology
Male
Melanocortins - physiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Neural Pathways - cytology
Neural Pathways - drug effects
Neural Pathways - metabolism
Pro-Opiomelanocortin - physiology
Receptor, Melanocortin, Type 4 - deficiency
Receptor, Melanocortin, Type 4 - genetics
Receptor, Serotonin, 5-HT2C - deficiency
Receptor, Serotonin, 5-HT2C - genetics
Serotonin - metabolism
Serotonin - physiology
Serotonin Uptake Inhibitors - pharmacology
Weight Loss - genetics
Weight Loss - physiology
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Summary:D-Fenfluramine (D-Fen) increases serotonin (5-HT) content in the synaptic cleft and exerts anorexigenic effects in animals and humans. However, the neural circuits that mediate these effects are not fully identified. To address this issue, we assessed the efficacy of D-Fen-induced hypophagia in mouse models with manipulations of several genes in selective populations of neurons. Expectedly, we found that global deletion of 5-HT 2C receptors (5-HT(2C)Rs) significantly attenuated D-Fen-induced anorexia. These anorexigenic effects were restored in mice with 5-HT(2C)Rs expressed only in pro-opiomelanocortin (POMC) neurons. Further, we found that deletion of melanocortin 4 receptors (MC4Rs), a downstream target of POMC neurons, abolished anorexigenic effects of D-Fen. Reexpression of MC4Rs only in SIM1 neurons in the hypothalamic paraventricular nucleus and neurons in the amygdala was sufficient to restore the hypophagic property of D-Fen. Thus, our results identify a neurochemically defined neural circuit through which D-Fen influences appetite and thereby indicate that this 5-HT(2C)R/POMC-MC4R/SIM1 circuit may yield a more refined target to exploit for weight loss.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.5412-09.2010