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 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.
Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Yong
Y
Xu
Juli E
JE
Jones
Danielle A
DA
Lauzon
Jason G
JG
Anderson
Nina
N
Balthasar
Lora K
LK
Heisler
Andrew R
AR
Zinn
Bradford B
BB
Lowell
Joel K
JK
Elmquist
D000818:Animals; D000855:Anorexia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D005277:Fenfluramine / Q000494:pharmacology*; D008297:Male; D053486:Melanocortins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009434:Neural Pathways / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000502:physiology; D044105:Receptor, Melanocortin, Type 4 / Q000172:deficiency / Q000235:genetics; D044405:Receptor, Serotonin, 5-HT2C / Q000172:deficiency / Q000235:genetics; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D015431:Weight Loss / Q000235:genetics / Q000502:physiology
D005277:Fenfluramine; D053486:Melanocortins; D011333:Pro-Opiomelanocortin; D044105:Receptor, Melanocortin, Type 4; D044405:Receptor, Serotonin, 5-HT2C; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors