title: Cocaine- and amphetamine-regulated transcript: stimulation of expression in rat vagal afferent neurons by cholecystokinin and suppression by ghrelin.
abstract: The neuropeptide transmitter cocaine- and amphetamine-regulated transcript (CART) inhibits food intake and is expressed by both vagal afferent and hypothalamic neurons. Here we report that cholecystokinin (CCK) regulates CART expression in rat vagal afferent neurons. Thus, CART was virtually undetectable after energy restriction for 24 h, but administration of CCK to fasted rats increased CART immunoreactivity, and refeeding of fasted animals promptly increased CART by a mechanism sensitive to a CCK-1 receptor antagonist. In vagal afferent neurons incubated in serum-free medium, CART was virtually undetectable, whereas the orexigenic peptide melanin-concentrating hormone (MCH) was readily detected. The addition of CCK rapidly induced CART expression and downregulated MCH. Using a CART promoter-luciferase reporter vector transfected into cultured vagal afferent neurons, we showed that CCK stimulation of CART transcription was mediated by activation of protein kinase C and cAMP response element-binding protein (CREB). The action of CCK on CART expression was inhibited by the orexigenic peptide ghrelin, through a mechanism that involved exclusion of phosphorylated CREB from the nucleus. Thus, CCK reciprocally regulates expression of CART and MCH within the same vagal afferent neuron; ghrelin inhibits the effect of CCK at least in part through control of the nuclear localization of phosphoCREB, revealing previously unsuspected modulation of gut-brain signals implicated in control of food intake.
authors.affiliation: Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Liverpool L69 3BX, United Kingdom.
authors.forename: Guillaume
authors.initials: G
authors.lastname: de Lartigue
authors.forename: Rod
authors.initials: R
authors.lastname: Dimaline
authors.forename: Andrea
authors.initials: A
authors.lastname: Varro
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Dockray
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002766:Cholecystokinin / Q000378:metabolism / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D054439:Ghrelin; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D009620:Nodose Ganglion / Q000187:drug effects / Q000378:metabolism; D036361:Peptide Hormones / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism*; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
chemical_list: D054439:Ghrelin; D009419:Nerve Tissue Proteins; D036361:Peptide Hormones; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D002766:Cholecystokinin