title: Hypothalamic ceramide levels regulated by CPT1C mediate the orexigenic effect of ghrelin.
abstract: Recent data suggest that ghrelin exerts its orexigenic action through regulation of hypothalamic AMP-activated protein kinase pathway, leading to a decline in malonyl-CoA levels and desinhibition of carnitine palmitoyltransferase 1A (CPT1A), which increases mitochondrial fatty acid oxidation and ultimately enhances the expression of the orexigenic neuropeptides agouti-related protein (AgRP) and neuropeptide Y (NPY). However, it is unclear whether the brain-specific isoform CPT1C, which is located in the endoplasmic reticulum of neurons, may play a role in this action. Here, we demonstrate that the orexigenic action of ghrelin is totally blunted in CPT1C knockout (KO) mice, despite having the canonical ghrelin signaling pathway activated. We also demonstrate that ghrelin elicits a marked upregulation of hypothalamic C18:0 ceramide levels mediated by CPT1C. Notably, central inhibition of ceramide synthesis with myriocin negated the orexigenic action of ghrelin and normalized the levels of AgRP and NPY, as well as their key transcription factors phosphorylated cAMP-response element-binding protein and forkhead box O1. Finally, central treatment with ceramide induced food intake and orexigenic neuropeptides expression in CPT1C KO mice. Overall, these data indicate that, in addition to formerly reported mechanisms, ghrelin also induces food intake through regulation of hypothalamic CPT1C and ceramide metabolism, a finding of potential importance for the understanding and treatment of obesity.
authors.affiliation: Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Ramírez
authors.forename: Luís
authors.initials: L
authors.lastname: Martins
authors.forename: Jordi
authors.initials: J
authors.lastname: Jacas
authors.forename: Patricia
authors.initials: P
authors.lastname: Carrasco
authors.forename: Macarena
authors.initials: M
authors.lastname: Pozo
authors.forename: Josep
authors.initials: J
authors.lastname: Clotet
authors.forename: Dolors
authors.initials: D
authors.lastname: Serra
authors.forename: Fausto G
authors.initials: FG
authors.lastname: Hegardt
authors.forename: Carlos
authors.initials: C
authors.lastname: Diéguez
authors.forename: Miguel
authors.initials: M
authors.lastname: López
authors.forename: Núria
authors.initials: N
authors.lastname: Casals
mesh_terms: D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism*; D002518:Ceramides / Q000378:metabolism*; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D054439:Ghrelin / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D054369:Agouti-Related Protein; D002518:Ceramides; D054439:Ghrelin; D009478:Neuropeptide Y; D002334:Carnitine O-Palmitoyltransferase