Hypothalamic Ceramide Levels regulated by CPT1C mediate the Orexigenic effect of Ghrelin
Per accedir als documents amb el text complet, si us plau, seguiu el següent enllaç: http://hdl.handle.net/10803/276184,
Autor/a
Ramírez Flores, Sara
Altres autors/es
Casals Farré, Núria
Universitat Internacional de Catalunya. Departament de Ciències Bàsiques
Data de defensa
2014-07-31T12:52:30Z2014-07-31T12:52:30Z
2014-07-18
Resum
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. Furthermore, central treatment with ceramide induced food intake and orexigenic neuropeptides expression in CPT1C KO mice. Third, we demonstrate that ceramides act increasing the BSX expression, the transcription factor that works coordinately with pCREB and FoxO1 to increase orexigenic neuropeptides. Finally we link CPT1C and longevity as we have seen that CPT1CKO mice have reduced lifespan. Overall, these data indicate that, in addition to formerly reported mechanisms, ghrelin also induces food intake through regulation of hypothalamic CPT1C and ceramide metabolism
Tipus de document
Tesi
Versió publicada
Llengua
English
Matèries i paraules clau
Carnitina palmitoiltransferas 1c
Carnitine
palmitoyltransferase 1C
Ghrelina
Ghrelin
Ceramides
Ceramide
BSX
NPY
AgRP
Neuro
576
577
Pàgines
175 p.
application/pdf
application/pdf
Publicat per
Universitat Internacional de Catalunya
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