Hypothalamic ceramide levels regulated by CPT1C mediate the orexigenic effect of ghrelin

Autor: Luís Martins, Carlos Dieguez, Josep Clotet, Fausto G. Hegardt, Patricia Carrasco, Jordi Jacas, Macarena Pozo, Núria Casals, Sara Ramírez, Miguel López, Dolors Serra
Rok vydání: 2013
Předmět:
Male
medicine.medical_specialty
Ceramide
Farmacologia
Physiology
Endocrinology
Diabetes and Metabolism
Hypothalamus
Neuropeptide
Fisiologia
Biology
Ceramides
Eating
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Orexigenic
Internal medicine
Internal Medicine
medicine
Animals
Agouti-Related Protein
Neuropeptide Y
Pharmacokinetics
Protein kinase A
Original Research
030304 developmental biology
Mice
Knockout
Pharmacology
0303 health sciences
Carnitine O-Palmitoyltransferase
Farmacocinètica
Carnitina palmitoïl-transferasa 1
digestive
oral
and skin physiology
Neuropeptide Y receptor
Sphingolipid
Ghrelin
Metabolisme
Endocrinology
Metabolism
chemistry
Carnitine palmitoyltransferase I
Signal transduction
030217 neurology & neurosurgery
hormones
hormone substitutes
and hormone antagonists
Signal Transduction
medicine.drug
Zdroj: Dipòsit Digital de la UB
Universidad de Barcelona
Diabetes
Popis: 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.
Databáze: OpenAIRE
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