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 (AMPK) 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 (ER) of neurons, may play a role on this action. Here, we demonstrate that ghrelin's orexigenic action is totally blunted in CPT1C knock-out (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 ghrelin's orexigenic action and normalized the levels of AgRP and NPY, as well as their key transcription factors pCREB and FoxO1. 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.