The Stimulation of Ketogenesis by Cannabinoids in Cultured Astrocytes Defines Carnitine Palmitoyltransferase I as a New Ceramide‐Activated Enzyme

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Abstract
The effects of cannabinoids on ketogenesis in primary cultures of rat astrocytes were studied. ▵9‐Tetrahydrocannabinol (THC), the major active component of marijuana, produced a malonyl‐CoA‐independent stimulation of carnitine palmitoyltransferase I (CPT‐I) and ketogenesis from [14C]palmitate. The THC‐induced stimulation of ketogenesis was mimicked by the synthetic cannabinoid HU‐210 and was prevented by pertussis toxin and the CB1 cannabinoid receptor antagonist SR141716. Experiments performed with different cellular modulators indicated that the THC‐induced stimulation of ketogenesis was independent of cyclic AMP, Ca2+, protein kinase C, and mitogen‐activated protein kinase (MAPK). The possible involvement of ceramide in the activation of ketogenesis by cannabinoids was subsequently studied. THC produced a CB1 receptor‐dependent stimulation of sphingomyelin breakdown that was concomitant to an elevation of intracellular ceramide levels. Addition of exogenous sphingomyelinase to the astrocyte culture medium led to a MAPK‐independent activation of ketogenesis that was quantitatively similar and not additive to that exerted by THC. Furthermore, ceramide activated CPT‐I in astrocyte mitochondria. Results thus indicate that cannabinoids stimulate ketogenesis in astrocytes by a mechanism that may rely on CB1 receptor activation, sphingomyelin hydrolysis, and ceramide‐mediated activation of CPT‐I.