The stimulation of ketogenesis by cannabinoids in cultured astrocytes defines carnitine palmitoyltransferase I as a new ceramide-activated enzyme

J Neurochem. 1999 Apr;72(4):1759-68. doi: 10.1046/j.1471-4159.1999.721759.x.


The effects of cannabinoids on ketogenesis in primary cultures of rat astrocytes were studied. Delta9-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Astrocytes / drug effects
  • Astrocytes / enzymology*
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Carnitine O-Palmitoyltransferase / metabolism*
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cyclic AMP / metabolism
  • Dose-Response Relationship, Drug
  • Dronabinol / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • Ketone Bodies / metabolism*
  • Malonyl Coenzyme A / metabolism
  • Mitochondria / enzymology
  • Piperidines / pharmacology
  • Protein Kinase C / metabolism
  • Psychotropic Drugs / pharmacology*
  • Pyrazoles / pharmacology
  • Rats
  • Receptors, Cannabinoid
  • Receptors, Drug / metabolism
  • Rimonabant
  • Sphingomyelin Phosphodiesterase / pharmacology
  • Sphingomyelins / metabolism*
  • Sphingosine / analogs & derivatives
  • Sphingosine / pharmacology


  • Enzyme Inhibitors
  • Ketone Bodies
  • N-acetylsphingosine
  • Piperidines
  • Psychotropic Drugs
  • Pyrazoles
  • Receptors, Cannabinoid
  • Receptors, Drug
  • Sphingomyelins
  • Malonyl Coenzyme A
  • Dronabinol
  • Cyclic AMP
  • Carnitine O-Palmitoyltransferase
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Sphingomyelin Phosphodiesterase
  • Sphingosine
  • Rimonabant
  • Calcium