Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity

J Clin Invest. 2005 May;115(5):1298-305. doi: 10.1172/JCI23057.


Endogenous cannabinoids acting at CB(1) receptors stimulate appetite, and CB(1) antagonists show promise in the treatment of obesity. CB(1) (-/-) mice are resistant to diet-induced obesity even though their caloric intake is similar to that of wild-type mice, suggesting that endocannabinoids also regulate fat metabolism. Here, we investigated the possible role of endocannabinoids in the regulation of hepatic lipogenesis. Activation of CB(1) in mice increases the hepatic gene expression of the lipogenic transcription factor SREBP-1c and its targets acetyl-CoA carboxylase-1 and fatty acid synthase (FAS). Treatment with a CB(1) agonist also increases de novo fatty acid synthesis in the liver or in isolated hepatocytes, which express CB(1). High-fat diet increases hepatic levels of the endocannabinoid anandamide (arachidonoyl ethanolamide), CB(1) density, and basal rates of fatty acid synthesis, and the latter is reduced by CB(1) blockade. In the hypothalamus, where FAS inhibitors elicit anorexia, SREBP-1c and FAS expression are similarly affected by CB(1) ligands. We conclude that anandamide acting at hepatic CB(1) contributes to diet-induced obesity and that the FAS pathway may be a common molecular target for central appetitive and peripheral metabolic regulation.

MeSH terms

  • Animals
  • Arachidonic Acids / pharmacology
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cannabinoid Receptor Modulators / metabolism*
  • Cannabinoid Receptor Modulators / pharmacology
  • DNA-Binding Proteins / metabolism
  • Diet*
  • Dietary Fats / metabolism
  • Endocannabinoids*
  • Fatty Acids / biosynthesis*
  • Fatty Liver / etiology
  • Fatty Liver / metabolism
  • Hypothalamus / metabolism
  • Liver / metabolism*
  • Mice
  • Obesity / etiology
  • Obesity / metabolism*
  • Polyunsaturated Alkamides
  • Receptor, Cannabinoid, CB1 / genetics
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors / metabolism


  • Arachidonic Acids
  • CCAAT-Enhancer-Binding Proteins
  • Cannabinoid Receptor Modulators
  • DNA-Binding Proteins
  • Dietary Fats
  • Endocannabinoids
  • Fatty Acids
  • Polyunsaturated Alkamides
  • Receptor, Cannabinoid, CB1
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors
  • anandamide