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Endogenous cannabinoids acting at CB₁ receptors stimulate appetite, and CB₁ antagonists show promise in the treatment of obesity. CB₁^–/– 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 CB₁ 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 CB₁ agonist also increases de novo fatty acid synthesis in the liver or in isolated hepatocytes, which express CB₁. High-fat diet increases hepatic levels of the endocannabinoid anandamide (arachidonoyl ethanolamide), CB₁ density, and basal rates of fatty acid synthesis, and the latter is reduced by CB₁ …