E ndogenous 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 blockade. In the hypothalamus, where FAS inhibitors elicit anorexia, SREBP-1c and FAS expression are similarly affected by CB₁ ligands. We conclude that anandamide acting at hepatic CB₁ contributes to diet-induced obesity and that the FAS pathway may be a common molecular target for central appetitive and peripheral metabolic regulation.