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

D Osei-Hyiaman, M DePetrillo… - The Journal of …, 2005 - Am Soc Clin Investig
D Osei-Hyiaman, M DePetrillo, P Pacher, J Liu, S Radaeva, S Bátkai, J Harvey-White…
The Journal of clinical investigation, 2005Am Soc Clin Investig
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 …
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 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.
The Journal of Clinical Investigation