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

TLDR

Endocannabinoids acting on CB1 receptors stimulate appetite and influence fat metabolism, as shown by CB1 antagonists reducing obesity and CB1‑deficient mice resisting diet‑induced weight gain despite similar caloric intake. The study examined whether endocannabinoids regulate hepatic lipogenesis. CB1 activation upregulates hepatic lipogenic genes (SREBP‑1c, ACC‑1, FAS) and de novo fatty‑acid synthesis, and high‑fat diet elevates endocannabinoid levels and CB1 density, with blockade reducing synthesis; thus anandamide at hepatic CB1 promotes diet‑induced obesity via the FAS pathway.

Abstract

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.