ABSTRACT
BACKGROUND & AIMS: Obesity and associated metabolic syndrome have quickly become a pandemic and a major detriment to global human health. The presence of non-alcoholic fatty liver disease (NAFLD; hepatosteatosis) in obesity has been linked to the worsening of the metabolic syndrome, including the development of insulin resistance and cardiovascular disease. Currently, there are few options to treat NAFLD, including life style changes and insulin sensitizers. Recent evidence suggests that the cannabinoids Δ(9)-tetrahydrocannabivarin (THCV) and cannabidiol (CBD) improve insulin sensitivity; we aimed at studying their effects on lipid levels. METHODS: The effects of THCV and CBD on lipid levels were examined in a variety of in vitro and in vivo systems, with special emphasis on models of hepatosteatosis. Transcriptional, post-translational and metabolomic changes were assayed. RESULTS: THCV and CBD directly reduce accumulated lipid levels in vitro in a hepatosteatosis model and adipocytes. Nuclear magnetic resonance- (NMR) based metabolomics confirmed these results and further identified specific metabolic changes in THCV and CBD-treated hepatocytes. Treatment also induced post-translational changes in a variety of proteins such as CREB, PRAS40, AMPKa2 and several STATs indicating increased lipid metabolism and, possibly, mitochondrial activity. These results are supported by in vivo data from zebrafish and obese mice indicating that these cannabinoids are able to increase yolk lipid mobilization and inhibit the development of hepatosteatosis respectively. CONCLUSIONS: Our results suggest that THCV and CBD might be used as new therapeutic agents for the pharmacological treatment of obesity- and metabolic syndrome-related NAFLD/hepatosteatosis.