Adi Eitan, Ofer Gover and Prof. Betty Schwartz

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith, Faculty of Agriculture, Food and Environment, Hebrew University of Jerusalem, Rehovot 7610001; Israel

Obesity is associated with several metabolic impairments such as insulin resistance, non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and cancer. It is well established that the endocannabinoid system (ECS) is involved in regulating energy balance and the development of obesity, making it a compelling target for obesity treatment. Previous reports have shown the capability of exogenous cannabinoid receptor ligands i.e., phytocannabinoids from the plant Cannabis sativa, in reducing weight gain and improving metabolic complications in rodent obesity models. However, limited studies have evaluated per-os administration in obesity models and even fewer compared the two major phytocannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Moreover, there is insufficient evidence on the role they play in liver steatosis, a vital contributor to obesity-induced metabolic dysregulation. Our objective is to investigate the therapeutic effect of chronically per-os administration of purified forms of the phytocannabinoids on obesity and related comorbidities, with emphasis on liver steatosis. In our murine diet-induced obesity model, we considered the onset of tolerance in chronic cannabis consumption by increasing the dose of the cannabis treatments during our experiment. We demonstrated an opposite biphasic effect of THC on weight gain and glucose-tolerance at the different dose-concentrations, suggesting a unique effect of THC when inducing tolerance.  At the end of the treatment regime, mice treated with purified THC exhibited significantly reduced weight gain and markedly improved glucose tolerance, followed by distinct improvement in steatosis markers. In contrast, treatment with CBD showed only a dose-dependent improvement on glucose tolerance regardless of weight gain and steatosis markers. In-vitro model of steatosis with human and murine hepatocyte cell lines demonstrate direct affect of THC tolerance on reduction of steatosis markers. Our findings suggest that the therapeutic effect of THC was not mediated by the modulation of the endocannabinoid system, but rather alteration of gene expression associated with lipid formation and oxidation.