Aim: The endocannabinoid system (ECS) is involved in various metabolic functions, such as nutrient transport and energy storage. The cannabinoid type 1 receptor (CB1R) inverse agonist rimonabant was identified and sold as an anti-obesity drug, but withdrawn from the market due to psychiatric side effects. Mechanistically, we have shown that rimonabant potentiates the sympathetic activation of brown fat. The aim of the current project is to provide proof that rimonabant attenuates dyslipidemia and atherosclerosis in APOE*3-Leiden.CETP transgenic mice, a well-established mouse model for human-like lipoprotein metabolism.

Methods: Female mice were fed a Western-type diet (containing 16% fat and 0.1% cholesterol) with or without supplementation of 0.017% w/w rimonabant. Body weight and food intake were monitored throughout the study. After 4 weeks, body composition was determined by echo-MRI, and plasma triglycerides (TG) and cholesterol were measured in 4h fasted plasma samples. In addition, we measured energy expenditure by means of indirect calorimetry.

Results: Rimonabant transiently reduced food intake, which normalized after 4 days of treatment, and reduced fat mass after 4 weeks of treatment (-48%, p<0.05). In addition, rimonabant reduced the respiratory quotient during the light period (0.80 vs. 0.82, p<0.01) indicative of increased fatty acid oxidation. As a consequence, rimonabant lowered plasma cholesterol (-31%, p<0.05) and TG (-49%, p<0.01).

Conclusion: In conclusion, rimonabant treatment of cholesterol-fed APOE*3-Leiden.CETP mice alleviates dyslipidemia, probably as a consequence of brown fat activation. Current experiments focus on investigating underlying mechanisms and studying the potential benefit of ECS modulation for atherosclerosis development. We hypothesize that modulating endocannabinoid synthesis and degradation enzymes provides a safe alternative for rimonabant, that can be used in the treatment of both metabolic and cardiovascular disorders.