Aim: Recently endocannabinoid synthesis enzyme inhibitors have been developed that may provide novel treatment modalities to combat metabolic disorders. Here we provide proof-of-concept that inhibition of the endocannabinoid system not only reduce obesity but also counteract dyslipidemia and atherosclerosis development in a well-established mouse model for human-like lipoprotein metabolism.

Methods: Female APOE*3-Leiden.CETP transgenic mice were fed a Western-type diet (containing 16% fat and 0.15% cholesterol) with or without supplementation of the cannabinoid 1 receptor inverse agonist rimonabant (0.017% w/w) for 20 weeks. Throughout the study, body composition was determined by echo-MRI, and plasma triglycerides (TG), total cholesterol and HDL-cholesterol (HDL-C) were measured in 4h fasted plasma samples. In the aortic valve region, atherosclerotic lesions were scored.

Results: Rimonabant lowered body fat (-34%, p<0.05), plasma TG levels (-56%, p<0.001) and non-HDL-C exposure (-19%, p<0.05), and increased HDL-C exposure (+56%, p<0.001). Importantly, rimonabant prevented atherosclerotic lesion progression (-50% severe lesions, p<0.05) and reduced overall lesion area (-64%, p<0.01), which showed strong correlation with non-HDL-C exposure (R²=0.60, p<0.001).

Conclusion: In conclusion, inhibition of the endocannabinoid system in APOE*3-Leiden.CETP mice not only improves adiposity but also attenuates dyslipidemia and atherosclerosis. We anticipate that modulating endocannabinoid synthesis enzymes provides a novel tool in the treatment of both metabolic and cardiovascular disorders.