CANNABINOID 1 RECEPTOR BLOCKADE DIMINISHES OBESITY AND DYSLIPIDEMIA VIA PERIPHERAL ACTIVATION OF BROWN ADIPOSE TISSUE

The endocannabinoid system is an important player in energy metabolism by regu-lating appetite, lipolysis and energy expenditure. Chronic blockade of the cannabinoid 1 receptor (CB1R) leads to long-term maintained weight loss and reduction of dyslipidemia in experimental and human obesity. The molecular mechanism by which CB1R blockade reverses dyslipidemia in obesity has not been clarified yet. In this study, we show that systemic CB1R blockade by rimonabant in a diet-induced obese mouse model for human-like lipoprotein metabolism reversed obesity, increased energy expenditure and lowered plasma VLDL-triglycerides (TG). Mechanistic studies showed that rimonabant selectively increased VLDL-TG clearance by brown adipose tissue (BAT) accompanied by decreased lipid droplet size in BAT. Of note, the mechanism involved peripheral activation of BAT since the effects were still present at thermoneutral temperature at which sympathetic output towards BAT is negligible and could be fully recapitulated by using the strictly peripheral CB1R antagonist AM6545. In support, we demonstrate that the CB1R is highly expressed in BAT and that in vitro blockade of the CB1R in cultured brown adipocytes increased UCP-1 content and lipolysis. Our data indicate that selective targeting of the peripheral CB1R in BAT has therapeutic potential in attenuating dyslipidemia and obesity.