Objectives:
The endocannabinoid system is an important player in energy metabolism by regulating 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. Brown adipose tissue (BAT) that burns lipids towards heat using UCP1, recently emerged as a major player in lipoprotein metabolism and is present and active in human adults. The aim of the present study was to elucidate the mechanism by which CB1R blockade reverses dyslipidemia and obesity, with special focus on BAT.
Methods and results:
Diet-induced obese
APOE*3-Leiden.CETP
transgenic mice, a well-established model for human-like lipoprotein metabolism, were treated with the systemic CB1R blocker rimonabant (10 mg/kg/day) for 4 weeks. Rimonabant persistently decreased body weight (-25%, p<0.001), fat mass (-32%, p<0.001) and plasma triglyceride (TG) levels (-60%, p<0.05), despite a modest and transient reduction in food intake. Interestingly, rimonabant reduced plasma TG levels, not by affecting VLDL-TG production by the liver, but rather by selectively increasing VLDL-TG clearance by BAT (+40%, p<0.05). This was accompanied by increased energy expenditure (+20%, p<0.05), decreased lipid droplet size and increased UCP1 content in BAT (+28%, p<0.05), all pointing to increased BAT activity. Next, we demonstrated that the CB1R is highly expressed in BAT and that
in vitro
blockade of the CB1R in cultured brown adipocytes resulted in 2.5-fold upregulation of UCP1. Importantly, the
in vivo
results could be fully recapitulated using the strictly peripheral CB1R antagonist AM6545 (10 mg/kg/day) that does not induce hypophagia.
Conclusion:
CB1R blockade reduces dyslipidemia and obesity by peripheral activation of BAT. Selective targeting of peripheral CB1R in BAT has thus great therapeutic potential in decreasing dyslipidemia and obesity and ultimately cardiovascular diseases.
β-Adrenergic Receptor Blockade Does Not Inhibit Cold-Induced Thermogenesis in Humans: Possible Involvement of Brown Adipose Tissue
