Metabolic and inflammatory functions of cannabinoid receptor type 1 are differentially modulated by adiponectin

BACKGROUND: Antagonists of cannabinoid type 1 receptor (CB1) have been shown to promote body weight loss and improve insulin sensitivity. Cannabinoids decrease adiponectin, and CB1 blocker increase adiponectin. However, the mediators of CB1 actions are not well defined. AIM: To investigate whether the beneficial effects of CB1 inhibition are, at least in part, mediated by adiponectin. METHODS: We compared metabolic and inflammatory phenotypes of wild-type (WT) mice, CB1-null (CB1(-/-)) and CB1/adiponectin double-knockout (DKO) mice. We assessed the insulin sensitivity using insulin tolerance test and glucose tolerance test, and inflammation using flow cytometry analysis of macrophages. RESULTS: CB1 (-/-) mice exhibited significantly reduced body weight and fat mass when compared to WT mice. While no significance was found in total daily food intake and locomotor activity, CB1(-/-) mice showed increased energy expenditure, enhanced thermogenesis in brown adipose tissue (BAT), and improved insulin sensitivity compared to WT mice. DKO showed no difference in body weight, adiposity, nor insulin sensitivity; only showed a modestly elevated thermogenesis in BAT compared to CB1(-/-) mice. The metabolic phenotype of DKO is largely similar to CB1(-/-) mice, suggesting that adiponectin is not a key mediator of the metabolic effects of CB1. Interestingly, CB1(-/-) mice showed reduced pro-inflammatory macrophage polarization in both peritoneal macrophages and adipose tissue macrophages compared to WT mice; in contrast, DKO mice exhibited increased pro-inflammatory macrophage polarization in these macrophages compared to CB1(-/-) mice, suggesting that adiponectin is an important mediator of the inflammatory effect of CB1. CONCLUSION: Our findings reveal that CB1 functions through both adiponectin-dependent and adiponectin-independent mechanisms: CB1 regulates energy metabolism in an adiponectin-independent manner, and inflammation in an adiponectin-dependent manner. The differential effects of adiponectin on CB1-mediated metabolic and inflammatory functions should be taken into consideration in CB1 antagonist utilization.