CB1R antagonist increases hepatic insulin clearance in fat-fed dogs likely via upregulation of liver adiponectin receptors.

The improvement of hepatic insulin sensitivity by the cannabinoid receptor 1 antagonist rimonabant (RIM) has been recently been reported to be due to upregulation of adiponectin. Several studies demonstrated that improvement in insulin clearance accompanies the enhancement of hepatic insulin sensitivity. However, the effects of RIM on hepatic insulin clearance (HIC) have not been fully explored. The aim of this study was to explore the molecular mechanism (s) by which RIM affects HIC, specifically to determine whether upregulation of liver adiponectin receptors (ADRs) and other key genes regulated by adiponectin mediate the effects. To induce insulin resistance in the skeletal muscle and the liver, dogs were fed a hypercaloric high-fat diet (HFD) for 6 weeks. Thereafter, while still maintained on a HFD, animals received either RIM (HFD+RIM; n=11) or placebo (HFD+PL; n=9) for an additional 16 weeks. HIC calculated as the metabolic clearance rate (MCR), was estimated from the euglycemic hyperinsulinemic clamp. HFD+PL group showed a decrease in MCR. In contrast, HFD+RIM group increased MCR. Consistently, the expression of genes involved in HIC, CEACAM1 and IDE as well as gene expression of liver ADRs, were increased in HFD+RIM group, but not in the HFD+PL group. We also found a positive correlation between CEACAM1 and IDE with ADRs. Interestingly, expression of liver genes regulated by adiponectin and involved in lipid oxidation were increased in the HFD+RIM group. We conclude that in fat-fed dogs, RIM enhances HIC, which appears to be linked to an upregulation of the adiponectin pathway.
Copyright © 2015, American Journal of Physiology – Endocrinology and Metabolism.