Abstract
Rimonabant has been shown to not only decrease the food intake and body weight but also to increase serum adiponectin levels. This increase of the serum adiponectin levels has been hypothesized to be related to the rimonabant-induced amelioration of insulin resistance linked to obesity, although experimental evidence to support this hypothesis is lacking. To test this hypothesis experimentally, we generated adiponectin knock-out (adipo(-/-))ob/ob mice. After 21 days of 30 mg/kg rimonabant, the body weight and food intake decreased to similar degrees in the ob/ob and adipo(-/-)ob/ob mice. Significant improvement of insulin resistance was observed in the ob/ob mice following rimonabant treatment, associated with significant up-regulation of the plasma adiponectin levels, in particular, of high molecular weight adiponectin. Amelioration of insulin resistance in the ob/ob mice was attributed to the decrease of glucose production and activation of AMP-activated protein kinase (AMPK) in the liver induced by rimonabant but not to increased glucose uptake by the skeletal muscle. Interestingly, the rimonabant-treated adipo(-/-)ob/ob mice also exhibited significant amelioration of insulin resistance, although the degree of improvement was significantly lower as compared with that in the ob/ob mice. The effects of rimonabant on the liver metabolism, namely decrease of glucose production and activation of AMPK, were also less pronounced in the adipo(-/-)ob/ob mice. Thus, it was concluded that rimonabant ameliorates insulin resistance via both adiponectin-dependent and adiponectin-independent pathways.
Highlights
Adiponectin is an adipokine that is and abundantly expressed in the adipose tissue and released into the circulation, which directly sensitizes the body to insulin [19, 20]
We reported that pioglitazone may induce amelioration of insulin resistance and diabetes via an adiponectin-dependent mechanism in the liver and an adiponectin-independent mechanism in the skeletal muscle [30]
We found that rimonabant significantly decreased the body weight and food intake to similar degrees in the ob/ob and adipo(Ϫ/Ϫ)ob/ob mice
Summary
Rimonabant has been shown to decrease the food intake and body weight and to increase serum adiponectin levels. Amelioration of insulin resistance in the ob/ob mice was attributed to the decrease of glucose production and activation of AMP-activated protein kinase (AMPK) in the liver induced by rimonabant but not to increased glucose uptake by the skeletal muscle. Whether the rimonabant-induced increase in the plasma levels of adiponectin might be causally involved in the effects of rimonabant, in particular its insulin-sensitizing effects, has not been addressed experimentally To address this issue, in the present study, we used adipo(Ϫ/Ϫ)ob/ob mice [30] to investigate whether rimonabant might be capable of ameliorating insulin resistance in the absence of adiponectin. The results suggest that rimonabant ameliorates insulin resistance via both adiponectin-dependent and adiponectin-independent pathways
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