Inducible overexpression of adiponectin receptors highlight the roles of adiponectin-induced ceramidase signaling in lipid and glucose homeostasis

Objective Adiponectin and the signaling induced by its cognate receptors, AdipoR1 and AdipoR2, have garnered attention for their ability to promote insulin sensitivity and oppose steatosis. Activation of these receptors promotes the deacylation of ceramide, a lipid metabolite that appears to play a causal role in impairing insulin signaling. Methods Here, we have developed transgenic mice that overexpress AdipoR1 or AdipoR2 under the inducible control of a tetracycline response element. These represent the first inducible genetic models that acutely manipulate adiponectin receptor signaling in adult mouse tissues, which allows us to directly assess AdipoR signaling on glucose and lipid metabolism. Results Overexpression of either adiponectin receptor isoform in the adipocyte or hepatocyte is sufficient to enhance ceramidase activity, whole body glucose metabolism, and hepatic insulin sensitivity, while opposing hepatic steatosis. Importantly, metabolic improvements fail to occur in an adiponectin knockout background. When challenged with a leptin-deficient genetic model of type 2 diabetes, AdipoR2 expression in adipose or liver is sufficient to reverse hyperglycemia and glucose intolerance. Conclusion These observations reveal that adiponectin is critical for AdipoR-induced ceramidase activation which enhances hepatic glucose and lipid metabolism via rapidly acting “cross-talk” between liver and adipose tissue sphingolipids.
Highlights • Adiponectin receptor signaling in adipose prompts beneficial effects on whole-body glucose and lipid metabolism. • The small molecule adiponectin receptor antagonist AdipoRon lowers hepatic ceramides. • Depletion of ceramides in adipocytes results in diminished hepatic ceramide accumulation. • Depletion of ceramides in hepatocytes results in diminished adipose sphingolipid accumulation. • Adiponectin is essential for the beneficial effects of adiponectin receptors on glucose, ceramide, and lipid metabolism.