Signaling mechanisms underlying the insulin-sensitizing effects of adiponectin

Adiponectin is an insulin-sensitizing adipokine with protective effects against a cluster of obesity-related metabolic and cardiovascular disorders. The adipokine exerts its insulin-sensitizing effects by alleviation of obesity-induced ectopic lipid accumulation, lipotoxicity and chronic inflammation, as well as by direct cross-talk with insulin signaling cascades. Adiponectin and insulin signaling pathways converge at the adaptor protein APPL1. On the one hand, APPL1 interacts with adiponectin receptors and mediates both metabolic and vascular actions of adiponectin through activation of AMP-activated protein kinase and p38 MAP kinase. On the other hand, APPL1 potentiates both the actions and secretion of insulin by fine-tuning the Akt activity in multiple insulin target tissues. In obese animals, reduced APPL1 expression contributes to both insulin resistance and defective insulin secretion. This review summarizes recent advances on the molecular mechanisms by which adiponectin sensitizes insulin actions, and discusses the roles of APPL1 in regulating both adiponectin and insulin signaling cascades.