Deletion of Nckl attenuates hepatic ER stress signaling and improves glucose tolerance and insulin signaling in liver of obese mice

摘要

Obesity has been shown to create stress in the endoplasmic reticulum (ER), and that initiates the activation of the unfolded protein response (UPR). This has been reported to cause insulin resistance in selective tissues through activation of the inosi-tol-requiring enzyme la (IREla)-c-Jun NH2-terminal kinase (JNK) pathway, which results in the phosphorylation of the insulin receptor substrate-1 (IRS-1) at an inhibitory site and blocks insulin receptor signaling. In this study, we report that the Sic homology domain-containing adaptor protein Nckl, previously shown to modulate the UPR, is of functional importance in obesity-induced ER stress signaling and inhibition of insulin actions. We have examined obese Nckl~!~ and Nckl+/+ mice for glucose tolerance, insulin sensitivity, and signaling as well as for ER stress markers and IRS-1 phosphorylation at Ser307. Our findings show that obese Nckl-deficient mice display improved glucose disposal accompanied by enhanced insulin signaling in liver. This correlates with attenuated IRE la and JNK activation and IRS-1 phosphorylation at Ser307 compared with obese wild-type mice. Consistent with our in vivo data, we report that downregulation of Nckl using siRNA in HepG2 cells results in decreased thapsigargin-induced IRE la activation and signaling and IRS-1 phosphorylation at Ser307, whereas it markedly enhances insulin signaling. Overall, in liver and in cultured cells, we show that depletion of Nckl attenuates the UPR signal and its inhibitory action on insulin signaling. Taken all together, our findings implicate Nckl in regulating the UPR, which secondary to obesity impairs glucose homeostasis and insulin actions.