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Dual Regulation of Glucose Homeostasis by the Adaptor Proteins Nck

Nck1 and Nck2 adaptor proteins mediate intracellular signaling from activated plasma membrane receptor tyrosine kinases. Previous studies reported that the Nck expression levels vary with insulin sensitivity, suggesting a role for Nck in regulating insulin signaling. We previously showed that Nck1−/− mice fed a high fat diet (HFD) display better glucose disposal ability and hepatic insulin signaling compared with HFD insulin resistant Nck1+/+ littermates. In fact, we found that Nck1 interacts with and mediates signaling from IRE1α, an important component of the Unfolded Protein Response that inhibits insulin signaling by inducing JNK‐dependent phosphorylation of the insulin receptor substrate 1 (IRS‐1) on an inhibitory site. In contrast, we observed that Nck2−/− mice fed a normal chow diet (NCD) or a high fat diet (HFD) display greater glucose intolerance and insulin resistance compared to Nck2+/+ littermates mice. In agreement, we found decreased insulin‐induced hepatic Akt phosphorylation/activation in NCD Nck2−/− mice compared with their littermate controls. All together, our data provide strong evidence that the two Nck adaptors have distinct role in modulating insulin signaling in vivo. Further studies are in progress to define the mechanisms by which Nck differentially regulate glucose homeostasis. Work supported by CIHR and CDA. JD holds a FRSQ postdoctoral fellowship.