Insulin regulates TRB3 and other stress-responsive gene expression through induction of C/EBPbeta.

Pseudokinase TRB3 is an inducible gene whose expression is regulated by stress response and insulin and associated with insulin resistance and metabolic syndrome. In this report, we have investigated the mechanism under which insulin regulates TRB3 gene expression and demonstrated that insulin induces TRB3 expression via C/EBPbeta. We found that in Fao hepatoma and 3T3-L1 adipocytes, C/EBPbeta expression induced by insulin preceded that of TRB3 and that mutation of the C/EBPbeta binding site in TRB3 promoter abolished the responsiveness of the TRB3 gene to insulin. We further showed that ectopic expression of C/EBPbeta augmented, whereas knockdown of C/EBPbeta reduced, TRB3 expression induced by insulin. In addition, we presented data to show that insulin, through a similar mechanism under which insulin induces TRB3 expression, promotes the expression of genes such as ANAS, ATF3, BIP, and CHOP, which are typical stress-responsive genes. We also examined the impact of C/EBPbeta expression on Akt activation and found that inaction of C/EBPbeta not only augmented Akt activation but also obliterated the suppression of Akt activation due to prolonged insulin stimulation. We suggest, through induction of C/EBPbeta in hepatic cells and adipocytes, that insulin induces the expression of stress-responsive genes, which may represent a novel insulin action.