CREB/GSK-3β signaling pathway regulates the expression of TR4 orphan nuclear receptor gene

•Glucose regulates TR4 expression in 3T3-L1 preadipocytes through the GSK-3β–CREB pathway.•GSK-3β enhances CREB stimulation of TR4 expression in 3T3-L1 preadipocytes.•CREB stimulates TR4 expression by binding to the CRE in the murine TR4 5′ promoter.•Knockdown of TR4 reduces CREB-induced lipogenesis in 3T3-L1 adipocytes.

In this study, we show that reduction of glucose concentration increases TR4 expression in 3T3-L1 cells via stimulation of the GSK-3β–CREB pathway. While GSK-3β and CREB increased TR4 expression in 3T3-L1 cells, inhibition of CREB expression or activity resulted in loss of GSK-3β-mediated enhancement of TR4 expression. In addition, CREB enhanced murine TR4 promoter activity via direct binding to a cAMP response element located in the promoter, and this CREB effect was further strengthened by GSK-3β. Moreover, silencing of TR4 expression by a gene-specific microRNA inhibited CREB-induced lipid accumulation in 3T3-L1 adipocytes, suggesting that TR4 could be a key mediator of CREB-induced lipogenesis.