Foxo1 increases pro-inflammatory gene expression by inducing C/EBPbeta in TNF-alpha-treated adipocytes.

Obesity is associated with a low-grade inflammation in adipose tissue resulting from increased production of pro-inflammatory cytokines and which can subsequently contribute to the development of insulin resistance. However, the mechanisms underlying the transcriptional regulation of pro-inflammatory genes are still unclear. Here we show that tumor necrosis factor (TNF)-alpha treatment attenuated Akt-dependent phosphorylation of Foxo1 and enhanced transcriptional activity of Foxo1. We found that Foxo1 increased the expression of CCAAT/enhancer binding protein (C/EBPbeta, a positive regulator of monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 genes, through directly binding to its promoter. Furthermore, knockdown of Foxo1 as well as C/EBPbeta inhibits TNF-alpha-induced expression of MCP-1 and IL-6 in 3T3-L1 adipocytes. These findings suggest that activation of Foxo1 triggered by TNF-alpha up-regulates the expression of C/EBPbeta in 3T3-L1 adipocytes, thereby leading to an increased production of pro-inflammatory cytokines, MCP-1 and IL-6.