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.
Ito
Yu
Y
Center for Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.
Daitoku
Hiroaki
H
Fukamizu
Akiyoshi
A
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics*; D051379:Mice; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D022782:CCAAT-Enhancer-Binding Protein-beta; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt