STANDARD_NAME RUAN_RESPONSE_TO_TNF_UP SYSTEMATIC_NAME M1512 COLLECTION C2:CGP MSIGDB_URL https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/RUAN_RESPONSE_TO_TNF_UP NAMESPACE MOUSE_SEQ_ACCESSION DESCRIPTION_BRIEF Adipocyte abundant genes up-regulated in 3T3-L1 cells (fibroblasts induced to differentiate to adipocytes) in response to TNF [GeneID=7124]. DESCRIPTION_FULL Troglitazone (TGZ), a member of the thiazolidinedione class of anti-diabetic compounds and a peroxisome proliferator activator receptor-gamma (PPAR-gamma) agonist, restores systemic insulin sensitivity and improves the full insulin resistance syndrome in vivo. The mechanisms underlying its in vivo function are not understood. Here we investigated the potential functional interaction between PPAR-gamma and NF-kappaB in adipocytes. We show that TGZ selectively blocked tumor necrosis factor-alpha-induced and NF-kappaB-dependent repression of multiple adipocyte-specific genes and induction of growth phase and other genes. This occurs without interfering with NF-kappaB expression, activation, nuclear translocation, or DNA binding and without suppressing NF-kappaB-dependent survival signals. Notably, the expressions of some tumor necrosis factor-alpha-induced genes in adipocytes were unaffected by PPAR-gamma activation. In reporter gene assays in HeLa cells, ectopic expression of PPAR-gamma abolished induction of a NF-kappaB-responsive reporter gene by the p65 subunit (RelA) of NF-kappaB, and the inhibition was further enhanced in the presence of TGZ. Conversely, overexpression of p65 inhibited induction of a PPAR-gamma-responsive reporter gene by activated PPAR-gamma in a dose-dependent manner. The inhibitory effect was independent of the presence of NF-kappaB-binding sites in the promoter region. Other NF-kappaB family members, p50 and c-Rel as well as the S276A mutant of p65, blocked PPAR-gamma-mediated gene transcription less effectively. Thus, p65 antagonizes the transcriptional regulatory activity of PPAR-gamma in adipocytes, and PPAR-gamma activation can at least partially override the inhibitory effects of p65 on the expression of key adipocyte genes. Our data suggest that inhibition of NF-kappaB activity is a mechanism by which PPAR-gamma agonists improve insulin sensitivity in vivo and that adipocyte NF-kappaB is a potential therapeutic target for obesity-linked type 2 diabetes. PMID 12732648 GEOID AUTHORS Ruan H,Pownall HJ,Lodish HF CONTRIBUTOR John Newman CONTRIBUTOR_ORG University of Washington EXACT_SOURCE Table 1: Fold-TNFa >= 1.3 FILTERED_BY_SIMILARITY EXTERNAL_NAMES_FOR_SIMILAR_TERMS EXTERNAL_DETAILS_URL SOURCE_MEMBERS AJ007970,AL078630,L35528,M27134,M28233,M64086,M69069,M96827,U06924,U49430,U60091,U89915,X00246,X53929,X75926,X95279,Y00629 GENE_SYMBOLS GBP2,OR2H2,,,IFNGR1,SERPINA3,HLA-B,HP,STAT1,CP,TAP2,,HLA-B,DCN,ABCA1,THRSP,HLA-E FOUNDER_NAMES