Troglitazone Antagonizes Tumor Necrosis Factor-α-induced Reprogramming of Adipocyte Gene Expression by Inhibiting the Transcriptional Regulatory Functions of NF-κB

Troglitazone (TGZ), a member of the thiazolidinedione class of anti-diabetic compounds and a peroxisome proliferator activator receptor-γ (PPAR-γ) 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-γ and NF-κB in adipocytes. We show that TGZ selectively blocked tumor necrosis factor-α-induced and NF-κB-dependent repression of multiple adipocyte-specific genes and induction of growth phase and other genes. This occurs without interfering with NF-κB expression, activation, nuclear translocation, or DNA binding and without suppressing NF-κB-dependent survival signals. Notably, the expressions of some tumor necrosis factor-α-induced genes in adipocytes were unaffected by PPAR-γ activation. In reporter gene assays in HeLa cells, ectopic expression of PPAR-γ abolished induction of a NF-κB-responsive reporter gene by the p65 subunit (RelA) of NF-κB, and the inhibition was further enhanced in the presence of TGZ. Conversely, overexpression of p65 inhibited induction of a PPAR-γ-responsive reporter gene by activated PPAR-γ in a dose-dependent manner. The inhibitory effect was independent of the presence of NF-κB-binding sites in the promoter region. Other NF-κB family members, p50 and c-Rel as well as the S276A mutant of p65, blocked PPAR-γ-mediated gene transcription less effectively. Thus, p65 antagonizes the transcriptional regulatory activity of PPAR-γ in adipocytes, and PPAR-γ 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-κB activity is a mechanism by which PPAR-γ agonists improve insulin sensitivity in vivo and that adipocyte NF-κB is a potential therapeutic target for obesity-linked type 2 diabetes.