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Troglitazone antagonizes tumor necrosis factor-alpha-induced reprogramming of adipocyte gene expression by inhibiting the transcriptional regulatory functions of NF-kappaB.
J Biol Chem. 2003 Jul 25; 278(30):28181-92.JB

Abstract

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.

Authors+Show Affiliations

Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12732648

Citation

Ruan, Hong, et al. "Troglitazone Antagonizes Tumor Necrosis Factor-alpha-induced Reprogramming of Adipocyte Gene Expression By Inhibiting the Transcriptional Regulatory Functions of NF-kappaB." The Journal of Biological Chemistry, vol. 278, no. 30, 2003, pp. 28181-92.
Ruan H, Pownall HJ, Lodish HF. Troglitazone antagonizes tumor necrosis factor-alpha-induced reprogramming of adipocyte gene expression by inhibiting the transcriptional regulatory functions of NF-kappaB. J Biol Chem. 2003;278(30):28181-92.
Ruan, H., Pownall, H. J., & Lodish, H. F. (2003). Troglitazone antagonizes tumor necrosis factor-alpha-induced reprogramming of adipocyte gene expression by inhibiting the transcriptional regulatory functions of NF-kappaB. The Journal of Biological Chemistry, 278(30), 28181-92.
Ruan H, Pownall HJ, Lodish HF. Troglitazone Antagonizes Tumor Necrosis Factor-alpha-induced Reprogramming of Adipocyte Gene Expression By Inhibiting the Transcriptional Regulatory Functions of NF-kappaB. J Biol Chem. 2003 Jul 25;278(30):28181-92. PubMed PMID: 12732648.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Troglitazone antagonizes tumor necrosis factor-alpha-induced reprogramming of adipocyte gene expression by inhibiting the transcriptional regulatory functions of NF-kappaB. AU - Ruan,Hong, AU - Pownall,Henry J, AU - Lodish,Harvey F, Y1 - 2003/05/05/ PY - 2003/5/7/pubmed PY - 2003/8/27/medline PY - 2003/5/7/entrez SP - 28181 EP - 92 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 278 IS - 30 N2 - 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. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/12732648/Troglitazone_antagonizes_tumor_necrosis_factor_alpha_induced_reprogramming_of_adipocyte_gene_expression_by_inhibiting_the_transcriptional_regulatory_functions_of_NF_kappaB_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=12732648 DB - PRIME DP - Unbound Medicine ER -