TNF-a inhibits PPARß/d activity and SIRT1 expression through NF-?B in human adipocytes.
Por:
Serrano-Marco L, Chacón MR, Maymó-Masip E, Barroso E, Salvadó L, Wabitsch M, Garrido-Sánchez L, Tinahones FJ, Palomer FX, Vendrell J and Vazquez M
Publicada:
1 sep 2012
Resumen:
The mechanisms linking low-grade chronic inflammation with obesity-induced insulin resistance have only been partially elucidated. PPARß/d and SIRT1 might play a role in this association. In visceral adipose tissue (VAT) from obese insulin-resistant patients we observed enhanced p65 nuclear translocation and elevated expression of the pro-inflammatory cytokines TNF-a and IL-6 compared to control subjects. Inflammation was accompanied by a reduction in the levels of SIRT1 protein and an increase in PPARß/d mRNA levels. Stimulation of human mature SGBS adipocytes with TNF-a caused similar changes in PPARß/d and SIRT1 to those reported in obese patients. Unexpectedly, PPAR DNA-binding activity and the expression of PPARß/d-target genes was reduced following TNF-a stimulation, suggesting that the activity of this transcription factor was inhibited by cytokine treatment. Interestingly, the PPARß/d ligand GW501516 prevented the expression of inflammatory markers and the reduction in the expression of PPARß/d-target genes in adipocytes stimulated with TNF-a. Consistent with a role for NF-?B in the changes caused by TNF-a, treatment with the NF-?B inhibitor parthenolide restored PPAR DNA-binding activity, the expression of PPARß/d-target genes and the expression of SIRT1 and PPARß/d. These findings suggest that the reduction in PPARß/d activity and SIRT1 expression caused by TNF-a stimulation through NF-?B helps perpetuate the inflammatory process in human adipocytes.
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