TNF-α inhibits PPARβ/δ activity and SIRT1 expression through NF-κB in human adipocytes

The mechanisms linking low-grade chronic inflammation with obesity-induced insulin resistance have only been partially elucidated. PPAR beta/delta 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-alpha and IL-6 compared to control subjects. Inflammation was accompanied by a reduction in the levels of SIRT1 protein and an increase in PPAR beta/delta mRNA levels. Stimulation of human mature SGBS adipocytes with TNF-alpha caused similar changes in PPAR beta/delta and SIRT1 to those reported in obese patients. Unexpectedly, PPAR DNA-binding activity and the expression of PPAR beta/delta-target genes was reduced following TNF-alpha stimulation, suggesting that the activity of this transcription factor was inhibited by cytokine treatment. Interestingly, the PPAR beta/delta ligand GW501516 prevented the expression of inflammatory markers and the reduction in the expression of PPAR beta/delta-target genes in adipocytes stimulated with TNF-alpha. Consistent with a role for NF-kappa B in the changes caused by TNF-alpha, treatment with the NF-kappa B inhibitor parthenolide restored PPAR DNA-binding activity, the expression of PPAR beta/delta-target genes and the expression of SIRT1 and PPAR beta/delta. These findings suggest that the reduction in PPAR beta/delta activity and SIRT1 expression caused by TNF-alpha stimulation through NF-kappa B helps perpetuate the inflammatory process in human adipocytes. (C) 2012 Elsevier B.V. All rights reserved.