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Biochim Biophys Acta. 2012 Sep;1821(9):1177-85. doi: 10.1016/j.bbalip.2012.05.006. Epub 2012 Jun 7.

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

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Department of Pharmacology and Therapeutic Chemistry, University of Barcelona, Barcelona, Spain.


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

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