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. 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.
Department of Pharmacology and Therapeutic Chemistry, University of Barcelona, Barcelona, Spain.
Lucía
L
Serrano-Marco
Matilde R
MR
Chacón
Elsa
E
Maymó-Masip
Emma
E
Barroso
Laia
L
Salvadó
Martin
M
Wabitsch
Lourdes
L
Garrido-Sánchez
Francisco J
FJ
Tinahones
Xavier
X
Palomer
Joan
J
Vendrell
Manuel
M
Vázquez-Carrera
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000378:metabolism / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D047494:PPAR delta / Q000378:metabolism*; D048068:PPAR-beta / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology; D056564:Sirtuin 1 / Q000096:biosynthesis*; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C508600:IL6 protein, human; D015850:Interleukin-6; D047494:PPAR delta; D048068:PPAR-beta; C498143:RELA protein, human; D012717:Sesquiterpenes; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C002669:parthenolide; C447939:SIRT1 protein, human; D056564:Sirtuin 1