Tumour necrosis factor-alpha inhibits adipogenesis via a beta-catenin/TCF4(TCF7L2)-dependent pathway

W. P. Cawthorn, F. Heyd, K. Hegyi, J. K. Sethi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Tumour necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, is a potent negative regulator of adipocyte differentiation. However, the mechanism of TNF-alpha-mediated antiadipogenesis remains incompletely understood. In this study, we first confirm that TNF-alpha inhibits adipogenesis of 3T3-L1 preadipocytes by preventing the early induction of the adipogenic transcription factors peroxisome proliferator-activated receptor-gamma (PPARc) and CCAAT/ enhancer binding protein-alpha (C/EBP alpha). This suppression coincides with enhanced expression of several reported mediators of antiadipogenesis that are also targets of the Wnt/beta-catenin/T-cell factor 4 (TCF4) pathway. Indeed, we found that TNF-alpha enhanced TCF4-dependent transcriptional activity during early antiadipogenesis, and promoted the stabilisation of beta-catenin throughout antiadipogenesis. We analysed the effect of TNF-alpha on adipogenesis in 3T3-L1 cells in which beta-catenin/TCF signalling was impaired, either via stable knockdown of beta-catenin, or by overexpression of dominant-negative TCF4 (dnTCF4). The knockdown of beta-catenin enhanced the adipogenic potential of 3T3-L1 preadipocytes and attenuated TNF-alpha-induced antiadipogenesis. However, beta-catenin knockdown also promoted TNF-alpha-induced apoptosis in these cells. In contrast, overexpression of dnTCF4 prevented TNF-alpha-induced antiadipogenesis but showed no apparent effect on cell survival. Finally, we show that TNF-alpha-induced antiadipogenesis and stabilisation of beta-catenin requires a functional death domain of TNF-alpha receptor 1 (TNFR1). Taken together these data suggest that TNFR1-mediated death domain signals can inhibit adipogenesis via a beta-catenin/TCF4-dependent pathway.

Original languageEnglish
Pages (from-to)1361-1373
Number of pages13
JournalCell Death and Differentiation
Volume14
Issue number7
DOIs
Publication statusPublished - Jul 2007

Keywords

  • adipocyte differentiation
  • adipogenesis
  • Wnt signalling
  • TNF-alpha
  • beta-catenin
  • TCF4
  • TCF7L2
  • TNFR1
  • ACTIVATED RECEPTOR-GAMMA
  • C-MYC EXPRESSION
  • NF-KAPPA-B
  • BETA-CATENIN
  • ADIPOCYTE DIFFERENTIATION
  • PPAR-GAMMA
  • C/EBP-ALPHA
  • TNF
  • TRANSCRIPTION
  • CELLS

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