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

W P Cawthorn1, F Heyd, K Hegyi

  • 1Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.

Cell Death and Differentiation
|April 28, 2007
PubMed

Insights

Tumour necrosis factor-alpha (TNF-alpha) inhibits fat cell development by activating the Wnt/beta-catenin pathway. This pathway

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Tumour necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that negatively regulates adipocyte differentiation.
  • The precise molecular mechanisms underlying TNF-alpha-mediated antiadipogenesis are not fully elucidated.
  • Adipocyte differentiation is a complex process regulated by key transcription factors like PPARgamma and C/EBPalpha.

Purpose of the Study:

  • To investigate the role of the Wnt/beta-catenin/TCF4 pathway in TNF-alpha-induced inhibition of adipogenesis.
  • To determine the involvement of TNF-alpha receptor 1 (TNFR1) in TNF-alpha's antiadipogenic effects.

Main Methods:

  • Utilized 3T3-L1 preadipocytes to study adipocyte differentiation.
  • Employed stable knockdown of beta-catenin and overexpression of dominant-negative TCF4 (dnTCF4) to impair Wnt/beta-catenin/TCF4 signaling.
  • Assessed adipogenic potential, gene expression, beta-catenin stability, and apoptosis.
  • Investigated the role of TNF-alpha receptor 1 (TNFR1) using functional death domain analysis.

Main Results:

  • TNF-alpha inhibited 3T3-L1 adipogenesis by preventing PPARgamma and C/EBPalpha induction, correlating with enhanced Wnt/beta-catenin/TCF4 activity.
  • TNF-alpha promoted beta-catenin stabilization and TCF4-dependent transcription during adipogenesis.
  • Impairing beta-catenin/TCF4 signaling via knockdown or dnTCF4 overexpression modulated TNF-alpha's antiadipogenic effects and cell survival.
  • TNFR1's death domain is crucial for TNF-alpha-induced antiadipogenesis and beta-catenin stabilization.

Conclusions:

  • TNF-alpha inhibits adipocyte differentiation through a pathway involving TNFR1 and beta-catenin/TCF4 signaling.
  • TNFR1-mediated signals can suppress adipogenesis via the beta-catenin/TCF4 pathway.
  • Understanding this mechanism provides insights into the regulation of fat cell formation and potential therapeutic targets.

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