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TNF-alpha inhibits UCP-1 expression in brown adipocytes via ERKs. Opposite effect of p38MAPK

A Valladares1, C Roncero, M Benito

  • 1Departamento de Bioquímica y Biología Molecular II, Instituto de Bioquímica (Centro Mixto del Consejo Superior de Investigaciones Científicas (C.S.I.C.) y de la Universidad Complutense de Madrid (U.C.M.)), Madrid, Spain.

FEBS Letters
|March 30, 2001
PubMed

Insights

Tumor necrosis factor-alpha (TNF-alpha) inhibits brown adipocyte gene expression via ERK and p38MAPK pathways. These pathways differentially regulate uncoupling protein-1 (UCP-1) and adipogenic genes, involving transcription factors.

Area of Science:

  • Cellular and Molecular Biology
  • Adipocyte Differentiation and Function
  • Signal Transduction Pathways

Background:

  • Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine with known effects on adipocytes.
  • Brown adipocytes are crucial for thermogenesis and energy expenditure, regulated by specific genes like UCP-1.
  • Mitogen-activated protein kinase (MAPK) pathways, including ERK and p38MAPK, are key signaling cascades in cellular responses.

Purpose of the Study:

  • To investigate the role of extracellular-regulated kinases (ERKs) and p38 mitogen-activated protein kinase (p38MAPK) in TNF-alpha-induced inhibition of gene expression in rat fetal brown adipocytes.
  • To elucidate the specific contributions of ERK and p38MAPK pathways to the regulation of uncoupling protein-1 (UCP-1) and adipocyte-specific genes.
  • To explore the involvement of transcription factors, such as C/EBPalpha and C/EBPbeta, in mediating TNF-alpha's effects.

Main Methods:

  • Primary culture of rat fetal brown adipocytes.
  • Treatment with TNF-alpha and specific inhibitors: PD98059 (MEK inhibitor) and SB203580 (p38MAPK inhibitor).
  • Analysis of UCP-1 and adipogenic gene expression.
  • Assessment of C/EBPalpha and C/EBPbeta protein levels and DNA binding activity.

Main Results:

  • TNF-alpha inhibited UCP-1 and adipogenic gene expression in brown adipocytes.
  • MEK inhibition (PD98059) blocked TNF-alpha's effect on UCP-1 but not on adipogenic genes.
  • p38MAPK inhibition (SB203580) potentiated TNF-alpha's inhibitory effects on both UCP-1 and adipogenic genes.
  • TNF-alpha's action was partly linked to altered C/EBPalpha/beta protein levels and DNA binding activity.

Conclusions:

  • ERK and p38MAPK pathways mediate TNF-alpha's inhibitory effects on brown adipocyte gene expression.
  • ERKs differentially regulate UCP-1 and adipogenic genes, suggesting distinct downstream mechanisms.
  • p38MAPK activation exacerbates TNF-alpha's inhibitory impact.
  • C/EBP transcription factors play a partial role, but other factors likely contribute to the differential gene regulation.

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