TRAIL (TNF-related apoptosis-inducing ligand) regulates adipocyte metabolism by caspase-mediated cleavage of PPARgamma.

M. Keuper, I. Wernstedt Asterholm, P. E. Scherer, M. A. Westhoff, P. Möller, K. M. Debatin, G. Strauss, M. Wabitsch, P. Fischer-Posovszky

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Tumor necrosis factor α (TNFα) and other members of the TNF family affect adipose tissue metabolism and contribute to the obesity-related inflammation of adipose tissue. Here, we sought to identify the effects of TRAIL (TNF-related apoptosis-inducing ligand) on fat cell biology. TRAIL-receptor 2 (TRAIL-R2) and its mouse homolog DR5 were regulated upon acute and chronic energy imbalance in murine and human adipose tissue. TRAIL inhibited insulin-stimulated glucose uptake and de novo lipogenesis in human adipocytes. Interestingly, TRAIL did not interfere with the phosphorylation of insulin-stimulated kinases such as Akt or Erk and did not activate the NF-κB pathway. Instead, TRAIL activated cleavage of caspase-8 and caspase-3. The subsequent cleavage of PPARγ led to its inactivation and resulted in reduced expression of lipogenic genes, such as Glut-4, FASN, and ACC. Taken together, we discovered a so far unknown function of the death ligand TRAIL in regulating adipocyte metabolism. Our results imply that TRAIL/TRAIL-R system might provide a new target for the prevention and treatment of obesity and its co-morbidities.

Original languageEnglish (US)
JournalUnknown Journal
Volume4
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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    Keuper, M., Wernstedt Asterholm, I., Scherer, P. E., Westhoff, M. A., Möller, P., Debatin, K. M., Strauss, G., Wabitsch, M., & Fischer-Posovszky, P. (2013). TRAIL (TNF-related apoptosis-inducing ligand) regulates adipocyte metabolism by caspase-mediated cleavage of PPARgamma. Unknown Journal, 4. https://doi.org/10.1038/cddis.2012.212