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

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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)
Article numbere474
JournalCell death & disease
Volume4
DOIs
StatePublished - 2013

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TNF-Related Apoptosis-Inducing Ligand
PPAR gamma
Caspases
Adipocytes
Tumor Necrosis Factor-alpha
Apoptosis
Ligands
Adipose Tissue
Obesity
Insulin
TNF-Related Apoptosis-Inducing Ligand Receptors
Lipogenesis
Peroxisome Proliferator-Activated Receptors
Caspase 8
Caspase 3
Cell Biology
Phosphotransferases
Phosphorylation
Inflammation
Morbidity

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Keuper, M., Wernstedt Asterholm, I., Scherer, P. E., Westhoff, M. A., Möller, P., Debatin, K. M., ... Fischer-Posovszky, P. (2013). TRAIL (TNF-related apoptosis-inducing ligand) regulates adipocyte metabolism by caspase-mediated cleavage of PPARgamma. Cell death & disease, 4, [e474]. https://doi.org/10.1038/cddis.2012.212

TRAIL (TNF-related apoptosis-inducing ligand) regulates adipocyte metabolism by caspase-mediated cleavage of PPARgamma. / Keuper, M.; Wernstedt Asterholm, I.; Scherer, P. E.; Westhoff, M. A.; Möller, P.; Debatin, K. M.; Strauss, G.; Wabitsch, M.; Fischer-Posovszky, P.

In: Cell death & disease, Vol. 4, e474, 2013.

Research output: Contribution to journalArticle

Keuper, M, Wernstedt Asterholm, I, Scherer, PE, Westhoff, MA, Möller, P, Debatin, KM, Strauss, G, Wabitsch, M & Fischer-Posovszky, P 2013, 'TRAIL (TNF-related apoptosis-inducing ligand) regulates adipocyte metabolism by caspase-mediated cleavage of PPARgamma.', Cell death & disease, vol. 4, e474. https://doi.org/10.1038/cddis.2012.212
Keuper, M. ; Wernstedt Asterholm, I. ; Scherer, P. E. ; Westhoff, M. A. ; Möller, P. ; Debatin, K. M. ; Strauss, G. ; Wabitsch, M. ; Fischer-Posovszky, P. / TRAIL (TNF-related apoptosis-inducing ligand) regulates adipocyte metabolism by caspase-mediated cleavage of PPARgamma. In: Cell death & disease. 2013 ; Vol. 4.
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