TY - JOUR
T1 - TRAIL (TNF-related apoptosis-inducing ligand) regulates adipocyte metabolism by caspase-mediated cleavage of PPARgamma.
AU - Keuper, M.
AU - Wernstedt Asterholm, I.
AU - Scherer, P. E.
AU - Westhoff, M. A.
AU - Möller, P.
AU - Debatin, K. M.
AU - Strauss, G.
AU - Wabitsch, M.
AU - Fischer-Posovszky, P.
N1 - Funding Information:
Acknowledgements. We thank Alexandra Killian and Susann Baumgart for excellent technical assistance. PFP is funded by a Margarete von Wrangell scholarship financed by the Baden-Wuerttemberg Ministry of Science, Research and Arts, the European Social Fund, and Ulm University. This study was partly supported by the German Research Association (FI 1700/1-1, WA 1096/3–2).
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
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U2 - 10.1038/cddis.2012.212
DO - 10.1038/cddis.2012.212
M3 - Article
C2 - 23348588
AN - SCOPUS:84878987176
SN - 1744-165X
VL - 4
JO - Unknown Journal
JF - Unknown Journal
ER -