TRAIL (TNF-related apoptosis-inducing ligand) regulates adipocyte metabolism by caspase-mediated cleavage of PPARgamma.
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.
Division of Pediatric Endocrinology, Diabetes and Obesity Unit, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
M
M
Keuper
I
I
Wernstedt Asterholm
P E
PE
Scherer
M-A
MA
Westhoff
P
P
Möller
K-M
KM
Debatin
G
G
Strauss
M
M
Wabitsch
P
P
Fischer-Posovszky
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
D051275:Glucose Transporter Type 4; D007328:Insulin; D016328:NF-kappa B; D047495:PPAR gamma; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D064429:Fatty Acid Synthases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D053181:Caspase 8; D005947:Glucose