Division of Pediatric Endocrinology, Diabetes and Obesity Unit, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
Cell Death Dis. 2013 Jan 24;4(1):e474. doi: 10.1038/cddis.2012.212.
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.
肿瘤坏死因子 α（TNFα）和 TNF 家族的其他成员影响脂肪组织代谢，并导致与肥胖相关的脂肪组织炎症。在这里，我们试图确定 TRAIL（TNF 相关凋亡诱导配体）对脂肪细胞生物学的影响。TRAIL 受体 2（TRAIL-R2）及其小鼠同源物 DR5 在小鼠和人类脂肪组织的急性和慢性能量失衡中受到调节。TRAIL 抑制人脂肪细胞中胰岛素刺激的葡萄糖摄取和从头脂肪生成。有趣的是，TRAIL 不干扰胰岛素刺激的激酶如 Akt 或 Erk 的磷酸化，也不激活 NF-κB 途径。相反，TRAIL 激活了 caspase-8 和 caspase-3 的裂解。随后的 PPARγ 裂解导致其失活，并导致脂肪生成基因如 Glut-4、FASN 和 ACC 的表达减少。总之，我们发现了死亡配体 TRAIL 在调节脂肪细胞代谢中的一个迄今未知的功能。我们的结果表明，TRAIL/TRAIL-R 系统可能为肥胖及其合并症的预防和治疗提供新的靶点。
