Tumour necrosis factor-alpha inhibits adipogenesis via a beta-catenin/TCF4(TCF7L2)-dependent pathway.
Tumour necrosis factor-alpha inhibits adipogenesis via a beta-catenin/TCF4(TCF7L2)-dependent pathway.
复制标题
DOI：
10.1038/sj.cdd.4402127
复制
发表时间：
2007-07
影响因子：
12.4
通讯作者：
Sethi, J. K.
中科院分区：
文献类型：
--
作者：
Cawthorn, W. P.;Heyd, F.;Hegyi, K.;Sethi, J. K.
肿瘤坏死因子-α（TNF-α）是一种促炎细胞因子，是脂肪细胞分化的有效负调节因子。然而，TNF-α介导的抗脂肪形成的机制仍不完全清楚。在本研究中，我们首先证实TNF-α通过阻止脂肪形成转录因子过氧化物酶体增殖物激活受体-γ（PPARγ）和CCAAT/增强子结合蛋白-α（C/EBPα）的早期诱导来抑制3 T3-L1前脂肪细胞的脂肪形成。这种抑制与几种已报道的抗脂肪生成介质的表达增强一致，这些介质也是Wnt/β-连环蛋白/T细胞因子4（TCF 4）通路的靶点。事实上，我们发现TNF-α在早期抗脂肪形成过程中增强了TCF 4依赖的转录活性，并在整个抗脂肪形成过程中促进了β-连环蛋白的稳定。我们分析了TNF-α对3 T3-L1细胞中脂肪形成的影响，在3 T3-L1细胞中，β-连环蛋白/TCF信号传导受损，通过稳定敲除β-连环蛋白或过表达显性负性TCF 4（dnTCF 4）。β-catenin的敲低增强了3 T3-L1前脂肪细胞的成脂潜能，并减弱了TNF-α诱导的抗脂肪生成作用。然而，β-catenin敲低也促进了TNF-α诱导的这些细胞的凋亡。相反，过表达dnTCF 4阻止了TNF-α诱导的抗脂肪生成，但对细胞存活没有明显影响。最后，我们发现TNF-α诱导的抗脂肪生成和β-连环蛋白的稳定需要TNF-α受体1（TNFR 1）的功能性死亡结构域。总而言之，这些数据表明TNFR 1介导的死亡结构域信号可以通过β-连环蛋白/TCF 4依赖性途径抑制脂肪形成。
Tumour necrosis factor-α (TNF-α), a proinflammatory cytokine, is a potent negative regulator of adipocyte differentiation. However, the mechanism of TNF-α-mediated antiadipogenesis remains incompletely understood. In this study, we first confirm that TNF-α inhibits adipogenesis of 3T3-L1 preadipocytes by preventing the early induction of the adipogenic transcription factors peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT/enhancer binding protein-α (C/EBPα). This suppression coincides with enhanced expression of several reported mediators of antiadipogenesis that are also targets of the Wnt/β-catenin/T-cell factor 4 (TCF4) pathway. Indeed, we found that TNF-α enhanced TCF4-dependent transcriptional activity during early antiadipogenesis, and promoted the stabilisation of β-catenin throughout antiadipogenesis. We analysed the effect of TNF-α on adipogenesis in 3T3-L1 cells in which β-catenin/TCF signalling was impaired, either via stable knockdown of β-catenin, or by overexpression of dominant-negative TCF4 (dnTCF4). The knockdown of β-catenin enhanced the adipogenic potential of 3T3-L1 preadipocytes and attenuated TNF-α-induced antiadipogenesis. However, β-catenin knockdown also promoted TNF-α-induced apoptosis in these cells. In contrast, overexpression of dnTCF4 prevented TNF-α-induced antiadipogenesis but showed no apparent effect on cell survival. Finally, we show that TNF-α-induced antiadipogenesis and stabilisation of β-catenin requires a functional death domain of TNF-α receptor 1 (TNFR1). Taken together these data suggest that TNFR1-mediated death domain signals can inhibit adipogenesis via a β-catenin/TCF4-dependent pathway.
登录
查看更多内容
DOI：
10.1210/me.2005-0536
发表时间：
2006-08
期刊：
Molecular endocrinology (Baltimore, Md.)
影响因子：
--
作者：
Nawaratne R;Gray A;Jørgensen CH;Downes CP;Siddle K;Sethi JK
通讯作者：
Sethi JK
影响因子：
4.8
作者：
Gustafson, B;Smith, U
通讯作者：
Smith, U
影响因子：
4.8
作者：
Fu, MF;Rao, M;Pestell, RG
通讯作者：
Pestell, RG
影响因子：
3.7
作者：
Castro-Muñozledo, F;Beltrán-Langarica, A;Kuri-Harcuch, W
通讯作者：
Kuri-Harcuch, W
DOI：
10.1073/pnas.90.20.9611
发表时间：
1993-10-15
影响因子：
11.1
作者：
NINOMIYATSUJI, J;TORTI, FM;RINGOLD, GM
通讯作者：
RINGOLD, GM