| First Author | Cawthorn WP | Year | 2007 |
| Journal | Cell Death Differ | Volume | 14 |
| Issue | 7 | Pages | 1361-73 |
| PubMed ID | 17464333 | Mgi Jnum | J:139288 |
| Mgi Id | MGI:3807650 | Doi | 10.1038/sj.cdd.4402127 |
| Citation | Cawthorn WP, et al. (2007) Tumour necrosis factor-alpha inhibits adipogenesis via a beta-catenin/TCF4(TCF7L2)-dependent pathway. Cell Death Differ 14(7):1361-73 |
| abstractText | Tumour necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, is a potent negative regulator of adipocyte differentiation. However, the mechanism of TNF-alpha-mediated antiadipogenesis remains incompletely understood. In this study, we first confirm that TNF-alpha inhibits adipogenesis of 3T3-L1 preadipocytes by preventing the early induction of the adipogenic transcription factors peroxisome proliferator-activated receptor-gamma (PPARgamma) and CCAAT/enhancer binding protein-alpha (C/EBPalpha). This suppression coincides with enhanced expression of several reported mediators of antiadipogenesis that are also targets of the Wnt/beta-catenin/T-cell factor 4 (TCF4) pathway. Indeed, we found that TNF-alpha enhanced TCF4-dependent transcriptional activity during early antiadipogenesis, and promoted the stabilisation of beta-catenin throughout antiadipogenesis. We analysed the effect of TNF-alpha on adipogenesis in 3T3-L1 cells in which beta-catenin/TCF signalling was impaired, either via stable knockdown of beta-catenin, or by overexpression of dominant-negative TCF4 (dnTCF4). The knockdown of beta-catenin enhanced the adipogenic potential of 3T3-L1 preadipocytes and attenuated TNF-alpha-induced antiadipogenesis. However, beta-catenin knockdown also promoted TNF-alpha-induced apoptosis in these cells. In contrast, overexpression of dnTCF4 prevented TNF-alpha-induced antiadipogenesis but showed no apparent effect on cell survival. Finally, we show that TNF-alpha-induced antiadipogenesis and stabilisation of beta-catenin requires a functional death domain of TNF-alpha receptor 1 (TNFR1). Taken together these data suggest that TNFR1-mediated death domain signals can inhibit adipogenesis via a beta-catenin/TCF4-dependent pathway. |
