Lundberg Laboratory for Diabetes Research, Center of Excellence for Metabolic and Cardiovascular Research, Department of Molecular and Clinical Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg 413 45, Sweden.
J Biol Chem. 2010 Apr 30;285(18):14031-41. doi: 10.1074/jbc.M110.102855. Epub 2010 Feb 23.
Canonical Wnt ligands are secreted by several cell types in the adipose tissue. We examined if mature adipocytes can also be target cells and found that canonical Wnt activation by Wnt3a induced a marked dedifferentiation of both 3T3-L1 and human adipocytes. Typical adipogenic markers were reduced while undifferentiated cell markers like Pref-1/Dlk1, Wnt10b, and Gata2 were increased. The cells also became insulin-resistant with impaired upstream insulin signaling and reduced glucose uptake. Wnt3a stabilized beta-catenin in the absence of the LRP6 receptor and with maintained axin and Dickkopf-1 protein expression. PPARgamma was repressed and PPARgamma ligands could not restore the adipogenic markers or reduce the beta-catenin levels. The dedifferentiated adipocytes expressed the myofibroblast marker alpha-smooth muscle actin and were also susceptible to osteogenic transdifferentiation. These results identify a novel pathway in mature adipose cells that is critical for maintaining the normal adipocyte phenotype and insulin sensitivity.
经典 Wnt 配体由脂肪组织中的几种细胞类型分泌。我们研究了成熟的脂肪细胞是否也可以成为靶细胞，结果发现 Wnt3a 激活经典 Wnt 通路可显著诱导 3T3-L1 和人脂肪细胞去分化。典型的脂肪生成标记物减少，而未分化细胞标记物如 Pref-1/Dlk1、Wnt10b 和 Gata2 增加。细胞对胰岛素也产生抵抗，上游胰岛素信号受损，葡萄糖摄取减少。Wnt3a 在没有 LRP6 受体的情况下稳定了β-连环蛋白，同时保持了轴蛋白和 Dickkopf-1 蛋白的表达。PPARγ 受到抑制，PPARγ 配体不能恢复脂肪生成标记物或降低β-连环蛋白水平。去分化的脂肪细胞表达肌成纤维细胞标记物α-平滑肌肌动蛋白，并且也容易发生成骨细胞转分化。这些结果确定了成熟脂肪细胞中一种新的通路，对于维持正常脂肪细胞表型和胰岛素敏感性至关重要。
