Kennell Jennifer A, MacDougald Ormond A
Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0622, USA.
J Biol Chem. 2005 Jun 24;280(25):24004-10. doi: 10.1074/jbc.M501080200. Epub 2005 Apr 22.
Wnt signaling has been reported to block apoptosis and regulate differentiation of mesenchymal progenitors through inhibition of glycogen synthase kinase 3 and stabilization of beta-catenin. The effects of Wnt in preadipocytes may be mediated through Frizzled (Fz) 1 and/or Fz2 as these Wnt receptors are expressed in preadipocytes and their expression declines upon induction of differentiation. We ectopically expressed constitutively active chimeras between Wnt8 and Fz1 or Fz2 in preadipocytes and mesenchymal precursor cells. Our results indicated that activated Fz1 increases stability of beta-catenin, inhibits apoptosis, induces osteoblastogenesis, and inhibits adipogenesis. Although activated Fz2 does not influence apoptosis or osteoblastogenesis, it inhibits adipogenesis through a mechanism independent of beta-catenin. An important mediator of the beta-catenin-independent pathway appears to be calcineurin because inhibitors of this serine/threonine phosphatase partially rescue the block to adipogenesis caused by Wnt3a or activated Fz2. These data supported a model in which Wnt signaling inhibits adipogenesis through both beta-catenin-dependent and beta-catenin-independent mechanisms.
据报道，Wnt信号通路可通过抑制糖原合酶激酶3和稳定β-连环蛋白来阻止细胞凋亡并调节间充质祖细胞的分化。Wnt在前脂肪细胞中的作用可能通过卷曲蛋白（Fz）1和/或Fz2介导，因为这些Wnt受体在前脂肪细胞中表达，且其表达在分化诱导后下降。我们在前脂肪细胞和间充质前体细胞中异位表达了Wnt8与Fz1或Fz2之间的组成型活性嵌合体。我们的结果表明，激活的Fz1增加β-连环蛋白的稳定性，抑制细胞凋亡，诱导成骨细胞生成，并抑制脂肪生成。虽然激活的Fz2不影响细胞凋亡或成骨细胞生成，但它通过一种独立于β-连环蛋白的机制抑制脂肪生成。β-连环蛋白非依赖性途径的一个重要介质似乎是钙调神经磷酸酶，因为这种丝氨酸/苏氨酸磷酸酶的抑制剂可部分挽救由Wnt3a或激活的Fz2引起的脂肪生成阻滞。这些数据支持了一个模型，即Wnt信号通路通过β-连环蛋白依赖性和β-连环蛋白非依赖性机制抑制脂肪生成。
