Wnt/β-Catenin Mediates AICAR Effect to Increase GATA3 Expression and Inhibit Adipogenesis*
Wnt/β-Catenin Mediates AICAR Effect to Increase GATA3 Expression and Inhibit Adipogenesis*
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DOI：
10.1074/jbc.m115.641332
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发表时间：
2015-06
期刊：
影响因子：
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通讯作者：
Li Wang;L. Di
中科院分区：
文献类型：
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作者：
Li Wang;L. Di
背景：脂肪生成可以通过多种信号通路和转录因子调节。结果：AICAR 激活的 AMPK 使 GSK3β 失活，从而刺激 Wnt/β-catenin 信号传导并缓解 CtBP 抑制，从而增加 GATA3 并抑制脂肪生成。结论：AMPK 通过灭活 GSK3β 来控制 Wnt/β-catenin/GATA3 轴，协调调节脂肪生成。意义：这些发现为脂肪生成的分子机制和信号转导提供了新的见解。更好地了解脂肪生成严格调控的细胞分化过程的机制和操作可能有助于减少肥胖和糖尿病。多种转录因子和信号通路参与脂肪生成的调节。在这里，我们报道了 AMP 激活的蛋白激酶激活剂 5-氨基咪唑-4-甲酰胺核糖核苷 (AICAR) 可以激活前脂肪细胞中的 AMPK，从而增加抗脂肪形成因子 GATA3 的表达。然而，AICAR 增加的 GATA3 是通过刺激前脂肪细胞中的 Wnt/β-catenin 信号转导介导的。从机制上讲，AICAR 激活的 AMPK 通过稳定 β-连环蛋白的磷酸化过程抑制 GSK3β。然后，这种稳定的 β-连环蛋白易位到细胞核中，与 T 细胞因子 (TCF) 相互作用，导致 β-连环蛋白/TCF 转录活性增加，从而诱导 GATA3 表达。此外，AICAR 还通过将 CtBP 转移远离 GATA3 启动子处的 β-连环蛋白·TCF 复合物来减轻 C 端结合蛋白 (CtBP) 共阻遏物的抑制作用。 GATA3 和 AICAR 的抗脂肪形成作用会因 Wnt/β-catenin 信号传导的破坏而持续减弱。此外，GATA3 通过与这些调节因子的启动子结合来抑制关键的脂肪形成调节因子，例如过氧化物酶体增殖物激活受体-γ (PPARγ) 基因，并且 Wnt/β-连环蛋白信号传导的破坏会减少 GATA3 在 PPARγ 启动子上的结合。在分化的脂肪细胞中，β-连环蛋白水平的下调、β-连环蛋白结合的减少以及 GATA3 启动子处 CtBP 结合的增加促进了 GATA3 表达抑制。我们的研究结果表明不同的调节途径和脂肪形成调节剂通过串扰共同调节脂肪细胞分化，从而揭示了脂肪形成的分子机制。
Background: Adipogenesis can be modulated by various signaling pathways and transcription factors. Results: AICAR-activated AMPK inactivates GSK3β, which stimulates Wnt/β-catenin signaling and relieves CtBP repression, thus increasing GATA3 and inhibiting adipogenesis. Conclusion: AMPK controls the Wnt/β-catenin/GATA3 axis via inactivating GSK3β to coordinately modulate adipogenesis. Significance: These findings provide new insight into the molecular mechanism and signal transduction of adipogenesis. A better understanding of the mechanism and manipulation of the tightly regulated cellular differentiation process of adipogenesis may contribute to a reduction in obesity and diabetes. Multiple transcription factors and signaling pathways are involved in the regulation of adipogenesis. Here, we report that the AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) can activate AMPK in preadipocytes and thus increase the expression of GATA3, an anti-adipogenic factor. However, AICAR-increased GATA3 is mediated by the stimulation of Wnt/β-catenin signaling in preadipocytes. Mechanistically, AICAR-activated AMPK inhibits GSK3β through a phosphorylation process that stabilizes β-catenin. This stabilized β-catenin then translocates into nucleus where it interacts with T-cell factors (TCF), leading to the increased β-catenin/TCF transcriptional activity that induces GATA3 expression. In addition, AICAR also relieves the repressing effect of the C-terminal-binding protein (CtBP) co-repressor by diverting CtBP away from the β-catenin·TCF complex at the GATA3 promoter. The anti-adipogenic effect of GATA3 and AICAR is consistently attenuated by the disruption of Wnt/β-catenin signaling. Furthermore, GATA3 suppresses key adipogenic regulators by binding to the promoters of these regulators, such as the peroxisome proliferator-activated receptor-γ (PPARγ) gene, and the disruption of Wnt/β-catenin signaling reduces the GATA3 binding at the PPARγ promoter. In differentiated adipocytes, GATA3 expression inhibition is facilitated by the down-regulation of β-catenin levels, the reduction in β-catenin binding, and the increase in CtBP binding at the GATA3 promoter. Our findings shed light on the molecular mechanism of adipogenesis by suggesting that different regulation pathways and adipogenic regulators collectively modulate adipocyte differentiation through cross-talk.