Activation of Wnt/β-catenin signaling restores insulin sensitivity in insulin resistant neurons through transcriptional regulation of IRS-1
Activation of Wnt/β-catenin signaling restores insulin sensitivity in insulin resistant neurons through transcriptional regulation of IRS-1
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Wnt/β-连环蛋白信号的激活通过 IRS-1 的转录调节恢复胰岛素抵抗神经元的胰岛素敏感性
DOI：
10.1111/jnc.15277
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发表时间：
2020-12-31
影响因子：
4.7
通讯作者：
Sun, Xiulian
中科院分区：
文献类型：
--
作者：
Tian, Shijiao;Tan, Shichuan;Sun, Xiulian
胰岛素受体底物1 （IRS-1）的异常表达和磷酸化与脑胰岛素抵抗有关。然而，潜在的机制仍然难以捉摸。胰岛素信号和Wnt/ β -连环蛋白信号是正常细胞功能的两个关键途径，它们在外周组织和大脑中相互作用，并可能导致胰岛素抵抗。在本研究中，我们旨在探讨Wnt/ β -catenin信号在初级神经元中对IRS-1及其下游胰岛素信号的调控。我们发现Wnt激动剂Wnt3a通过上调IRS-1来增强基础状态神经元的胰岛素信号。此外，Wnt3a上调IRS-1表达，有效改善慢性高胰岛素暴露大鼠原代神经元的胰岛素抵抗。在基础状态和胰岛素抵抗状态下，Wnt3a也会刺激胰岛素介导的葡萄糖摄取。我们观察到，Wnt激活通过不同的Wnt/ β -catenin信号激活方式，包括S33Y β -catenin过表达、CHIR99021和Wnt3a处理，上调SH-SY5Y细胞和大鼠原代神经元中ir -1基因转录和随后的蛋白表达。我们进一步阐明了Wnt/ β -catenin信号通路激活IRS-1转录的分子机制。Wnt转录因子TCF4结合人IRS-1启动子片段-529 bp至-516 bp，激活IRS-1转录。总的来说，这些数据表明Wnt/ β -连环蛋白信号正调控IRS-1和胰岛素信号，并保护神经元免受胰岛素抵抗。
Aberrant expression and phosphorylation of insulin receptor substrate 1 (IRS-1) contribute to brain insulin resistance. However, the underlying mechanism remains elusive. The insulin signaling and Wnt/beta-catenin signaling are two critical pathways for normal cellular function, which interact in both peripheral tissues and the brain and may contribute to insulin resistance. In this study, we aimed to investigate the regulation of IRS-1 and its downstream insulin signaling by Wnt/beta-catenin signaling in primary neurons. We found that the Wnt agonist Wnt3a enhances the insulin signaling in neurons at the basal state via up-regulation of IRS-1. Moreover, Wnt3a up-regulates IRS-1 expression and effectively ameliorates insulin resistance in rat primary neurons induced by chronic high insulin exposure. The insulin-mediated glucose uptake is also stimulated by Wnt3a at both basal and insulin resistant states. We observed that Wnt activation up-regulates IRS-1 gene transcription and the subsequent protein expression in SH-SY5Y cells and rat primary neurons via different means of Wnt/beta-catenin signaling activation, including S33Y beta-catenin over-expression, CHIR99021 and Wnt3a treatment. We further clarified the molecular mechanism of IRS-1 transcriptional activation by Wnt/beta-catenin signaling. The Wnt transcription factor TCF4 binds to the -529 bp to -516 bp of the human IRS-1 promoter fragment and activates IRS-1 transcription. Overall, these data suggested that Wnt/beta-catenin signaling positively regulates IRS-1 and insulin signaling and protects against insulin resistance in neurons.