Wnt3a upregulates brain-derived insulin by increasing NeuroD1 via Wnt/β-catenin signaling in the hypothalamus.
Wnt3a upregulates brain-derived insulin by increasing NeuroD1 via Wnt/β-catenin signaling in the hypothalamus.
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DOI：
10.1186/s13041-016-0207-5
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发表时间：
2016-03-08
期刊：
影响因子：
3.6
通讯作者：
Kim EK
中科院分区：
文献类型：
--
作者：
Lee J;Kim K;Yu SW;Kim EK
胰岛素在大脑中起着不同的作用。虽然胰岛素由胰腺β细胞产生，穿过血脑屏障是脑胰岛素的主要来源，但最近的研究表明，胰岛素也在脑内局部产生。然而，脑源性胰岛素（BDI）产生的机制尚不清楚。在这里，我们研究了Wnt 3a对下丘脑细胞系和下丘脑组织中BDI产生的影响。在N39下丘脑细胞中，Wnt 3a处理通过激活Wnt/β-连环蛋白信号传导显著增加Ins 2基因的表达，Ins 2基因编码小鼠脑中主要的胰岛素同种型。Wnt 3a处理的细胞的培养基中的胰岛素浓度高于未处理的细胞。有趣的是，Wnt/β-catenin信号转导的靶点和胰岛素的转录因子之一神经源性分化1（NeuroD 1）也以时间和剂量依赖性方式被Wnt 3a处理诱导。此外，GSK 3抑制剂BIO的处理也增加了Ins 2和NeuroD 1的表达。慢病毒shRNA敲低NeuroD 1可降低Ins 2的基础表达，并抑制Wnt 3a诱导的Ins 2表达。为了确认体内Wnt 3a诱导的Ins 2表达增加，将Wnt 3a注射到小鼠的下丘脑中。Wnt 3a以类似于体外观察到的方式增加下丘脑中NeuroD 1和Ins 2的表达。总之，这些结果表明，BDI的产生是由下丘脑中的Wnt/β-catenin/NeuroD 1通路调节的。我们的研究结果将有助于解开下丘脑BDI生产的调节。本文的在线版本（doi：10.1186/s13041-016-0207-5）包含补充材料，可供授权用户使用。
Insulin plays diverse roles in the brain. Although insulin produced by pancreatic β-cells that crosses the blood–brain barrier is a major source of brain insulin, recent studies suggest that insulin is also produced locally within the brain. However, the mechanisms underlying the production of brain-derived insulin (BDI) are not yet known. Here, we examined the effect of Wnt3a on BDI production in a hypothalamic cell line and hypothalamic tissue. In N39 hypothalamic cells, Wnt3a treatment significantly increased the expression of the Ins2 gene, which encodes the insulin isoform predominant in the mouse brain, by activating Wnt/β-catenin signaling. The concentration of insulin was higher in culture medium of Wnt3a-treated cells than in that of untreated cells. Interestingly, neurogenic differentiation 1 (NeuroD1), a target of Wnt/β-catenin signaling and one of transcription factors for insulin, was also induced by Wnt3a treatment in a time- and dose-dependent manner. In addition, the treatment of BIO, a GSK3 inhibitor, also increased the expression of Ins2 and NeuroD1. Knockdown of NeuroD1 by lentiviral shRNAs reduced the basal expression of Ins2 and suppressed Wnt3a-induced Ins2 expression. To confirm the Wnt3a-induced increase in Ins2 expression in vivo, Wnt3a was injected into the hypothalamus of mice. Wnt3a increased the expression of NeuroD1 and Ins2 in the hypothalamus in a manner similar to that observed in vitro. Taken together, these results suggest that BDI production is regulated by the Wnt/β-catenin/NeuroD1 pathway in the hypothalamus. Our findings will help to unravel the regulation of BDI production in the hypothalamus. The online version of this article (doi:10.1186/s13041-016-0207-5) contains supplementary material, which is available to authorized users.