Dynamic glucoregulation and mammalian-like responses to metabolic and developmental disruption in zebrafish.
Dynamic glucoregulation and mammalian-like responses to metabolic and developmental disruption in zebrafish.
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DOI：
10.1016/j.ygcen.2010.10.010
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发表时间：
2011-01-15
影响因子：
2.7
通讯作者：
diIorio P
中科院分区：
文献类型：
--
作者：
Jurczyk A;Roy N;Bajwa R;Gut P;Lipson K;Yang C;Covassin L;Racki WJ;Rossini AA;Phillips N;Stainier DY;Greiner DL;Brehm MA;Bortell R;diIorio P
斑马鱼胚胎正在成为葡萄糖代谢模型。然而，内源性葡萄糖水平的模式以及胰岛在葡萄糖调节中的作用尚不清楚。我们测量了斑马鱼和小鼠胚胎的绝对葡萄糖水平，并证明了这两个物种的相似的动态葡萄糖波动。此外，我们发现化学和遗传扰动会在斑马鱼胚胎中引起类似哺乳动物的血糖反应。我们发现，在早期斑马鱼和小鼠胚胎中，葡萄糖是检测不到的，但在这两个物种中，葡萄糖随着胰岛的形成而增加。在斑马鱼中，葡萄糖的增加与糖异生磷酸烯醇丙酮酸羧激酶 1 (pck1) 转录的激活有关。非肝 Pck1 蛋白在小鼠胚胎中表达。我们使用 RNA 原位杂交证明，斑马鱼 pck1 mRNA 在肝发生前在多种细胞类型中表达相似。此外，我们证明 Pck1 抑制剂 3-巯基甲酸可抑制早期斑马鱼胚胎中正常的葡萄糖积累。这表明肝前和肝外 pck1 具有功能，并为快速发育的组织局部提供葡萄糖。为了确定早期鱼胚胎中的初级胰岛是否具有葡萄糖调节作用，我们将 pdx1 特异性吗啉注射到在 β 细胞中表达 GFP 的转基因胚胎中。大多数形态性胰岛是低形态的，而不是遗传性的，但胚胎仍然表现出持续的高血糖。我们从这些数据得出结论，早期斑马鱼的胰岛是有功能的，并且调节内源性葡萄糖。总之，我们确定了斑马鱼胚胎中的葡萄糖调节机制，这些机制在胚胎和成年哺乳动物中是保守的。这些观察结果证明了在人类代谢疾病的机制研究中使用该模型的合理性。
Zebrafish embryos are emerging as models of glucose metabolism. However, patterns of endogenous glucose levels, and the role of the islet in glucoregulation, are unknown. We measured absolute glucose levels in zebrafish and mouse embryos, and demonstrate similar, dynamic glucose fluctuations in both species. Further, we show that chemical and genetic perturbations elicit mammalian-like glycemic responses in zebrafish embryos. We show that glucose is undetectable in early zebrafish and mouse embryos, but increases in parallel with pancreatic islet formation in both species. In zebrafish, increasing glucose is associated with activation of gluconeogenic phosphoenolpyruvate carboxykinase1 (pck1) transcription. Non-hepatic Pck1 protein is expressed in mouse embryos. We show, using RNA in situ hybridization, that zebrafish pck1 mRNA is similarly expressed in multiple cell types prior to hepatogenesis. Further, we demonstrate that the Pck1 inhibitor 3-mercaptopicolinic acid suppresses normal glucose accumulation in early zebrafish embryos. This shows that pre- and extra-hepatic pck1 is functional, and provides glucose locally to rapidly developing tissues. To determine if the primary islet is glucoregulatory in early fish embryos, we injected pdx1-specific morpholinos into transgenic embryos expressing GFP in beta cells. Most morphant islets were hypomorphic, not agenetic, but embryos still exhibited persistent hyperglycemia. We conclude from these data that the early zebrafish islet is functional, and regulates endogenous glucose. In summary, we identify mechanisms of glucoregulation in zebrafish embryos that are conserved with embryonic and adult mammals. These observations justify use of this model in mechanistic studies of human metabolic disease.
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影响因子：
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通讯作者：
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