Kinetic Trans-omic Analysis Reveals Key Regulatory Mechanisms for Insulin-Regulated Glucose Metabolism in Adipocytes-猫眼课题宝

DOI：

10.1016/j.isci.2020.101479

发表时间：

2020-08

期刊：

iScience

影响因子：

5.8

通讯作者：

中科院分区：

综合性期刊2区

文献类型：

作者：

S. Ohno;L. Quek;J. Krycer;K. Yugi;A. Hirayama;Satsuki Ikeda;F. Shoji;Kumi Suzuki;T. Soga;D. James;Shinya Kuroda

胰岛素通过成千上万的调节机制来调节糖代谢，然而，哪些调节机制是控制糖代谢的关键仍然是未知的。在这里，我们进行动力学trans-omic分析，通过整合同位素示踪葡萄糖流量和磷酸化蛋白质组数据从胰岛素刺激的脂肪细胞，并建立了一个动力学数学模型，以确定关键的变构调节和磷酸化酶的事件。我们确定了九个反应调节变构效应和酶磷酸化，并确定了这些反应的调节机制。胰岛素通过增强AS 160在S595处的磷酸化而促进Glut 4活性来刺激糖酵解，通过葡萄糖6-磷酸或果糖6-磷酸的变构激活而促进Acly活性来刺激脂肪酸合成，并且通过减轻谷氨酸对Gls的变构抑制来刺激谷氨酸合成。大多数糖酵解反应受底物和产物量的调控。因此，磷酸化或变构调节剂为基础的调控，只有少数关键酶足以改变胰岛素诱导的代谢。

Insulin regulates glucose metabolism through thousands of regulatory mechanisms; however, which regulatory mechanisms are keys to control glucose metabolism remains unknown. Here, we performed kinetic trans-omic analysis by integrating isotope-tracing glucose flux and phosphoproteomic data from insulin-stimulated adipocytes and built a kinetic mathematical model to identify key allosteric regulatory and phosphorylation events for enzymes. We identified nine reactions regulated by allosteric effectors and one by enzyme phosphorylation and determined the regulatory mechanisms for three of these reactions. Insulin stimulated glycolysis by promoting Glut4 activity by enhancing phosphorylation of AS160 at S595, stimulated fatty acid synthesis by promoting Acly activity through allosteric activation by glucose 6-phosphate or fructose 6-phosphate, and stimulated glutamate synthesis by alleviating allosteric inhibition of Gls by glutamate. Most of glycolytic reactions were regulated by amounts of substrates and products. Thus, phosphorylation or allosteric modulator-based regulation of only a few key enzymes was sufficient to change insulin-induced metabolism.

Kinetic Trans-omic Analysis Reveals Key Regulatory Mechanisms for Insulin-Regulated Glucose Metabolism in Adipocytes

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