磷酸二酯酶4B在TNF-α诱导的肝脏胰岛素抵抗中的作用及其调控机制研究

High level of TNF-α leads to hepatic insulin resistance through NOX induced activation of JNK and NFκB. Recent studies show that phosphodiesterase 4B (PDE4B) is a new regulator which can activates JNK and NFκB signaling pathway. But the role of PDE4B in insulin resistance is not clear. We have demonstrated previously for the first time that in cellular or animal insulin resistance models, increased expression of PDE4B was found both in hepatocytes and livers. Here we hypothesis that PDE4B participates in the regulation of TNF-α-induced hepatic insulin resistance by activation of JNK/ NFκB signaling. To test this hypothesis, we explore the role of PDE4B in TNF-α-induced hepatic insulin resistance from the molecular, cellular and the overall level using cellular and animal model; we investigate the mechanism of PDE4B regulated by TNF-α and the role of PDE4B in TNF-α-induced hepatic insulin resistance. The project will reveal the mechanism of hepatic insulin resistance in type 2 diabetes from the PDE4B and provide new perspective for its prevention.

TNF-α通过NADPH氧化酶（NOX）介导的活性氧（ROS）升高，激活JNK和NFκB信号通路，从而导致肝脏胰岛素抵抗。最新研究表明磷酸二酯酶4B（PDE4B）是JNK及NFκB信号通路新的调节因子，但PDE4B在胰岛素抵抗中的作用尚未见报道。我们的研究首次发现，在TNF-α诱导的肝脏胰岛素抵抗细胞和动物模型中，PDE4B的表达显著升高。由此提出假说：TNF-α可能通过PDE4B 调控JNK/NFκB信号通路，进而参与炎症诱导的肝脏胰岛素抵抗。为验证这一假说，本课题拟采用细胞和小鼠模型，从分子、细胞及动物整体水平等多层次明确PDE4B在肝脏胰岛素抵抗中的作用，阐明TNF-α对PDE4B的调控机理，探讨PDE4B在肝脏胰岛素抵抗中的作用机制。本研究将从PDE4B的新视点探讨肝脏胰岛素抵抗机制，为2型糖尿病的防治提供新的思路。