Transcription factor TIP27 regulates glucose homeostasis and insulin sensitivity in a PI3-kinase/Akt-dependent manner in mice
Transcription factor TIP27 regulates glucose homeostasis and insulin sensitivity in a PI3-kinase/Akt-dependent manner in mice
复制标题
转录因子 TIP27 以 PI3 激酶/Akt 依赖性方式调节小鼠葡萄糖稳态和胰岛素敏感性
DOI：
10.1038/ijo.2015.5
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发表时间：
2015-06-01
影响因子：
4.9
通讯作者：
Yang, G.
中科院分区：
文献类型：
--
作者：
Yuan, L.;Luo, X.;Yang, G.
背景/目的：与另一个锌指基因1（TIP 27或JAZF 1）并列的是一个27 kDa的转录因子，最近全基因组关联研究显示TIP 27与2型糖尿病相关。然而，很少有人知道它在代谢调节中的作用。在这项研究中，我们研究了TIP 27过表达对高脂饮食（HFD）喂养的TIP 27转基因（TIP 27-Tg）小鼠和db/db小鼠的葡萄糖稳态和胰岛素信号转导的影响。方法：我们评估了TIP 27过表达在TIP 27-Tg小鼠和db/db小鼠中对葡萄糖代谢和葡萄糖（GTT）和胰岛素（ITT）耐量试验期间胰岛素敏感性变化的影响。对TIP 27-Tg小鼠进行高胰岛素-正常血糖钳夹。结果：TIP 27-Tg小鼠和db/db小鼠中TIP 27的过表达可导致GTT和ITT期间总胆固醇和空腹血浆胰岛素水平降低，葡萄糖耐量和胰岛素敏感性增强。高胰岛素-正葡萄糖钳夹实验表明，HFD喂养的TIP 27-Tg小鼠与非转基因同窝小鼠相比，肝脏葡萄糖产生较低，胰岛素敏感性较高。此外，与非转基因同窝小鼠相比，HFD喂养的TIP 27-Tg小鼠肝脏中磷酸烯醇化羧激酶（PEPCK）、葡萄糖-6-磷酸酶（G6 β）mRNA和蛋白质的表达显著降低，而肝脏中胰岛素受体、胰岛素受体底物-1、腺苷单磷酸活化蛋白激酶和Akt激酶（Akt）的磷酸化显著增加。与对照组相比，腺病毒介导的TIP 27过表达在db/db小鼠中也降低了致瘤基因的表达，并增加了肝脏中胰岛素信号分子的磷酸化。最后，LY 294002，磷脂酰肌醇3-激酶（PI 3-kinase）抑制剂，取消了TIP 27过表达对PEPCK和G6 β蛋白表达的抑制作用。结论：TIP 27通过调节肝脏葡萄糖代谢和胰岛素敏感性在葡萄糖稳态中起重要作用。此外，这种调节需要PI 3-激酶的激活。
BACKGROUND/OBJECTIVES: Juxtaposed with another zinc-finger gene 1 (TIP27 or JAZF1) is a 27-kDa transcription factor, and genome-wide association studies have recently revealed TIP27 to be associated with type 2 diabetes. However, little is known about its role in the regulation of metabolism. In this study, we investigated the effects of TIP27 overexpression on glucose homeostasis and insulin signaling in high-fat diet (HFD)-fed TIP27 transgenic (TIP27-Tg) mice and db/db mice.METHODS: We assessed the effects of TIP27 overexpression in both TIP27-Tg mice and db/db mice on glucose metabolism and changes in insulin sensitivity during glucose (GTT) and insulin (ITT) tolerance tests. A hyperinsulinemic-euglycemic clamp was performed on TIP27-Tg mice. Real-time quantitative PCR and western blotting were used to assess mRNA and protein expressions.RESULTS: TIP27 overexpression in TIP27-Tg mice and in db/db mice led to reduced total cholesterol and fasting plasma insulin levels, and enhanced glucose tolerance and insulin sensitivity during GTT and ITT. Hyperinsulinemic-euglycemic clamp experiments demonstrated that HFD-fed TIP27-Tg mice had lower hepatic glucose production and higher insulin sensitivity compared with nontransgenic littermates. In addition, the hepatic expressions of phosphoenolpyruate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase) mRNAs and proteins were significantly decreased, whereas the phosphorylation of insulin receptor, insulin receptor substrate-1, adenosine monophosphate-activated protein kinase and Akt kinase (Akt) in the liver was significantly increased in HFD-fed TIP27-Tg mice compared with nontransgenic littermates. Adenovirus-mediated TIP27 overexpression in db/db mice also decreased the expression of gluconeogenic genes and increased the phosphorylation of insulin signaling molecules in the liver compared with controls. Finally, LY294002, a phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, abolished the suppressive effect of TIP27 overexpression on PEPCK and G6Pase expression.CONCLUSIONS: TIP27 has an important role in glucose homeostasis through the regulation of hepatic glucose metabolism and insulin sensitivity. Furthermore, this regulation requires activation of PI3-kinase.