Yuan L, Luo X, Zeng M, Zhang Y, Yang M, Zhang L, Liu R, Boden G, Liu H, Ma Z A, Li L, Yang G
Department of Endocrinology, Second Affiliated Hospital Chongqing Medical University, Chongqing, China.
Key Laboratory of Diagnostic Medicine (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Int J Obes (Lond). 2015 Jun;39(6):949-58. doi: 10.1038/ijo.2015.5. Epub 2015 Jan 23.
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.
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.
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.
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.
背景/目的：与另一个锌指基因1（TIP27或JAZF1）并列的是一种27 kDa的转录因子，全基因组关联研究最近揭示TIP27与2型糖尿病有关。然而，其在代谢调节中的作用知之甚少。在本研究中，我们研究了TIP27过表达对高脂饮食（HFD）喂养的TIP27转基因（TIP27-Tg）小鼠和db/db小鼠葡萄糖稳态和胰岛素信号的影响。
我们评估了TIP27过表达在TIP27-Tg小鼠和db/db小鼠葡萄糖代谢以及葡萄糖（GTT）和胰岛素（ITT）耐量试验期间胰岛素敏感性变化方面的作用。对TIP27-Tg小鼠进行了高胰岛素-正常血糖钳夹试验。采用实时定量PCR和蛋白质印迹法评估mRNA和蛋白质表达。
TIP27在TIP27-Tg小鼠和db/db小鼠中的过表达导致总胆固醇和空腹血浆胰岛素水平降低，在GTT和ITT期间葡萄糖耐量和胰岛素敏感性增强。高胰岛素-正常血糖钳夹实验表明，与非转基因同窝小鼠相比，HFD喂养的TIP27-Tg小鼠肝脏葡萄糖生成较低且胰岛素敏感性较高。此外，与非转基因同窝小鼠相比，HFD喂养的TIP27-Tg小鼠肝脏中磷酸烯醇式丙酮酸羧激酶（PEPCK）、葡萄糖-6-磷酸酶（G6Pase）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、腺苷单磷酸激活的蛋白激酶和Akt激酶（Akt）的磷酸化显著增加。与对照组相比，腺病毒介导的TIP27在db/db小鼠中的过表达也降低了糖异生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，磷脂酰肌醇3激酶（PI3激酶）抑制剂LY294002消除了TIP27过表达对PEPCK和G6Pase表达的抑制作用。
TIP27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发挥重要作用。此外，这种调节需要PI3激酶的激活。
