Metformin Sensitizes Insulin Signaling Through AMPK-Mediated PTEN Down-Regulation in Preadipocyte 3T3-L1 Cells
Metformin Sensitizes Insulin Signaling Through AMPK-Mediated PTEN Down-Regulation in Preadipocyte 3T3-L1 Cells
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DOI：
10.1002/jcb.23000
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发表时间：
2011-05-01
影响因子：
4
通讯作者：
Kim, Hyeon Soo
中科院分区：
文献类型：
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作者：
Lee, Soo Kyung;Lee, Jung Ok;Kim, Hyeon Soo
胰岛素抵抗是2型糖尿病的主要病因。磷酸酶与张力蛋白同源物（PTEN）在胰岛素信号传导中起负向作用，对其抑制可提高胰岛素敏感性。二甲双胍是一种广泛使用的胰岛素增敏药物；然而，人们对二甲双胍的作用机制知之甚少。为了深入了解PTEN的作用，我们研究了二甲双胍对PTEN表达的影响。在脂肪前体细胞3T3 - L1中，二甲双胍以腺苷酸活化蛋白激酶（AMPK）依赖的方式抑制PTEN的表达。PTEN的敲低增强了胰岛素介导的Akt/ERK磷酸化的增加。二甲双胍还增加了c - Jun氨基末端激酶（JNK）- c - Jun和哺乳动物雷帕霉素靶蛋白（mTOR）- p70S6激酶通路的磷酸化。AMPK的药理抑制和敲低都阻断了二甲双胍诱导的JNK和mTOR的磷酸化。AMPK的敲低恢复了二甲双胍诱导的PTEN下调，表明AMPK参与了PTEN的调节。二甲双胍抑制PTEN启动子活性，并且通过药理抑制剂抑制mTOR和JNK可阻断二甲双胍诱导的PTEN启动子活性抑制。这些发现为AMPK在PTEN表达中的新作用提供了证据，从而提示了二甲双胍可能有助于其对胰岛素信号传导产生有益作用的一种可能机制。《细胞生物化学杂志》2011年第112卷第1259 - 1267页。（C）2010威利 - 利斯公司
Insulin resistance is the primary cause responsible for type 2 diabetes. Phosphatase and tensin homolog (PTEN) plays a negative role in insulin signaling and its inhibition improves insulin sensitivity. Metformin is a widely used insulin-sensitizing drug; however, the mechanism by which metformin acts is poorly understood. To gain insight into the role of PTEN, we examined the effect of metformin on PTEN expression. Metformin suppressed the expression of PTEN in an AMP-activated protein kinase (AMPK)-dependent manner in preadipocyte 3T3-L1 cells. Knock-down of PTEN potentiated the increase in insulin-mediated phosphorylation of Akt/ERK. Metformin also increased the phosphorylation of c-Jun N-terminal kinase (JNK)-c-Jun and mammalian target of rapamycin (mTOR)-p70S6 kinase pathways. Both pharmacologic inhibition and knock-down of AMPK blocked metformin-induced phosphorylation of JNK and mTOR. Knock-down of AMPK recovered the metformin-induced PTEN down-regulation, suggesting the involvement of AMPK in PTEN regulation. PTEN promoter activity was suppressed by metformin and inhibition of mTOR and JNK by pharmacologic inhibitors blocked metformin-induced PTEN promoter activity suppression. These findings provide evidence for a novel role of AMPK on PTEN expression and thus suggest a possible mechanism by which metformin may contribute to its beneficial effects on insulin signaling. J. Cell. Biochem. 112: 1259-1267, 2011. (C) 2010 Wiley-Liss, Inc.