Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b
Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b
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DOI：
10.1038/nature11793
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发表时间：
2013-02-07
期刊：
影响因子：
64.8
通讯作者：
Bruening, Jens C.
中科院分区：
文献类型：
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作者：
Kornfeld, Jan-Wilhelm;Baitzel, Catherina;Bruening, Jens C.
胰岛素抵抗是2型糖尿病发展过程中以及肥胖相关的葡萄糖和脂质代谢紊乱发病机制中的一个标志（1-3）。近年来，微RNA（microRNA，miRNA）依赖的转录后基因沉默被认为可以控制包括胰岛素抵抗的2型糖尿病在内的疾病发生和发展过程中的基因表达。miRNAs miR-143（参考文献4）、miR-181（参考文献5）、miR-103和miR-107（参考文献6）的失调改变了肝脏胰岛素敏感性。在这里，我们报告了miR-802在两个肥胖小鼠模型和肥胖人类受试者的肝脏中的表达增加。小鼠中miR-802的可诱导转基因过表达导致葡萄糖耐量受损并减弱胰岛素敏感性，而miR-802表达的减少改善葡萄糖耐量和胰岛素作用。我们将Hnf 1b（也称为Tcf 2）确定为miR-802依赖性沉默的靶点，并表明短发夹RNA（shRNA）介导的肝脏Hnf 1b减少导致葡萄糖耐受不良，损害胰岛素信号传导并促进肝脏新生。反过来，肝脏Hnf 1b的过表达改善了Lepr（db/db）小鼠的胰岛素敏感性。因此，本研究通过靶向Hnf 1b，确定了miR-802表达失调在肥胖相关的葡萄糖代谢障碍发展中的关键作用，并将Hnf 1b在控制肝脏胰岛素敏感性方面的作用出乎意料。
Insulin resistance represents a hallmark during the development of type 2 diabetes mellitus and in the pathogenesis of obesity-associated disturbances of glucose and lipid metabolism(1-3). MicroRNA (miRNA)-dependent post-transcriptional gene silencing has been recognized recently to control gene expression in disease development and progression, including that of insulin-resistant type 2 diabetes. The deregulation of miRNAs miR-143 (ref. 4), miR-181 (ref. 5), and miR-103 and miR-107 (ref. 6) alters hepatic insulin sensitivity. Here we report that the expression of miR-802 is increased in the liver of two obese mouse models and obese human subjects. Inducible transgenic overexpression of miR-802 in mice causes impaired glucose tolerance and attenuates insulin sensitivity, whereas reduction of miR-802 expression improves glucose tolerance and insulin action. We identify Hnf1b (also known as Tcf2) as a target of miR-802-dependent silencing, and show that short hairpin RNA (shRNA)-mediated reduction of Hnf1b in liver causes glucose intolerance, impairs insulin signalling and promotes hepatic gluconeogenesis. In turn, hepatic overexpression of Hnf1b improves insulin sensitivity in Lepr(db/db) mice. Thus, this study defines a critical role for deregulated expression of miR-802 in the development of obesity-associated impairment of glucose metabolism through targeting of Hnf1b, and assigns Hnf1b an unexpected role in the control of hepatic insulin sensitivity.