IRS-2 Partially Compensates for the Insulin Signal Defects in IRS-1(-/-) Mice Mediated by miR-33.
IRS-2 Partially Compensates for the Insulin Signal Defects in IRS-1(-/-) Mice Mediated by miR-33.
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IRS-2 部分补偿 miR-33 介导的 IRS-1(-/-) 小鼠胰岛素信号缺陷
DOI：
10.14348/molcells.2017.2228
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发表时间：
2017-02
影响因子：
3.8
通讯作者：
Zhou HD
中科院分区：
文献类型：
--
作者：
Tang CY;Man XF;Guo Y;Tang HN;Tang J;Zhou CL;Tan SW;Wang M;Zhou HD
胰岛素信号传导由胰岛素受体底物（IRS）协调。许多胰岛素反应，特别是血糖代谢，主要通过Irs-1和Irs-2介导。Irs-1基因敲除小鼠表现出生长迟缓和胰岛素信号传导缺陷，这可以通过体内其他IRS来补偿;然而，其潜在机制尚不清楚。在这里，我们提出了一个Irs-1截断突变小鼠（Irs-1−/−）与生长迟缓和皮下脂肪细胞萎缩。Irs-1−/−小鼠表现出轻度胰岛素抵抗，如胰岛素耐量试验所示。在Irs-1缺乏的肝脏、骨骼肌和皮下脂肪细胞中，磷脂酰肌醇3-激酶（PI 3 K）活性和磷酸化蛋白激酶B（PKB/AKT）表达升高。此外，IRS-2及其磷酸化版本的表达在肝脏和骨骼肌中明显升高。通过miRNA微阵列分析，我们发现miR-33在Irs-1−/−小鼠的骨髓基质细胞（BMSCs）中下调，而其靶基因Irs-2在体外研究中上调。此外，miR-33在Irs-1存在下下调，而在空腹状态下上调。此外，miR-33在再喂养状态下恢复表达。同时，在Irs-1−/−小鼠的肝脏、骨骼肌和皮下脂肪细胞中，miR-33水平降低，Irs-2水平升高。在用miR-33抑制剂转染的原代培养的肝细胞中，IRS-2、PI 3 K和磷酸化AKT（p-AKT）的表达增加，而在miR-33模拟物存在下观察到相反的结果。因此，降低miR-33水平可以上调IRS-2表达，这似乎可以弥补Irs-1缺陷小鼠胰岛素信号通路的缺陷。
Insulin signaling is coordinated by insulin receptor substrates (IRSs). Many insulin responses, especially for blood glucose metabolism, are mediated primarily through Irs-1 and Irs-2. Irs-1 knockout mice show growth retardation and insulin signaling defects, which can be compensated by other IRSs in vivo; however, the underlying mechanism is not clear. Here, we presented an Irs-1 truncated mutated mouse (Irs-1−/−) with growth retardation and subcutaneous adipocyte atrophy. Irs-1−/− mice exhibited mild insulin resistance, as demonstrated by the insulin tolerance test. Phosphatidylinositol 3-kinase (PI3K) activity and phosphorylated Protein Kinase B (PKB/AKT) expression were elevated in liver, skeletal muscle, and subcutaneous adipocytes in Irs-1 deficiency. In addition, the expression of IRS-2 and its phosphorylated version were clearly elevated in liver and skeletal muscle. With miRNA microarray analysis, we found miR-33 was down-regulated in bone marrow stromal cells (BMSCs) of Irs-1−/− mice, while its target gene Irs-2 was up-regulated in vitro studies. In addition, miR-33 was down-regulated in the presence of Irs-1 and which was up-regulated in fasting status. What’s more, miR-33 restored its expression in re-feeding status. Meanwhile, miR-33 levels decreased and Irs-2 levels increased in liver, skeletal muscle, and subcutaneous adipocytes of Irs-1−/− mice. In primary cultured liver cells transfected with an miR-33 inhibitor, the expression of IRS-2, PI3K, and phosphorylated-AKT (p-AKT) increased while the opposite results were observed in the presence of an miR-33 mimic. Therefore, decreased miR-33 levels can up-regulate IRS-2 expression, which appears to compensate for the defects of the insulin signaling pathway in Irs-1 deficient mice.