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Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia.胰岛素受体底物2的破坏会导致2型糖尿病，原因是肝脏胰岛素抵抗以及缺乏代偿性β细胞增生。
Diabetes. 2000 Nov;49(11):1880-9. doi: 10.2337/diabetes.49.11.1880.
2
Retinoblastoma protein phosphorylation via PI 3-kinase and mTOR pathway regulates adipocyte differentiation.通过PI 3激酶和mTOR途径的视网膜母细胞瘤蛋白磷酸化调节脂肪细胞分化。
Biochem Biophys Res Commun. 2000 Aug 18;275(1):115-20. doi: 10.1006/bbrc.2000.3201.
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Transcriptional regulation of adipogenesis.脂肪生成的转录调控
Genes Dev. 2000 Jun 1;14(11):1293-307.
4
Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes.固醇调节元件结合蛋白-1作为脂肪生成酶基因营养诱导的关键转录因子。
J Biol Chem. 1999 Dec 10;274(50):35832-9. doi: 10.1074/jbc.274.50.35832.
5
PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro.过氧化物酶体增殖物激活受体γ（PPARγ）是体内和体外脂肪组织分化所必需的。
Mol Cell. 1999 Oct;4(4):611-7. doi: 10.1016/s1097-2765(00)80211-7.
6
PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance.过氧化物酶体增殖物激活受体γ介导高脂饮食诱导的脂肪细胞肥大和胰岛素抵抗。
Mol Cell. 1999 Oct;4(4):597-609. doi: 10.1016/s1097-2765(00)80210-5.
7
ADD1/SREBP-1c is required in the activation of hepatic lipogenic gene expression by glucose.ADD1/SREBP-1c在葡萄糖激活肝脏脂肪生成基因表达过程中是必需的。
Mol Cell Biol. 1999 May;19(5):3760-8. doi: 10.1128/MCB.19.5.3760.
8
Cross-regulation of C/EBP alpha and PPAR gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity.C/EBPα 和 PPARγ 的交叉调控控制着脂肪生成和胰岛素敏感性的转录途径。
Mol Cell. 1999 Feb;3(2):151-8. doi: 10.1016/s1097-2765(00)80306-8.
9
Inhibition of adipose differentiation by phosphatidylinositol 3-kinase inhibitors.磷脂酰肌醇3-激酶抑制剂对脂肪分化的抑制作用。
J Cell Physiol. 1999 Jan;178(1):9-16. doi: 10.1002/(SICI)1097-4652(199901)178:1<9::AID-JCP2>3.0.CO;2-#.
10
Posttranscriptional control of adipocyte differentiation through activation of phosphoinositide 3-kinase.通过磷酸肌醇3激酶的激活对脂肪细胞分化进行转录后调控。
J Biol Chem. 1998 Oct 30;273(44):28945-52. doi: 10.1074/jbc.273.44.28945.

胰岛素受体底物1（IRS-1）和IRS-2在脂肪细胞分化中的重要作用。

Essential role of insulin receptor substrate 1 (IRS-1) and IRS-2 in adipocyte differentiation.

作者信息

Miki H, Yamauchi T, Suzuki R, Komeda K, Tsuchida A, Kubota N, Terauchi Y, Kamon J, Kaburagi Y, Matsui J, Akanuma Y, Nagai R, Kimura S, Tobe K, Kadowaki T

机构信息

Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.

出版信息

Mol Cell Biol. 2001 Apr;21(7):2521-32. doi: 10.1128/MCB.21.7.2521-2532.2001.

DOI:10.1128/MCB.21.7.2521-2532.2001
PMID:11259600
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC86884/
Abstract

To investigate the role of insulin receptor substrate 1 (IRS-1) and IRS-2, the two ubiquitously expressed IRS proteins, in adipocyte differentiation, we established embryonic fibroblast cells with four different genotypes, i.e., wild-type, IRS-1 deficient (IRS-1(-/-)), IRS-2 deficient (IRS-2(-/-)), and IRS-1 IRS-2 double deficient (IRS-1(-/-) IRS-2(-/-)), from mouse embryos of the corresponding genotypes. The abilities of IRS-1(-/-) cells and IRS-2(-/-) cells to differentiate into adipocytes are approximately 60 and 15%, respectively, lower than that of wild-type cells, at day 8 after induction and, surprisingly, IRS-1(-/-) IRS-2(-/-) cells have no ability to differentiate into adipocytes. The expression of CCAAT/enhancer binding protein alpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma) is severely decreased in IRS-1(-/-) IRS-2(-/-) cells at both the mRNA and the protein level, and the mRNAs of lipoprotein lipase and adipocyte fatty acid binding protein are severely decreased in IRS-1(-/-) IRS-2(-/-) cells. Phosphatidylinositol 3-kinase (PI 3-kinase) activity that increases during adipocyte differentiation is almost completely abolished in IRS-1(-/-) IRS-2(-/-) cells. Treatment of wild-type cells with a PI 3-kinase inhibitor, LY294002, markedly decreases the expression of C/EBPalpha and PPARgamma, a result which is associated with a complete block of adipocyte differentiation. Moreover, histologic analysis of IRS-1(-/-) IRS-2(-/-) double-knockout mice 8 h after birth reveals severe reduction in white adipose tissue mass. Our results suggest that IRS-1 and IRS-2 play a crucial role in the upregulation of the C/EBPalpha and PPARgamma expression and adipocyte differentiation.

摘要

为了研究胰岛素受体底物1（IRS-1）和IRS-2这两种广泛表达的IRS蛋白在脂肪细胞分化中的作用，我们从相应基因型的小鼠胚胎中建立了四种不同基因型的胚胎成纤维细胞，即野生型、IRS-1缺陷型（IRS-1(-/-)）、IRS-2缺陷型（IRS-2(-/-)）和IRS-1 IRS-2双缺陷型（IRS-1(-/-) IRS-2(-/-)）。诱导后第8天，IRS-1(-/-)细胞和IRS-2(-/-)细胞分化为脂肪细胞的能力分别比野生型细胞低约60%和15%，令人惊讶的是，IRS-1(-/-) IRS-2(-/-)细胞没有分化为脂肪细胞的能力。在mRNA和蛋白质水平上，IRS-1(-/-) IRS-2(-/-)细胞中CCAAT/增强子结合蛋白α（C/EBPα）和过氧化物酶体增殖物激活受体γ（PPARγ）的表达均严重降低，并且IRS-1(-/-) IRS-2(-/-)细胞中脂蛋白脂肪酶和脂肪细胞脂肪酸结合蛋白的mRNA也严重降低。在脂肪细胞分化过程中增加的磷脂酰肌醇3激酶（PI 3激酶）活性在IRS-1(-/-) IRS-2(-/-)细胞中几乎完全被消除。用PI 3激酶抑制剂LY294002处理野生型细胞，可显著降低C/EBPα和PPARγ的表达，这一结果与脂肪细胞分化的完全阻断有关。此外，对出生后8小时的IRS-1(-/-) IRS-2(-/-)双敲除小鼠进行组织学分析，发现白色脂肪组织质量严重减少。我们的结果表明，IRS-1和IRS-2在C/EBPα和PPARγ表达上调及脂肪细胞分化中起关键作用。