Essential Role of Insulin Receptor Substrate 1 (IRS-1) and IRS-2 in Adipocyte Differentiation

doi:10.1128/MCB.21.7.2521-2532.2001

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Molecular and Cellular Biology, April 2001, p. 2521-2532, Vol. 21, No. 7
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.7.2521-2532.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Essential Role of Insulin Receptor Substrate 1 (IRS-1) and IRS-2 in Adipocyte Differentiation

Hiroshi Miki,¹ Toshimasa Yamauchi,¹ Ryo Suzuki,¹ Kajuro Komeda,² Atsuko Tsuchida,² Naoto Kubota,¹ Yasuo Terauchi,¹ Junji Kamon,¹ Yasushi Kaburagi,¹ Junji Matsui,¹ Yasuo Akanuma,³ Ryozo Nagai,¹ Satoshi Kimura,¹ Kazuyuki Tobe,¹ and Takashi Kadowaki¹^,^*

Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655,¹ Division of Laboratory Animal Science, Animal Research Center, Tokyo Medical University, Tokyo 160-8402,² and Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo 100-0005,³ Japan

Received 10 July 2000/Returned for modification 30 August 2000/Accepted 20 December 2000

To investigate the role of insulin receptor substrate 1 (IRS-1) and IRS-2, the two ubiquitously expressed IRS proteins, inadipocyte differentiation, we established embryonic fibroblastcells 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 abilitiesof IRS-1^/ cells and IRS-2^/ cells to differentiate into adipocytes are approximately 60 and15%, respectively, lower than that of wild-type cells, at day8 after induction and, surprisingly, IRS-1^/ IRS-2^/ cells have no ability to differentiate into adipocytes. The expressionof CCAAT/enhancer binding protein $alpha$ (C/EBP $alpha$ ) and peroxisome proliferator-activatedreceptor $gamma$ (PPAR $gamma$ ) is severely decreased in IRS-1^/ IRS-2^/ cells at both the mRNA and the protein level, and the mRNAs oflipoprotein lipase and adipocyte fatty acid binding protein areseverely decreased in IRS-1^/ IRS-2^/ cells. Phosphatidylinositol 3-kinase (PI 3-kinase) activity thatincreases during adipocyte differentiation is almost completelyabolished in IRS-1^/ IRS-2^/ cells. Treatment of wild-type cells with a PI 3-kinase inhibitor,LY294002, markedly decreases the expression of C/EBP $alpha$ and PPAR $gamma$ ,a result which is associated with a complete block of adipocytedifferentiation. Moreover, histologic analysis of IRS-1^/ IRS-2^/ double-knockout mice 8 h after birth reveals severe reductionin white adipose tissue mass. Our results suggest that IRS-1 andIRS-2 play a crucial role in the upregulation of the C/EBP $alpha$ andPPAR $gamma$ expression and adipocytedifferentiation.

^* Corresponding author. Mailing address: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo,7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-3-5800-8818.Fax: 81-3-5689-7209. E-mail: kadowaki-3im{at}h.u-tokyo.ac.jp.

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