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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, 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.

* 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.

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.


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