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Originally published In Press as doi:10.1074/jbc.C100160200 on August 23, 2001

J. Biol. Chem., Vol. 276, Issue 42, 38337-38340, October 19, 2001
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ACCELERATED PUBLICATION
Increased Expression of the Sterol Regulatory Element-binding Protein-1 Gene in Insulin Receptor Substrate-2minus /minus Mouse Liver*

Kazuyuki TobeDagger , Ryo SuzukiDagger , Masashi AoyamaDagger , Toshimasa YamauchiDagger , Junji KamonDagger , Naoto KubotaDagger , Yasuo TerauchiDagger , Junji MatsuiDagger , Yasuo Akanuma§, Satoshi KimuraDagger , Jun Tanaka, Manabu Abe, Jun Ohsumi, Ryozo NagaiDagger , and Takashi KadowakiDagger ||

From the Dagger  Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, § Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo, 100-0005, and  Biomedical Research Laboratories, Sankyo Corporation Ltd., Tokyo, 140-8710, Japan

Insulin receptor substrate (IRS)-2-/- mice develop diabetes because of insulin resistance in the liver and failure to undergo beta -cell hyperplasia. Here we show by DNA chip microarray analysis that expression of the sterol regulatory element-binding protein (SREBP)-1 gene, a downstream target of insulin, was paradoxically increased in 16-week-old IRS-2-/- mouse liver, where insulin-mediated intracellular signaling events were substantially attenuated. The expression of SREBP-1 downstream genes, such as the spot 14, ATP citrate-lyase, and fatty acid synthase genes, was also increased. Increased liver triglyceride content in IRS-2-/- mice assures the physiological importance of SREBP-1 gene induction. IRS-2-/- mice showed leptin resistance; low dose leptin administration, enough to reduce food intake and body weight in wild-type mice, failed to do so in IRS-2-/- mice. Interestingly, high dose leptin administration reduced SREBP-1 expression in IRS-2-/- mouse liver. Thus, IRS-2 gene disruption results in leptin resistance, causing an SREBP-1 gene induction, obesity, fatty liver, and diabetes.

* This work was supported by Health Sciences research grants (for research on human genome and gene therapy) from the Ministry of Health and Welfare and Grant 1-2000-231 from the Juvenile Diabetes Foundation International (to T. K.), by a grant-in-aid for the development of innovative technology and a grant-in-aid for creative basic research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to T. K. and K. T.), and by a health sciences research grant from the Ministry of Health and Welfare (to R. N.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom correspondence should be addressed: Dept. of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel.: 81-3-5800-8818; Fax: 81-3-5689-7209; E-mail: kadowaki-3im@h.u-tokyo.ac.jp.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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