Increased Expression of the Sterol Regulatory Element-binding Protein-1 Gene in Insulin Receptor Substrate-2−/−Mouse Liver

• Published in: The Journal of biological chemistry 2001-10, Vol.276 (42), p.38337
• Main Authors: Kazuyuki Tobe, Ryo Suzuki, Masashi Aoyama, Toshimasa Yamauchi, Junji Kamon, Naoto Kubota, Yasuo Terauchi, Junji Matsui, Yasuo Akanuma, Satoshi Kimura, Jun Tanaka, Manabu Abe, Jun Ohsumi, Ryozo Nagai, Takashi Kadowaki
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C100160200

Insulin receptor substrate (IRS)-2 −/− mice develop diabetes because of insulin resistance in the liver and failure to undergo β-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.