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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

121 Scopus citations

Abstract

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 citratelyase, 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.

Original languageEnglish
Pages (from-to)38337-38340
Number of pages4
JournalJournal of Biological Chemistry
Volume276
Issue number42
DOIs
StatePublished - 2001/10/19

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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