Targeted hepatic overexpression of human IRS-1: Postnatal effects in the developing mouse

Peter J. Giannone, Barham K. Abu Dayyeh, Theresa C. Bienieki, Jack R. Wands, Philip A. Gruppuso

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Insulin receptor substrate-1 (IRS-1) is an intracellular docking protein involved in insulin and insulin-like growth factor (IGF) signaling. The present studies examine postnatal liver development in transgenic mice with targeted hepatic overexpression of human insulin receptor substrate-1 (hIRS-1). In mature animals, hIRS-1 overexpression augments liver growth. Based on our previous studies that have shown markedly attenuated insulin signaling in the late-gestation and early-postnatal rat, we hypothesized that the liver growth effect of overexpressed hIRS-1 would be attenuated in the neonatal period. Wild-type and heterozygous transgenic mice were studied at 1, 2, 4 or 8 weeks of age. Transgene expression was seen at all ages, albeit at a lower level in the youngest animals. Liver-to-carcass weight ratios were similar in hIRS-1 and wild-type mice at 1 and 2 weeks of age. At 4 and 8 weeks, transgenic mice had larger livers accounted for by increased hepatocyte number, not size. In addition, the transgenic mice had increased liver glycogen content at 8 weeks but not at 1 week. Relative to transgene mRNA expression, hIRS-1 protein levels were restricted in the younger animals. However, IRS-1-associated phosphatidylinositol-3 kinase (PI3K) activity was not similarly suppressed. Downstream from IRS-1, we found activation of the signaling kinase Akt in 8-week-old but not in 1-week-old animals. Our findings indicate that hepatic IRS-1-mediated signaling may be limited in neonatal mice at two levels, post-transcriptional down-regulation of IRS-1 content and attenuated signaling beyond the level of PI3K activation.

Original languageEnglish (US)
Pages (from-to)112-119
Number of pages8
JournalBiochimica et Biophysica Acta - General Subjects
Volume1672
Issue number2
DOIs
StatePublished - May 3 2004
Externally publishedYes

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Keywords

  • Development
  • Glycogen
  • Insulin
  • IRS-1
  • Liver

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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