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 journalArticlepeer-review

4 Scopus citations


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
Pages (from-to)112-119
Number of pages8
JournalBiochimica et Biophysica Acta - General Subjects
Issue number2
StatePublished - May 3 2004

Bibliographical note

Funding Information:
This work was supported by the following grants from the National Institutes of Health: HD24455, DK/HD59815, HD/DK35831 (to P.A.G.) and CA35711, AA02666 and P20 RR15578 (to J.R.W.). P.J.G. was supported by T32 HD07511. Additional support for these studies was provided by the Rhode Island Hospital Department of Pediatrics Research Endowment.


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

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology


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