Targeted hepatic overexpression of human IRS-1: postnatal effects in the developing mouse.
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.
Giannone
Peter J
PJ
Division of Neonatology, Women and Infants Hospital of Rhode Island and Brown University, Providence, RI 02903, USA.
Abu Dayyeh
Barham K
BK
Bienieki
Theresa C
TC
Wands
Jack R
JR
Gruppuso
Philip A
PA
D000818:Animals; D017931:DNA Primers; D006801:Humans; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000378:metabolism*; D015398:Signal Transduction
D017931:DNA Primers; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; D010750:Phosphoproteins