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Published on: November 20, 2015
Insulin signaling during perinatal liver development in the rat
Padmanabhan Anand1, Joan M Boylan, Yangsi Ou
1Department of Pediatrics, Rhode Island Hospital and Brown University, Providence, Rhode Island 02903, USA.
Insights
Fetal rat liver exhibits significantly reduced insulin signaling, impacting growth and metabolism. Protein synthesis in late gestation appears independent of insulin and mTOR, suggesting a need to re-evaluate insulin
Area of Science:
- * Developmental biology
- * Endocrinology
- * Molecular biology
Background:
- * Insulin is crucial for fetal growth and metabolism.
- * Previous studies showed attenuated hepatic insulin signaling in late-gestation fetal rats.
- * The perinatal development of hepatic insulin signaling requires further investigation.
Purpose of the Study:
- * To investigate the perinatal ontogeny of hepatic insulin signaling from phosphatidylinositol 3-kinase (PI3K) to the ribosome.
- * To understand the role of insulin in regulating protein synthesis during fetal liver development.
Main Methods:
- * Assessed insulin-mediated activation of key signaling proteins: PI3K, Akt, insulin receptor substrate (IRS)-1 and IRS-2, ribosomal protein S6 kinase 1 (S6K1), 4E-BP1, eukaryotic initiation factor eIF4E, and mammalian target of rapamycin (mTOR).
- * Compared signaling pathways in fetal and adult rat livers.
- * Analyzed protein levels and phosphorylation states.
Main Results:
- * Fetal liver showed markedly decreased insulin-mediated activation of S6K1, Akt, and PI3K compared to adults.
- * Levels of IRS-1 and IRS-2 were significantly lower in fetal liver.
- * Insulin-mediated phosphorylation of 4E-BP1 and ribosomal protein S6 was attenuated in fetuses.
- * mTOR was present in low amounts, hypophosphorylated, and not insulin-sensitive in the fetus.
Conclusions:
- * Hepatic protein synthesis during late-gestation fetal development may be independent of insulin and mTOR.
- * The findings suggest a need to re-examine the role of insulin in fetal liver physiology.
- * Insulin signaling pathways mature postnatally, transitioning to the adult phenotype.
Abstract:
Insulin has long been assigned a key role in the regulation of growth and metabolism during fetal life. Our prior observations indicated that hepatic insulin signaling is attenuated in the late-gestation fetal rat. Therefore, we studied the perinatal ontogeny of hepatic insulin signaling extending from phosphatidylinositol 3-kinase (PI3K) to the ribosome. Initial studies demonstrated markedly decreased insulin-mediated activation of ribosomal protein S6 kinase 1 (S6K1) in the fetus. We found a similar pattern in the regulation of Akt, a kinase upstream from S6K1. Insulin produced minimal activation of insulin receptor substrate (IRS)-1-associated PI3K activity in fetal liver. A modest IRS-2-associated response was seen in the fetus. However, levels of both IRS-1 and IRS-2 were very low in fetal liver relative to adult liver. IRS-1 content and insulin responsiveness of PI3K, Akt, and S6K1 showed a transition to the adult phenotype during the first several postnatal weeks. Examination of downstream insulin signaling to the translational apparatus showed marked attenuation, relative to the adult, of fetal hepatic insulin-mediated phosphorylation of 4E-BP1, the regulatory protein for the eukaryotic initiation factor eIF4E, and ribosomal protein S6. The mammalian target of rapamycin (mTOR), a key integrator of nutritional and metabolic regulation of translation, was present in low amounts, was hypophosphorylated, and was not insulin sensitive in the fetus. Our results indicate that protein synthesis during late-gestation liver development may be mTOR and insulin independent. Reexamination of the role of insulin in fetal liver physiology may be warranted.
