Am J Physiol Endocrinol Metab 2020 09 3;319(3):E614-E628. Epub 2020 Aug 3.
Department of Biochemistry, University of Western Ontario, London, Ontario, Canada.
In cultured fetal liver cells, insulin-like growth factor (IGF) binding protein (IGFBP)-1 hyperphosphorylation in response to hypoxia and amino acid deprivation is mediated by inhibition of mechanistic target of rapamycin (mTOR) and activation of amino acid response (AAR) signaling and casein kinase (CK)2. We hypothesized that fetal liver mTOR inhibition, activation of AAR and CK2, and IGFBP-1 hyperphosphorylation occur before development of intrauterine growth restriction (IUGR). Pregnant baboons were fed a control (C) or a maternal nutrient restriction (MNR; 70% calories of control) diet starting at gestational day (GD) 30 (term GD 185). Umbilical blood and fetal liver tissue were obtained at GD 120 (C, = 7; MNR, = 10) and 165 (C, = 7; MNR, = 8). Fetal weights were unchanged at GD 120 but decreased at GD 165 in the MNR group (-13%, = 0.03). IGFBP-1 phosphorylation, as determined by parallel reaction monitoring mass spectrometry (PRM-MS), immunohistochemistry, and/or Western blot, was enhanced in MNR fetal liver and umbilical plasma at GD 120 and 165. IGF-I receptor autophosphorylation (-64%, = 0.05) was reduced in MNR fetal liver at GD 120. Furthermore, fetal liver CK2 (α/α'/β) expression, CK2β colocalization, proximity with IGFBP-1, and CK2 autophosphorylation were greater at GD 120 and 165 in MNR vs. C. Additionally, mTOR complex (mTORC)1 (p-P70S6K, -52%, = 0.05) and mTORC2 (p-Akt, -56%, < 0.001) activity were decreased and AAR was activated (p-GCN2, +117%, = 0.02; p-eIF2α, +294%, = 0.002; p-ERK, +111%, = 0.03) in MNR liver at GD 120. Our data suggest that fetal liver IGFBP-1 hyperphosphorylation, mediated by mTOR inhibition and both AAR and CK2 activation, is a key link between restricted nutrient and oxygen availability and the development of IUGR.