TY - JOUR
T1 - Hyperphosphorylation of fetal liver IGFBP-1 precedes slowing of fetal growth in nutrient-restricted baboons and may be a mechanism underlying IUGR
AU - Kakadia, Jenica H.
AU - Jain, Bhawani B.
AU - Biggar, Kyle
AU - Sutherland, Austen
AU - Nygard, Karen
AU - Li, Cun
AU - Nathanielsz, Peter W.
AU - Jansson, Thomas
AU - Gupta, Madhulika B.
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health (R03 HD-078313 to M.B.G. and T.J.), by Program Project grants (P01 HD-021350 and R03 HD-093950 to P.W.N.), and in part by a Lawson Research Grant (F0609 to M.B.G.).
Funding Information:
We thank Prof. David W. Litchfield (Department of Biochemistry, University of Western Ontario) for the antibodies for protein kinase CK2 and Dr. Mike Miller (Department of Paediatrics, University of Western Ontario) for guidance in statistical analyses. We thank Biotron Integrated Microscopy, Western University, London, ON, Canada, for immunohistochemical and image acquisition analyses. J.H.K. acknowledges a Children’s Health Research Institute (Graduate) Trainee Award funded by Children’s Health Foundation, London, ON, Canada.
PY - 2020/9
Y1 - 2020/9
N2 - Kakadia JH, Jain BB, Biggar K, Sutherland A, Nygard K, Li C, Nathanielsz PW, Jansson T, Gupta MB. Hyperphosphorylation of fetal liver IGFBP-1 precedes slowing of fetal growth in nutrient-restricted baboons and may be a mechanism underlying IUGR. Am J Physiol Endocrinol Metab 319: E614–E628, 2020. First published August 3, 2020; doi:10.1152/ajpendo.00220.2020.—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, n = 7; MNR, n = 10) and 165 (C, n = 7; MNR, n = 8). Fetal weights were unchanged at GD 120 but decreased at GD 165 in the MNR group (-13%, P = 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 autophosphorylationTyr1135 (-64%, P = 0.05) was reduced in MNR fetal liver at GD 120. Furthermore, fetal liver CK2 (a/a0/b) expression, CK2b colocalization, proximity with IGFBP-1, and CK2 autophosphorylationTyr182 were greater at GD 120 and 165 in MNR vs. C. Additionally, mTOR complex (mTORC)1 (pP70S6KThr389, -52%, P = 0.05) and mTORC2 (p-AktSer473, -56%, P < 0.001) activity were decreased and AAR was activated (pGCN2Thr898, +117%, P = 0.02; p-eIF2aSer51, +294%, P = 0.002; pERKThr202, +111%, P = 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.
AB - Kakadia JH, Jain BB, Biggar K, Sutherland A, Nygard K, Li C, Nathanielsz PW, Jansson T, Gupta MB. Hyperphosphorylation of fetal liver IGFBP-1 precedes slowing of fetal growth in nutrient-restricted baboons and may be a mechanism underlying IUGR. Am J Physiol Endocrinol Metab 319: E614–E628, 2020. First published August 3, 2020; doi:10.1152/ajpendo.00220.2020.—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, n = 7; MNR, n = 10) and 165 (C, n = 7; MNR, n = 8). Fetal weights were unchanged at GD 120 but decreased at GD 165 in the MNR group (-13%, P = 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 autophosphorylationTyr1135 (-64%, P = 0.05) was reduced in MNR fetal liver at GD 120. Furthermore, fetal liver CK2 (a/a0/b) expression, CK2b colocalization, proximity with IGFBP-1, and CK2 autophosphorylationTyr182 were greater at GD 120 and 165 in MNR vs. C. Additionally, mTOR complex (mTORC)1 (pP70S6KThr389, -52%, P = 0.05) and mTORC2 (p-AktSer473, -56%, P < 0.001) activity were decreased and AAR was activated (pGCN2Thr898, +117%, P = 0.02; p-eIF2aSer51, +294%, P = 0.002; pERKThr202, +111%, P = 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.
KW - Casein kinase II
KW - Fetal insulin-like growth factor I
KW - Primates
KW - TOR serine-threonine kinases
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U2 - 10.1152/ajpendo.00220.2020
DO - 10.1152/ajpendo.00220.2020
M3 - Article
C2 - 32744097
AN - SCOPUS:85090252475
VL - 319
SP - E614-E628
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 0193-1849
IS - 3
ER -