Maternal-fetal nutrient transport in pregnancy pathologies: the role of the placenta

Kendra Elizabeth Brett, Zachary Michael Ferraro, Julien Yockell-Lelievre, Andrée Gruslin, Kristi Bree Adamo, Kendra Elizabeth Brett, Zachary Michael Ferraro, Julien Yockell-Lelievre, Andrée Gruslin, Kristi Bree Adamo

Abstract

Appropriate in utero growth is essential for offspring development and is a critical contributor to long-term health. Fetal growth is largely dictated by the availability of nutrients in maternal circulation and the ability of these nutrients to be transported into fetal circulation via the placenta. Substrate flux across placental gradients is dependent on the accessibility and activity of nutrient-specific transporters. Changes in the expression and activity of these transporters is implicated in cases of restricted and excessive fetal growth, and may represent a control mechanism by which fetal growth rate attempts to match availability of nutrients in maternal circulation. This review provides an overview of placenta nutrient transport with an emphasis on macro-nutrient transporters. It highlights the changes in expression and activity of these transporters associated with common pregnancy pathologies, including intrauterine growth restriction, macrosomia, diabetes and obesity, as well as the potential impact of maternal diet. Molecular signaling pathways linking maternal nutrient availability and placenta nutrient transport are discussed. How sexual dimorphism affects fetal growth strategies and the placenta's response to an altered intrauterine environment is considered. Further knowledge in this area may be the first step in the development of targeted interventions to help optimize fetal growth.

Figures

Figure 1
Figure 1
Nutrient transport across the placenta, featuring the SCTB and the fetal endothelium, and the location of key proteins involved in macronutrient (glucose, amino acids, fatty acids) transport at the MVM and BM. The SCTB is bathed in maternal blood on the apical surface instigating substrate transport at the MVM. This is followed by movement of the nutrients through the cytoplasm of the intermembrane space and interaction with the BM prior to uptake by the fetal capillary endothelium on the opposing side. Glucose is transported across the MVM and BM primarily by GLUT1. The accumulative transporters, System A, mediate the uptake of small neutral amino acids across the MVM and BM into the syncytium. Amino acids are transported across the BM towards the fetal capillary by System L facilitated transporters (TAT1, LAT2, 3 and 4) and exchangers. The exchangers, transport one amino acid in exchange for another, and thus they are dependent on the activity of the accumulative and facilitative transporters. LPL and EL hydrolyze maternal (TG) into FFA that cross the MVM through FATPs, FAT/CD36 and FABPpm. FFAs are trafficked through the cytosol via FABPs and across the BM by FATPs and FAT/CD36. Abbreviations: SCTB—syncytiotrophoblast; MVM—microvillous membrane; BM—basal membrane; GLUT—glucose transporter; LAT—large neutral amino acid transport; TG—triglycerides; LPL—lipoprotein lipase; EL—endothelial lipase; FFA—fatty acid; FAT/CD36—fatty acid translocase; FATP—fatty acid transport protein; FABP—fatty acid binding protein; FABPpm—plasma membrane fatty acid binding protein; X—exchangers.
Figure 2
Figure 2
Regulation of the mTORC1. Various upstream kinases (Akt/PI3K, ERK1/2, RSK1) converge on TSC1/2, which regulates mTOR through Rheb. Activation of mTORC1 leads to the phosphorylation of S6K and the dissociation of eIF4E from 4E-BP, which in turn promotes protein synthesis. Insulin/ IGF phosphorylates Akt, which inhibits TSC2, thus releasing the inhibition of Rheb by TSC1/2. Activated Rheb stimulates mTORC1 signaling. AMPK, in response to low energy levels or hypoxia, phosphorylates TSC2, and thus inhibits mTORC1. Nutrients, specifically amino acids, activate mTORC1, independently of TSC1/2. Abbreviations: mTOR—mammalian target of rapamycin; mTORC1—mTOR complex 1; TSC—tuberous sclerosis complex; Akt/PKB—protein kinase B, ERK—extracellular-signal-regulated kinase, RSK1—MAPK-activated, p90 ribosomal S6 kinase 1; IGF—insulin like growth factor; IRS/PI3K—insulin receptor substrate/phosphoinositide 3-kinase; AMPK—AMP activated kinase; S6K1—p70 ribosomal S6 kinase 1; 4EBP1—eukaryotic initiation factor 4E-binding protein; eIF4E—eukaryotic initiation factor 4E; eIF4B—eukaryotic initiation factor 4B; S6—ribosomal protein S6

References

    1. Otten J., Pitzi Hellig J., Meyers L. Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. National Academic Press; Washington, DC, USA: 2006.
    1. Marconi A.M., Paolini C., Buscaglia M., Zerbe G., Battaglia F.C., Pardi G. The impact of gestational age and fetal growth on the maternal–fetal glucose concentration difference. Obstet. Gynecol. 1996;87:937–942. doi: 10.1016/0029-7844(96)00048-8.
    1. Baumann M.U., Deborde S., Illsley N.P. Placental glucose transfer and fetal growth. Endocrine. 2002;19:13–22. doi: 10.1385/ENDO:19:1:13.
    1. Freinkel N. Banting Lecture 1980. Of pregnancy and progeny. Diabetes. 1980;29:1023–1035.
    1. Poissonnet C.M., Burdi A.R., Garn S.M. The chronology of adipose tissue appearance and distribution in the human fetus. Early Hum. Dev. 1984;10:1–11. doi: 10.1016/0378-3782(84)90106-3.
    1. Haggarty P. Fatty acid supply to the human fetus. Annu. Rev. Nutr. 2010;30:237–255. doi: 10.1146/annurev.nutr.012809.104742.
    1. Sparks J.W., Girard J.R., Battaglia F.C. An estimate of the caloric requirements of the human fetus. Biol. Neonate. 1980;38:113–119. doi: 10.1159/000241351.
    1. Gerretsen G., Huisjes H.J., Elema J.D. Morphological changes of the spiral arteries in the placental bed in relation to pre-eclampsia and fetal growth retardation. Br. J. Obstet. Gynaecol. 1981;88:876–881. doi: 10.1111/j.1471-0528.1981.tb02222.x.
    1. Khong T.Y., de Wolf W.B., Robertson W.B., Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br. J. Obstet. Gynaecol. 1986;93:1049–1059. doi: 10.1111/j.1471-0528.1986.tb07830.x.
    1. Clandinin M.T., Chappell J.E., Heim T., Swyer P.R., Chance G.W. Fatty acid utilization in perinatal de novo synthesis of tissues. Early Hum. Dev. 1981;5:355–366. doi: 10.1016/0378-3782(81)90016-5.
    1. Clandinin M.T., Chappell J.E., Heim T., Swyer P.R., Chance G.W. Fatty acid accretion in fetal and neonatal liver: Implications for fatty acid requirements. Early Hum. Dev. 1981;5:7–14. doi: 10.1016/0378-3782(81)90066-9.
    1. Hull H.R., Thornton J.C., Ji Y., Paley C., Rosenn B., Mathews P., Navder K., Yu A., Dorsey K., Gallagher D. Higher infant body fat with excessive gestational weight gain in overweight women. Am. J. Obstet. Gynecol. 2011;205:211–217. doi: 10.1016/j.ajog.2011.04.004.
    1. Sewell M.F., Huston-Presley L., Super D.M., Catalano P. Increased neonatal fat mass, not lean body mass, is associated with maternal obesity. Am. J. Obstet. Gynecol. 2006;195:1100–1103. doi: 10.1016/j.ajog.2006.06.014.
    1. Josefson J.L., Hoffmann J.A., Metzger B.E. Excessive weight gain in women with a normal pre-pregnancy BMI is associated with increased neonatal adiposity. Pediatr. Obes. 2013;8:e33–e36. doi: 10.1111/j.2047-6310.2012.00132.x.
    1. Jansson T., Illsley N.P. Osmotic water permeabilities of human placental microvillous and basal membranes. J. Membr. Biol. 1993;132:147–155. doi: 10.1007/BF00239004.
    1. Johnson L.W., Smith C.H. Glucose transport across the basal plasma membrane of human placental syncytiotrophoblast. Biochim. Biophys. Acta. 1985;815:44–50. doi: 10.1016/0005-2736(85)90472-9.
    1. Firth J.A., Leach L. Not trophoblast alone: A review of the contribution of the fetal microvasculature to transplacental exchange. Placenta. 1996;17:89–96. doi: 10.1016/S0143-4004(96)80001-4.
    1. Eaton B.M., Leach L., Firth J.A. Permeability of the fetal villous microvasculature in the isolated perfused term human placenta. J. Physiol. 1993;463:141–155.
    1. Jansson T., Myatt L., Powell T.L. The role of trophoblast nutrient and ion transporters in the development of pregnancy complications and adult disease. Curr. Vasc. Pharmacol. 2009;7:521–533. doi: 10.2174/157016109789043982.
    1. Jansson T., Powell T.L. Role of placental nutrient sensing in developmental programming. Clin. Obstet. Gynecol. 2013;56:591–601. doi: 10.1097/GRF.0b013e3182993a2e.
    1. Sibley C.P., Birdsey T.J., Brownbill P., Clarson L.H., Doughty I., Glazier J.D., Greenwood S.L., Hughes J., Jansson T., Mylona P., et al. Mechanisms of maternofetal exchange across the human placenta. Biochem. Soc. Trans. 1998;26:86–91.
    1. Smith C.H., Moe A.J., Ganapathy V. Nutrient transport pathways across the epithelium of the placenta. Annu. Rev. Nutr. 1992;12:183–206. doi: 10.1146/annurev.nu.12.070192.001151.
    1. Lager S., Powell T.L. Regulation of nutrient transport across the placenta. J. Pregnancy. 2012;2012:179827.
    1. Larque E., Ruiz-Palacios M., Koletzko B. Placental regulation of fetal nutrient supply. Curr. Opin. Clin. Nutr. Metab. Care. 2013;16:292–297. doi: 10.1097/MCO.0b013e32835e3674.
    1. Fowden A.L., Ward J.W., Wooding F.P., Forhead A.J., Constancia M. Programming placental nutrient transport capacity. J. Physiol. 2006;572:5–15.
    1. Higgins L., Greenwood S.L., Wareing M., Sibley C.P., Mills T.A. Obesity and the placenta: A consideration of nutrient exchange mechanisms in relation to aberrant fetal growth. Placenta. 2011;32:1–7.
    1. Roland M.C., Friis C.M., Voldner N., Godang K., Bollerslev J., Haugen G., Henriksen T. Fetal growth versus birthweight: The role of placenta versus other determinants. PLoS One. 2012;7:e39324. doi: 10.1371/journal.pone.0039324.
    1. Wallace J.M., Horgan G.W., Bhattacharya S. Placental weight and efficiency in relation to maternal body mass index and the risk of pregnancy complications in women delivering singleton babies. Placenta. 2012;33:611–618. doi: 10.1016/j.placenta.2012.05.006.
    1. Naeye R.L. Do placental weights have clinical significance? Hum Pathol. 1987;18:387–391.
    1. Wilson M.E., Ford S.P. Comparative aspects of placental efficiency. Reprod. Suppl. 2001;58:223–332.
    1. Fowden A.L., Sferruzzi-Perri A.N., Coan P.M., Constancia M., Burton G.J. Placental efficiency and adaptation: Endocrine regulation. J. Physiol. 2009;587:3459–3472. doi: 10.1113/jphysiol.2009.173013.
    1. Salafia C.M., Zhang J., Miller R.K., Charles A.K., Shrout P., Sun W. Placental growth patterns affect birth weight for given placental weight. Birth Defects Res. A. 2007;79:281–288. doi: 10.1002/bdra.20345.
    1. Jansson N., Pettersson J., Haafiz A., Ericsson A., Palmberg I., Tranberg M., Ganapathy V., Powell T.L., Jansson T. Down-regulation of placental transport of amino acids precedes the development of intrauterine growth restriction in rats fed a low protein diet. J. Physiol. 2006;576:935–946. doi: 10.1113/jphysiol.2006.116509.
    1. Jansson T., Cetin I., Powell T.L., Desoye G., Radaelli T., Ericsson A., Sibley C.P. Placental transport and metabolism in fetal overgrowth—A workshop report. Placenta. 2006;27:S109–S113. doi: 10.1016/j.placenta.2006.01.017.
    1. Johansson M., Karlsson L., Wennergren M., Jansson T., Powell T.L. Activity and protein expression of Na+/K+ ATPase are reduced in microvillous syncytiotrophoblast plasma membranes isolated from pregnancies complicated by intrauterine growth restriction. J. Clin. Endocrinol. Metab. 2003;88:2831–2837. doi: 10.1210/jc.2002-021926.
    1. Jansson T., Powell T.L. IFPA 2005 Award in Placentology Lecture. Human placental transport in altered fetal growth: Does the placenta function as a nutrient sensor?—A review. Placenta. 2006;27:S91–S97.
    1. Malandro M.S., Beveridge M.J., Kilberg M.S., Novak D.A. Effect of low-protein diet-induced intrauterine growth retardation on rat placental amino acid transport. Am. J. Physiol. 1996;271:C295–C303.
    1. Godfrey K.M., Matthews N., Glazier J., Jackson A., Wilman C., Sibley C.P. Neutral amino acid uptake by the microvillous plasma membrane of the human placenta is inversely related to fetal size at birth in normal pregnancy. J. Clin. Endocrinol. Metab. 1998;83:3320–3326.
    1. Ogura K., Sakata M., Yamaguchi M., Kurachi H., Murata Y. High concentration of glucose decreases glucose transporter-1 expression in mouse placenta in vitro and in vivo. J. Endocrinol. 1999;160:443–452. doi: 10.1677/joe.0.1600443.
    1. Jones H.N., Powell T.L., Jansson T. Regulation of placental nutrient transport—A review. Placenta. 2007;28:763–774. doi: 10.1016/j.placenta.2007.05.002.
    1. Kalhan S., Parimi P. Gluconeogenesis in the fetus and neonate. Semin. Perinatol. 2000;24:94–106. doi: 10.1053/sp.2000.6360.
    1. Illsley N.P. Glucose transporters in the human placenta. Placenta. 2000;21:14–22. doi: 10.1053/plac.1999.0448.
    1. Jansson T., Wennergren M., Illsley N.P. Glucose transporter protein expression in human placenta throughout gestation and in intrauterine growth retardation. J. Clin. Endocrinol. Metab. 1993;77:1554–1562.
    1. Chiesa C., Osborn J.F., Haass C., Natale F., Spinelli M., Scapillati E., Spinelli A., Pacifico L. Ghrelin, leptin, IGF-1,IGFBP-3,and insulin concentrations at birth: Is there a relationship with fetal growth and neonatal anthropometry? Clin Chem. 2008;54:550–558.
    1. Baumann M.U., Schneider H., Malek A., Palta V., Surbek D.V., Sager R., Zamudio S., Illsley N.P. Regulation of human trophoblast GLUT1 glucose transporter by insulin-like growth factor I (IGF-I) PLoS One. 2014;9:e106037. doi: 10.1371/journal.pone.0106037.
    1. Brown K., Heller D.S., Zamudio S., Illsley N.P. Glucose transporter 3 (GLUT3) protein expression in human placenta across gestation. Placenta. 2011;32:1041–1049. doi: 10.1016/j.placenta.2011.09.014.
    1. Ericsson A., Hamark B., Powell T.L., Jansson T. Glucose transporter isoform 4 is expressed in the syncytiotrophoblast of first trimester human placenta. Hum. Reprod. 2005;20:521–530. doi: 10.1093/humrep/deh596.
    1. Cetin I., Marconi A.M., Corbetta C., Lanfranchi A., Baggiani A.M., Battaglia F.C., Pardi G. Fetal amino acids in normal pregnancies and in pregnancies complicated by intrauterine growth retardation. Early Hum. Dev. 1992;29:183–186. doi: 10.1016/0378-3782(92)90136-5.
    1. Jansson T. Amino acid transporters in the human placenta. Pediatr. Res. 2001;49:141–147. doi: 10.1203/00006450-200102000-00003.
    1. Hoeltzli S.D., Smith C.H. Alanine transport systems in isolated basal plasma membrane of human placenta. Am. J. Physiol. 1989;256:C630–C637.
    1. Desforges M., Mynett K.J., Jones R.L., Greenwood S.L., Westwood M., Sibley C.P., Glazier J.D. The SNAT4 isoform of the system A amino acid transporter is functional in human placental microvillous plasma membrane. J. Physiol. 2009;587:61–72.
    1. Jansson N., Greenwood S.L., Johansson B.R., Powell T.L., Jansson T. Leptin stimulates the activity of the system A amino acid transporter in human placental villous fragments. J. Clin. Endocrinol. Metab. 2003;88:1205–1211. doi: 10.1210/jc.2002-021332.
    1. Jones H.N., Jansson T., Powell T.L. IL-6 stimulates system A amino acid transporter activity in trophoblast cells through STAT3 and increased expression of SNAT2. Am. J. Physiol. Cell Physiol. 2009;297:C1228–C1235.
    1. Roos S., Lagerlof O., Wennergren M., Powell T.L., Jansson T. Regulation of amino acid transporters by glucose and growth factors in cultured primary human trophoblast cells is mediated by mTOR signaling. Am. J. Physiol. Cell Physiol. 2009;297:C723–C731. doi: 10.1152/ajpcell.00191.2009.
    1. Verrey F., System L. Heteromeric exchangers of large, neutral amino acids involved in directional transport. Pflugers Arch. 2003;445:529–533.
    1. Cleal J.K., Glazier J.D., Ntani G., Crozier S.R., Day P.E., Harvey N.C., Robinson S.M., Cooper C., Godfrey K.M., Hanson M.A. Facilitated transporters mediate net efflux of amino acids to the fetus across the basal membrane of the placental syncytiotrophoblast. J. Physiol. 2011;589:987–997. doi: 10.1113/jphysiol.2010.198549.
    1. Kudo Y., Boyd C.A. Characterisation of l-tryptophan transporters in human placenta: A comparison of brush border and basal membrane vesicles. J. Physiol. 2001;531:405–416. doi: 10.1111/j.1469-7793.2001.0405i.x.
    1. Glazier J.D., Cetin I., Perugino G., Ronzoni S., Grey A.M., Mahendran D., Marconi A.M., Pardi G., Sibley C.P. Association between the activity of the system A amino acid transporter in the microvillous plasma membrane of the human placenta and severity of fetal compromise in intrauterine growth restriction. Pediatr. Res. 1997;42:514–519. doi: 10.1203/00006450-199710000-00016.
    1. King J.C. Maternal obesity, metabolism, and pregnancy outcomes. Annu. Rev. Nutr. 2006;26:271–291. doi: 10.1146/annurev.nutr.24.012003.132249.
    1. Duttaroy A.K. Transport of fatty acids across the human placenta: A review. Prog. Lipid Res. 2009;48:52–61. doi: 10.1016/j.plipres.2008.11.001.
    1. Jaye M., Lynch K.J., Krawiec J., Marchadier D., Maugeais C., Doan K., South V., Amin D., Perrone M., Rader D.J. A novel endothelial-derived lipase that modulates HDL metabolism. Nat. Genet. 1999;21:424–428. doi: 10.1038/7766.
    1. Lindegaard M.L., Olivecrona G., Christoffersen C., Kratky D., Hannibal J., Petersen B.L., Zechner R., Damm P., Nielsen L.B. Endothelial and lipoprotein lipases in human and mouse placenta. J. Lipid Res. 2005;46:2339–2346. doi: 10.1194/jlr.M500277-JLR200.
    1. Waterman I.J., Emmison N., Dutta-Roy A.K. Characterisation of triacylglycerol hydrolase activities in human placenta. Biochim. Biophys. Acta. 1998;1394:169–176. doi: 10.1016/S0005-2760(98)00105-2.
    1. McCoy M.G., Sun G.S., Marchadier D., Maugeais C., Glick J.M., Rader D.J. Characterization of the lipolytic activity of endothelial lipase. J. Lipid Res. 2002;43:921–999.
    1. Kazantzis M., Stahl A. Fatty acid transport proteins, implications in physiology and disease. Biochim. Biophys. Acta. 2012;1821:852–857. doi: 10.1016/j.bbalip.2011.09.010.
    1. Schaiff W.T., Bildirici I., Cheong M., Chern P.L., Nelson D.M., Sadovsky Y. Peroxisome proliferator-activated receptor-gamma and retinoid X receptor signaling regulate fatty acid uptake by primary human placental trophoblasts. J. Clin. Endocrinol. Metab. 2005;90:4267–4275. doi: 10.1210/jc.2004-2265.
    1. Larque E., Demmelmair H., Klingler M., de Jonge S, Bondy B., Koletzko B. Expression pattern of fatty acid transport protein-1 (FATP-1), FATP-4 and heart-fatty acid binding protein (H-FABP) genes in human term placenta. Early Hum. Dev. 2006;82:697–701.
    1. Campbell F.M., Bush P.G., Veerkamp J.H., Dutta-Roy A.K. Detection and cellular localization of plasma membrane-associated and cytoplasmic fatty acid-binding proteins in human placenta. Placenta. 1998;19:409–415. doi: 10.1016/S0143-4004(98)90081-9.
    1. Cunningham P., McDermott L. Long chain PUFA transport in human term placenta. J. Nutr. 2009;139:636–639. doi: 10.3945/jn.108.098608.
    1. Mousiolis A.V., Kollia P., Skentou C., Messinis I.E. Effects of leptin on the expression of fatty acid-binding proteins in human placental cell cultures. Mol. Med. Rep. 2012;5:497–502.
    1. Magnusson-Olsson A.L., Hamark B., Ericsson A., Wennergren M., Jansson T., Powell T.L. Gestational and hormonal regulation of human placental lipoprotein lipase. J. Lipid Res. 2006;47:2551–2561.
    1. Lager S., Jansson N., Olsson A.L., Wennergren M., Jansson T., Powell T.L. Effect of IL-6 and TNF-α on fatty acid uptake in cultured human primary trophoblast cells. Placenta. 2011;32:121–127. doi: 10.1016/j.placenta.2010.10.012.
    1. Herrera E. Lipid metabolism in pregnancy and its consequences in the fetus and newborn. Endocrine. 2002;19:43–55.
    1. Woollett L.A. Review: Transport of maternal cholesterol to the fetal circulation. Placenta. 2011;32:S218–S221. doi: 10.1016/j.placenta.2011.01.011.
    1. Wittmaack F.M., Gafvels M.E., Bronner M., Matsuo H., McCrae K.R., Tomaszewski J.E., Robinson S.L., Strickland D.K., Strauss J.F., 3rd. Localization and regulation of the human very low density lipoprotein/apolipoprotein-E receptor: Trophoblast expression predicts a role for the receptor in placental lipid transport. Endocrinology. 1995;136:340–348.
    1. Furuhashi M., Seo H., Mizutani S., Narita O., Tomoda Y., Matsui N. Expression of low density lipoprotein receptor gene in human placenta during pregnancy. Mol. Endocrinol. 1989;3:1252–1256. doi: 10.1210/mend-3-8-1252.
    1. Wadsack C., Hammer A., Levak-Frank S., Desoye G., Kozarsky K.F., Hirschmugl B., Sattler W., Malle E. Selective cholesteryl ester uptake from high density lipoprotein by human first trimester and term villous trophoblast cells. Placenta. 2003;24:131–143. doi: 10.1053/plac.2002.0912.
    1. Stefulj J., Panzenboeck U., Becker T., Hirschmugl B., Schweinzer C., Lang I., Marsche G., Sadjak A., Lang U., Desoye G., et al. Human endothelial cells of the placental barrier efficiently deliver cholesterol to the fetal circulation via ABCA1 and ABCG1. Circ. Res. 2009;104:600–608. doi: 10.1161/CIRCRESAHA.108.185066.
    1. Aye I.L., Waddell B.J., Mark P.J., Keelan J.A. Placental ABCA1 and ABCG1 transporters efflux cholesterol and protect trophoblasts from oxysterol induced toxicity. Biochim. Biophys. Acta. 2010;1801:1013–1024. doi: 10.1016/j.bbalip.2010.05.015.
    1. Nikitina L., Wenger F., Baumann M., Surbek D., Korner M., Albrecht C. Expression and localization pattern of ABCA1 in diverse human placental primary cells and tissues. Placenta. 2011;32:420–430. doi: 10.1016/j.placenta.2011.03.003.
    1. Jansson T., Ylven K., Wennergren M., Powell T.L. Glucose transport and system A activity in syncytiotrophoblast microvillous and basal plasma membranes in intrauterine growth restriction. Placenta. 2002;23:392–399. doi: 10.1053/plac.2002.0826.
    1. Jansson T., Wennergren M., Powell T.L. Placental glucose transport and GLUT 1 expression in insulin-dependent diabetes. Am. J. Obstet. Gynecol. 1999;180:163–168. doi: 10.1016/S0002-9378(99)70169-9.
    1. Jansson T., Ekstrand Y., Wennergren M., Powell T.L. Placental glucose transport in gestational diabetes mellitus. Am. J. Obstet. Gynecol. 2001;184:111–116. doi: 10.1067/mob.2001.108075.
    1. Colomiere M., Permezel M., Riley C., Desoye G., Lappas M. Defective insulin signaling in placenta from pregnancies complicated by gestational diabetes mellitus. Eur. J. Endocrinol. 2009;160:567–578. doi: 10.1530/EJE-09-0031.
    1. Janzen C., Lei M.Y., Cho J., Sullivan P., Shin B.C., Devaskar S.U. Placental glucose transporter 3 (GLUT3) is up-regulated in human pregnancies complicated by late-onset intrauterine growth restriction. Placenta. 2013;34:1072–1078. doi: 10.1016/j.placenta.2013.08.010.
    1. Mahendran D., Donnai P., Glazier J.D., D’Souza S.W., Boyd R.D., Sibley C.P. Amino acid (system A) transporter activity in microvillous membrane vesicles from the placentas of appropriate and small for gestational age babies. Pediatr. Res. 1993;34:661–665. doi: 10.1203/00006450-199311000-00019.
    1. Kuruvilla A.G., D’Souza S.W., Glazier J.D., Mahendran D., Maresh M.J., Sibley C.P. Altered activity of the system A amino acid transporter in microvillous membrane vesicles from placentas of macrosomic babies born to diabetic women. J. Clin. Investig. 1994;94:689–695. doi: 10.1172/JCI117386.
    1. Jansson T., Ekstrand Y, Bjorn C., Wennergren M., Powell T.L. Alterations in the activity of placental amino acid transporters in pregnancies complicated by diabetes. Diabetes. 2002;51:2214–2219.
    1. Farley D.M., Choi J., Dudley D.J., Li C., Jenkins S.L., Myatt L., Nathanielsz P.W. Placental amino acid transport and placental leptin resistance in pregnancies complicated by maternal obesity. Placenta. 2010;31:718–724. doi: 10.1016/j.placenta.2010.06.006.
    1. Jansson N., Rosario F.J., Gaccioli F., Lager S., Jones H.N., Roos S., Jansson T., Powell T.L. Activation of placental mTOR signaling and amino acid transporters in obese women giving birth to large babies. J. Clin. Endocrinol. Metab. 2013;98:105–113. doi: 10.1210/jc.2012-2667.
    1. Jansson T., Scholtbach V., Powell T.L. Placental transport of leucine and lysine is reduced in intrauterine growth restriction. Pediatr. Res. 1998;44:532–537. doi: 10.1203/00006450-199810000-00011.
    1. Magnusson A.L., Waterman I.J., Wennergren M., Jansson T., Powell T.L. Triglyceride hydrolase activities and expression of fatty acid binding proteins in the human placenta in pregnancies complicated by intrauterine growth restriction and diabetes. J. Clin. Endocrinol. Metab. 2004;89:4607–4614. doi: 10.1210/jc.2003-032234.
    1. Gauster M., Hiden U., Blaschitz A., Frank S., Lang U., Alvino G., Cetin I., Desoye G., Wadsack C. Dysregulation of placental endothelial lipase and lipoprotein lipase in intrauterine growth-restricted pregnancies. J. Clin. Endocrinol. Metab. 2007;92:2256–2263.
    1. Radaelli T., Lepercq J., Varastehpour A., Basu S., Catalano P.M., Hauguel-de M.S. Differential regulation of genes for fetoplacental lipid pathways in pregnancy with gestational and type 1 diabetes mellitus. Am. J. Obstet. Gynecol. 2009;201:209. doi: 10.1016/j.ajog.2009.04.019.
    1. Dube E., Gravel A., Martin C., Desparois G., Moussa I., Ethier-Chiasson M., Forest J.C., Giguère Y., Masse A., Lafond J. Modulation of fatty acid transport and metabolism by maternal obesity in the human full-term placenta. Biol. Reprod. 2012;14:14–11. doi: 10.1095/biolreprod.111.098095.
    1. Brass E., Hanson E., O’Tierney-Ginn P.F. Placental oleic acid uptake is lower in male offspring of obese women. Placenta. 2013;34:503–509. doi: 10.1016/j.placenta.2013.03.009.
    1. Lindegaard M.L., Damm P., Mathiesen E.R., Nielsen L.B. Placental triglyceride accumulation in maternal type 1 diabetes is associated with increased lipase gene expression. J. Lipid Res. 2006;47:2581–2588. doi: 10.1194/jlr.M600236-JLR200.
    1. Gauster M., Hiden U., van Poppel M., Frank S., Wadsack C., Hauguel-de Mouzon S., Desoye G. Dysregulation of placental endothelial lipase in obese women with gestational diabetes mellitus. Diabetes. 2011;60:2457–2464. doi: 10.2337/db10-1434.
    1. Scifres C.M., Chen B., Nelson D.M., Sadovsky Y. Fatty acid binding protein 4 regulates intracellular lipid accumulation in human trophoblasts. J. Clin. Endocrinol. Metab. 2011;96:E1083–E1091. doi: 10.1210/jc.2010-2084.
    1. Coan P.M., Vaughan O.R., Sekita Y., Finn S.L., Burton G.J., Constancia M., Fowden A.L. Adaptations in placental phenotype support fetal growth during undernutrition of pregnant mice. J. Physiol. 2010;588:527–538. doi: 10.1113/jphysiol.2009.181214.
    1. Ma Y., Zhu M.J., Uthlaut A.B., Nijland M.J., Nathanielsz P.W., Hess B.W., Ford S.P. Upregulation of growth signaling and nutrient transporters in cotyledons of early to mid-gestational nutrient restricted ewes. Placenta. 2011;32:255–263.
    1. Kavitha J.V., Rosario F.J., Nijland M.J., McDonald T.J., Wu G., Kanai Y., Powell T.L., Nathanielsz P.W., Jansson T. Down-regulation of placental mTOR, insulin/IGF-I signaling, and nutrient transporters in response to maternal nutrient restriction in the baboon. FASEB J. 2014;28:1294–1305. doi: 10.1096/fj.13-242271.
    1. Jones H.N., Woollett L.A., Barbour N., Prasad P.D., Powell T.L., Jansson T. High-fat diet before and during pregnancy causes marked up-regulation of placental nutrient transport and fetal overgrowth in C57/BL6 mice. FASEB J. 2009;23:271–278. doi: 10.1096/fj.08-116889.
    1. Sferruzzi-Perri A.N., Vaughan O.R., Haro M., Cooper W.N., Musial B., Charalambous M., Pestana D., Ayyar S., Ferguson-Smith A.C., et al. An obesogenic diet during mouse pregnancy modifies maternal nutrient partitioning and the fetal growth trajectory. FASEB J. 2013;27:3928–3937.
    1. King V., Hibbert N., Seckl J.R., Norman J.E., Drake A.J. The effects of an obesogenic diet during pregnancy on fetal growth and placental gene expression are gestation dependent. Placenta. 2013;34:1087–1090. doi: 10.1016/j.placenta.2013.09.006.
    1. Prada J.A., Tsang R.C. Biological mechanisms of environmentally induced causes of IUGR. Eur. J. Clin. Nutr. 1998;52:S21–S27.
    1. Radulescu L., Munteanu O., Popa F., Cirstoiu M. The implications and consequences of maternal obesity on fetal intrauterine growth restriction. J. Med. Life. 2013;6:292–298.
    1. Rajasingam D., Seed P.T., Briley A.L., Shennan A.H., Poston L. A prospective study of pregnancy outcome and biomarkers of oxidative stress in nulliparous obese women. Am. J. Obstet. Gynecol. 2009;200:395–399. doi: 10.1016/j.ajog.2008.10.047.
    1. Perlow J.H., Morgan M.A., Montgomery D., Towers C.V., Porto M. Perinatal outcome in pregnancy complicated by massive obesity. Am. J. Obstet. Gynecol. 1992;167:958–962. doi: 10.1016/S0002-9378(12)80019-6.
    1. Sibley C.P., Turner M.A., Cetin I., Ayuk P., Boyd C.A., D’Souza S.W., Glazier J.D., Greenwood S.L., Jansson T., Powell T. Placental phenotypes of intrauterine growth. Pediatr. Res. 2005;58:827–832. doi: 10.1203/01.PDR.0000181381.82856.23.
    1. Sibley C.P. Understanding placental nutrient transfer—Why bother? New biomarkers of fetal growth. J. Physiol. 2009;587:3431–3440. doi: 10.1113/jphysiol.2009.172403.
    1. Norberg S., Powell T.L., Jansson T. Intrauterine growth restriction is associated with a reduced activity of placental taurine transporters. Pediatr. Res. 1998;44:233–238. doi: 10.1203/00006450-199808000-00016.
    1. Wadsack C., Tabano S., Maier A., Hiden U., Alvino G., Cozzi V., Hüttinger M., Schneider W.J., Lang U., Cetin I., et al. Intrauterine growth restriction is associated with alterations in placental lipoprotein receptors and maternal lipoprotein composition. Am. J. Physiol. Endocrinol. Metab. 2007;292:E476–E484. doi: 10.1152/ajpendo.00547.2005.
    1. Roseboom T.J., Painter R.C., de Rooij S.R., van Abeelen A.F., Veenendaal M.V., Osmond C., Barker D.J. Effects of famine on placental size and efficiency. Placenta. 2011;32:395–399. doi: 10.1016/j.placenta.2011.03.001.
    1. Ford S.P., Hess B.W., Schwope M.M., Nijland M.J., Gilbert J.S., Vonnahme K.A., Means W.J., Han H., Nathanielsz P.W. Maternal undernutrition during early to mid-gestation in the ewe results in altered growth, adiposity, and glucose tolerance in male offspring. J. Anim. Sci. 2007;85:1285–1294. doi: 10.2527/jas.2005-624.
    1. Catalano P.M., Presley L., Minium J., Hauguel-de M.S. Fetuses of obese mothers develop insulin resistance in utero. Diabetes Care. 2009;32:1076–1080. doi: 10.2337/dc08-2077.
    1. Luo Z.C., Nuyt A.M., Delvin E., Audibert F., Girard I., Shatenstein B., Cloutier A., Cousineau J., Djemli A., Deal C., et al. Maternal and fetal IGF-I and IGF-II levels, fetal growth, and gestational diabetes. J. Clin. Endocrinol. Metab. 2012;97:1720–1728. doi: 10.1210/jc.2011-3296.
    1. Dube E., Ethier-Chiasson M., Lafond J. Modulation of cholesterol transport by insulin-treated gestational diabetes mellitus in human full term placenta. Biol. Reprod. 2013;88:16. doi: 10.1095/biolreprod.112.105619.
    1. Kuhl C. Etiology and pathogenesis of gestational diabetes. Diabetes Care. 1998;21:B19–B26.
    1. Hull H.R., Dinger M.K., Knehans A.W., Thompson D.M., Fields D.A. Impact of maternal body mass index on neonate birthweight and body composition. Am. J. Obstet. Gynecol. 2008;198:416. doi: 10.1016/j.ajog.2007.10.796.
    1. Visiedo F., Bugatto F., Sanchez V., Cozar-Castellano I., Bartha J.L., Perdomo G. High glucose levels reduce fatty acid oxidation and increase triglyceride accumulation in human placenta. Am. J. Physiol. Endocrinol. Metab. 2013;305:E205–E212. doi: 10.1152/ajpendo.00032.2013.
    1. Desforges M., Greenwood S.L., Glazier J.D., Westwood M., Sibley C.P. The contribution of SNAT1 to system A amino acid transporter activity in human placental trophoblast. Biochem. Biophys. Res. Commun. 2010;398:130–134. doi: 10.1016/j.bbrc.2010.06.051.
    1. Zhu M.J., Ma Y., Long N.M., Du M., Ford S.P. Maternal obesity markedly increases placental fatty acid transporter expression and fetal blood triglycerides at midgestation in the ewe. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2010;299:R1224–R1231. doi: 10.1152/ajpregu.00309.2010.
    1. Clifton V.L. Review: Sex and the human placenta: Mediating differential strategies of fetal growth and survival. Placenta. 2010;31:S33–S39. doi: 10.1016/j.placenta.2009.11.010.
    1. Muralimanoharan S., Maloyan A., Myatt L. Evidence of sexual dimorphism in the placental function with severe preeclampsia. Placenta. 2013;34:1183–1189. doi: 10.1016/j.placenta.2013.09.015.
    1. Lin Y., Zhuo Y., Fang Z.F., Che L.Q., Wu D. Effect of maternal dietary energy types on placenta nutrient transporter gene expressions and intrauterine fetal growth in rats. Nutrition. 2012;28:1037–1043. doi: 10.1016/j.nut.2012.01.002.
    1. Roos S., Powell T.L., Jansson T. Placental mTOR links maternal nutrient availability to fetal growth. Biochem. Soc. Trans. 2009;37:295–298. doi: 10.1042/BST0370295.
    1. Laplante M., Sabatini D.M. mTOR signaling in growth control and disease. Cell. 2012;149:274–293. doi: 10.1016/j.cell.2012.03.017.
    1. Jones H.N., Jansson T., Powell T.L. Full-length adiponectin attenuates insulin signaling and inhibits insulin-stimulated amino acid transport in human primary trophoblast cells. Diabetes. 2010;59:1161–1170. doi: 10.2337/db09-0824.
    1. Von Versen-Hoynck F., Rajakumar A., Parrott M.S., Powers R.W. Leptin affects system A amino acid transport activity in the human placenta: Evidence for STAT3 dependent mechanisms. Placenta. 2009;30:361–367.
    1. Nelson D.M., Smith S.D., Furesz T.C., Sadovsky Y., Ganapathy V., Parvin C.A., Smith C.H. Hypoxia reduces expression and function of system A amino acid transporters in cultured term human trophoblasts. Am. J. Physiol. Cell Physiol. 2003;284:C310–C315. doi: 10.1152/ajpcell.00253.2002.
    1. Rosario F.J., Schumacher M.A., Jiang J., Kanai Y., Powell T.L., Jansson T. Chronic maternal infusion of full-length adiponectin in pregnant mice down-regulates placental amino acid transporter activity and expression and decreases fetal growth. J. Physiol. 2012;590:1495–1509. doi: 10.1113/jphysiol.2011.226399.
    1. Inoki K., Zhu T., Guan K.L. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115:577–590. doi: 10.1016/S0092-8674(03)00929-2.
    1. Xu J., Ji J., Yan X.H. Cross-talk between AMPK and mTOR in regulating energy balance. Crit. Rev. Food Sci. Nutr. 2012;52:373–381. doi: 10.1080/10408398.2010.500245.
    1. Liu X., Chhipa R.R., Pooya S., Wortman M., Yachyshin S., Chow L.M., Kumar A., Zhou X., Sun Y., Quinn B., et al. Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK. Proc. Natl. Acad. Sci. USA. 2014;111:E435–E444. doi: 10.1073/pnas.1311121111.
    1. Roos S., Jansson N., Palmberg I., Saljo K., Powell T.L., Jansson T. Mammalian target of rapamycin in the human placenta regulates leucine transport and is down-regulated in restricted fetal growth. J. Physiol. 2007;582:449–459. doi: 10.1113/jphysiol.2007.129676.
    1. Roos S., Kanai Y., Prasad P.D., Powell T.L., Jansson T. Regulation of placental amino acid transporter activity by mammalian target of rapamycin. Am. J. Physiol. Cell Physiol. 2009;296:C142–C150.
    1. Rosario F.J., Kanai Y., Powell T.L., Jansson T. Mammalian target of rapamycin signalling modulates amino acid uptake by regulating transporter cell surface abundance in primary human trophoblast cells. J. Physiol. 2013;591:609–625. doi: 10.1113/jphysiol.2012.238014.
    1. Proud C.G. Amino acids and mTOR signalling in anabolic function. Biochem. Soc. Trans. 2007;35:1187–1190. doi: 10.1042/BST0351187.
    1. Fang J., Mao D., Smith C.H., Fant M.E. IGF regulation of neutral amino acid transport in the BeWo choriocarcinoma cell line (b30 clone): Evidence for MAP kinase-dependent and MAP kinase-independent mechanisms. Growth Horm. IGF Res. 2006;16:318–325. doi: 10.1016/j.ghir.2006.08.002.
    1. Yung H.W., Calabrese S., Hynx D., Hemmings B.A., Cetin I., Charnock-Jones D.S., Burton G.J. Evidence of placental translation inhibition and endoplasmic reticulum stress in the etiology of human intrauterine growth restriction. Am. J. Pathol. 2008;173:451–462. doi: 10.2353/ajpath.2008.071193.
    1. Rosario F.J., Jansson N., Kanai Y., Prasad P.D., Powell T.L., Jansson T. Maternal protein restriction in the rat inhibits placental insulin, mTOR, and STAT3 signaling and down-regulates placental amino acid transporters. Endocrinology. 2011;152:1119–1129. doi: 10.1210/en.2010-1153.
    1. Gaccioli F., White V., Capobianco E., Powell T.L., Jawerbaum A., Jansson T. Maternal overweight induced by a diet with high content of saturated fat activates placental mTOR and eIF2 alpha signaling and increases fetal growth in rats. Biol. Reprod. 2013;89:96. doi: 10.1095/biolreprod.113.109702.
    1. Zhu M.J., Du M., Nijland M.J., Nathanielsz P.W., Hess B.W., Moss G.E., Ford S.P. Down-regulation of growth signaling pathways linked to a reduced cotyledonary vascularity in placentomes of over-nourished, obese pregnant ewes. Placenta. 2009;30:405–410.
    1. Wullschleger S., Loewith R., Hall M.N. TOR signaling in growth and metabolism. Cell. 2006;124:471–484. doi: 10.1016/j.cell.2006.01.016.
    1. Di Renzo G.C., Rosati A., Sarti R.D., Cruciani L., Cutuli A.M. Does fetal sex affect pregnancy outcome? Gend. Med. 2007;4:19–30.
    1. Eriksson J.G., Kajantie E., Osmond C., Thornburg K., Barker D.J. Boys live dangerously in the womb. Am. J. Hum. Biol. 2010;22:330–335. doi: 10.1002/ajhb.20995.
    1. Aiken C.E., Ozanne S.E. Sex differences in developmental programming models. Reproduction. 2013;145:R1–R13.
    1. Van Abeelen A.F., de Rooij S.R., Osmond C., Painter R.C., Veenendaal M.V., Bossuyt P.M., Elias S.G., Grobbee D.E., van der Schouw Y.T. The sex-specific effects of famine on the association between placental size and later hypertension. Placenta. 2011;32:694–698.
    1. Tarrade A., Rousseau-Ralliard D., Aubriere M.C., Peynot N., Dahirel M., Bertrand-Michel J., Aguirre-Lavin T., Morel O., Beaujean N., Duranthon V., et al. Sexual dimorphism of the feto-placental phenotype in response to a high fat and control maternal diets in a rabbit model. PLoS One. 2013;8:e83458.
    1. Cox L.A., Li C., Glenn J.P., Lange K., Spradling K.D., Nathanielsz P.W., Jansson T. Expression of the placental transcriptome in maternal nutrient reduction in baboons is dependent on fetal sex. J. Nutr. 2013;143:1698–1708. doi: 10.3945/jn.112.172148.
    1. Walker S.P., Ugoni A.M., Lim R., Lappas M. Inverse relationship between gestational weight gain and glucose uptake in human placenta from female foetuses. Pediatr. Obes. 2014;9:e73–e76. doi: 10.1111/j.2047-6310.2013.00206.x.
    1. Lewis R.M., Greenwood S.L., Cleal J.K., Crozier S.R., Verrall L., Inskip H.M., Cameron I.T., Cooper C., Sibley C.P., Hanson M.A., et al. Maternal muscle mass may influence system A activity in human placenta. Placenta. 2010;31:418–422. doi: 10.1016/j.placenta.2010.02.001.
    1. Kim S.Y., Sharma A.J., Sappenfield W., Wilson H.G., Salihu H.M. Association of maternal body mass index, excessive weight gain, and gestational diabetes mellitus with large-for-gestational-age births. Obstet. Gynecol. 2014;123:737–744. doi: 10.1097/AOG.0000000000000177.
    1. Ferraro Z.M., Barrowman N., Prud’homme D., Walker M., Wen S.W., Rodger M., Adamo K.B. Excessive gestational weight gain predicts large for gestational age neonates independent of maternal body mass I ndex. J. Matern. Fetal Neonatal Med. 2012;25:538–542. doi: 10.3109/14767058.2011.638953.

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