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Maternal-fetal hepatic and placental metabolome profiles are associated with reduced fetal growth in a rat model of maternal obesity

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Abstract

Introduction

Maternal obesity is associated with a range of pregnancy complications, including fetal growth restriction (FGR), whereby a fetus fails to reach its genetically determined growth. Placental insufficiency and reduced nutrient transport play a role in the onset of FGR.

Objectives

Metabolomic profiling was used to reveal altered maternal and fetal metabolic pathways in a model of diet induced obesity during pregnancy, leading to reduced fetal growth.

Methods

We examined the metabolome of maternal and fetal livers, and placenta following a high fat and salt intake. Sprague–Dawley rats were assigned to (a) control diet (CD; 1 % salt, 10 % kcal from fat), (b) high salt diet (SD; 4 % salt, 10 % kcal from fat), (c) high fat diet (HF; 1 % salt, 45 % kcal from fat) or (d) high-fat high-salt diet (HFSD; 4 % salt, 45 % kcal from fat) 21 days prior to pregnancy and during gestation. Metabolites from maternal and fetal livers, and placenta were identified using gas and liquid chromatography combined with mass spectrometry.

Results

Maternal HF intake resulted in reduced fetal weight. Altered metabolite profiles were observed in the HF maternal and fetal liver, and placenta. Polyunsaturated fatty acid metabolism was significantly altered in maternal and fetal liver by maternal fat intake.

Conclusion

Excess of linoleic and α-linoleic acid (essential fatty acids) may be detrimental during placentation and associated with a reduction in fetal weight. Additionally, maternal, placental and fetal response to increased fat consumption seems likely to involve palmitoleic acid utilization as an adaptive response during maternal obesity.

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References

  • Aggio, R., Villas-Boas, S. G., & Ruggiero, K. (2011). Metab: An R package for high-throughput analysis of metabolomics data generated by GC-MS. Bioinformatics, 27, 2316–2318. doi:10.1093/bioinformatics/btr379.

    Article  CAS  PubMed  Google Scholar 

  • Akyol, A., Langley-Evans, S. C., & McMullen, S. (2009). Obesity induced by cafeteria feeding and pregnancy outcome in the rat. British Journal of Nutrition, 102, 1601–1610. doi:10.1017/S0007114509990961.

    Article  CAS  PubMed  Google Scholar 

  • Anderson, N. H., Sadler, L. C., Stewart, A. W., Fyfe, E. M., & McCowan, L. M. E. (2013). Independent risk factors for infants who are small for gestational age by customised birthweight centiles in a multi-ethnic New Zealand population. Australian and New Zealand Journal of Obstetrics and Gynaecology, 53, 136–142. doi:10.1111/ajo.12016.

    Article  PubMed  Google Scholar 

  • Austdal, M., et al. (2015a). First trimester urine and serum metabolomics for prediction of preeclampsia and gestational hypertension: A prospective screening study. International Journal of Molecular Sciences, 16, 21520–21538. doi:10.3390/ijms160921520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Austdal, M., et al. (2015b). Metabolic profiles of placenta in preeclampsia using HR-MAS MRS metabolomics. Placenta, 36, 1455–1462. doi:10.1016/j.placenta.2015.10.019.

    Article  CAS  PubMed  Google Scholar 

  • Ay, L., et al. (2009). Maternal anthropometrics are associated with fetal size in different periods of pregnancy and at birth. The Generation R Study. The Generation R Study. BJOG, 116, 953–963. doi:10.1111/j.1471-0528.2009.02143.x.

    CAS  PubMed  Google Scholar 

  • Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate—a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society Series B-Methodological, 57, 289–300.

    Google Scholar 

  • Brown, M., et al. (2011). Automated workflows for accurate mass-based putative metabolite identification in LC/MS-derived metabolomic datasets. Bioinformatics, 27, 1108–1112. doi:10.1093/bioinformatics/btr079.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cao, H., Gerhold, K., Mayers, J. R., Wiest, M. M., Watkins, S. M., & Hotamisligil, G. S. (2008). Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell, 134, 933–944. doi:10.1016/j.cell.2008.07.048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cetin, I., et al. (2002). Intrauterine growth restriction is associated with changes in polyunsaturated fatty acid fetal-maternal relationships. Pediatric Research, 52, 750–755. doi:10.1203/01.Pdr.0000031923.07968.D5.

    Article  CAS  PubMed  Google Scholar 

  • Development Core Team, R. (2008). R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing.

    Google Scholar 

  • Diaz, S. O., et al. (2013). Second trimester maternal urine for the diagnosis of trisomy 21 and prediction of poor pregnancy outcomes. Journal of Proteome Research, 12, 2946–2957. doi:10.1021/pr4002355.

    Article  CAS  PubMed  Google Scholar 

  • Economides, D. L., Nicolaides, K. H., & Campbell, S. (1991). Metabolic and endocrine findings in appropriate and small for gestational age fetuses. Journal of Perinatal Medicine, 19, 97–105.

    Article  CAS  PubMed  Google Scholar 

  • Fanos, V., Atzori, L., Makarenko, K., Melis, G. B., & Ferrazzi, E. (2013). Metabolomics application in maternal-fetal medicine. BioMed Research International, 2013, 720514. doi:10.1155/2013/720514.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gardosi, J., Kady, S. M., McGeown, P., Francis, A., & Tonks, A. (2005). Classification of stillbirth by relevant condition at death (ReCoDe): Population based cohort study. British Medical Journal, 331, 1113–1117. doi:10.1136/bmj.38629.587639.7C.

    Article  PubMed  PubMed Central  Google Scholar 

  • Garg, M. L., Blake, R. J., Wills, R. B., & Clayton, E. H. (2007). Macadamia nut consumption modulates favourably risk factors for coronary artery disease in hypercholesterolemic subjects. Lipids, 42, 583–587. doi:10.1007/s11745-007-3042-8.

    Article  CAS  PubMed  Google Scholar 

  • Gueorguieva, R., & Krystal, J. H. (2004). Move over ANOVA—Progress in analyzing repeated-measures data and its reflection in papers published in the archives of general psychiatry. Archives of General Psychiatry, 61, 310–317. doi:10.1001/archpsyc.61.3.310.

    Article  PubMed  Google Scholar 

  • Hajer, G. R., van Haeften, T. W., & Visseren, F. L. (2008). Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. European Heart Journal, 29, 2959–2971. doi:10.1093/eurheartj/ehn387.

    Article  CAS  PubMed  Google Scholar 

  • Hayes, E. K., et al. (2012). Adverse Fetal and neonatal outcomes associated with a life-long high fat diet: Role of altered development of the placental vasculature. PLoS One. doi:10.1371/journal.pone.0033370.

    Google Scholar 

  • Hill, M., Parizek, A., Kancheva, R., & Jirasek, J. E. (2011). Reduced progesterone metabolites in human late pregnancy. Physiological Research, 60, 225–241.

    CAS  PubMed  Google Scholar 

  • Horgan, R. P., et al. (2011). Metabolic profiling uncovers a phenotypic signature of small for gestational age in early pregnancy. Journal of Proteome Research, 10, 3660–3673. doi:10.1021/pr2002897.

    Article  CAS  PubMed  Google Scholar 

  • Howie, G. J., Sloboda, D. M., Kamal, T., & Vickers, M. H. (2009). Maternal nutritional history predicts obesity in adult offspring independent of postnatal diet. Journal of Physiology, 587, 905–915. doi:10.1113/jphysiol.2008.163477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang, L., Yu, X., Keim, S., Li, L., Zhang, L., & Zhang, J. (2014). Maternal prepregnancy obesity and child neurodevelopment in the Collaborative Perinatal Project. International Journal of Epidemiology, 43, 783–792. doi:10.1093/ije/dyu030.

    Article  PubMed  Google Scholar 

  • Innis, S. M. (2008). Dietary omega 3 fatty acids and the developing brain. Brain Research, 1237, 35–43. doi:10.1016/j.brainres.2008.08.078.

    Article  CAS  PubMed  Google Scholar 

  • Kenny, L. C., et al. (2010). Robust early pregnancy prediction of later preeclampsia using metabolomic biomarkers. Hypertension, 56, 741–749. doi:10.1161/HYPERTENSIONAHA.110.157297.

    Article  CAS  PubMed  Google Scholar 

  • Kovo, M., et al. (2013). The placental factor in early- and late-onset normotensive fetal growth restriction. Placenta, 34, 320–324. doi:10.1016/j.placenta.2012.11.010.

    Article  CAS  PubMed  Google Scholar 

  • Kusinski, L. C., et al. (2012). eNOS knockout mouse as a model of fetal growth restriction with an impaired uterine artery function and placental transport phenotype. American Journal of Physiology-Regulatory Integrative and Comparative Physiology, 303, R86–R93. doi:10.1152/ajpregu.00600.2011.

    Article  CAS  Google Scholar 

  • Kyriakakou, M., et al. (2009). The role of IGF-1 and ghrelin in the compensation of intrauterine growth restriction. Reproductive Sciences, 16, 1193–1200. doi:10.1177/1933719109344629.

    Article  CAS  PubMed  Google Scholar 

  • Mark, P. J., et al. (2011). A maternal high-fat diet in rat pregnancy reduces growth of the fetus and the placental junctional zone, but not placental labyrinth zone growth. Journal of Developmental Origins of Health and Disease, 2, 63–70. doi:10.1017/S2040174410000681.

    Article  CAS  Google Scholar 

  • Matthan, N. R., Dillard, A., Lecker, J. L., Ip, B., & Lichtenstein, A. H. (2009). Effects of dietary palmitoleic acid on plasma lipoprotein profile and aortic cholesterol accumulation are similar to those of other unsaturated fatty acids in the F1B golden Syrian hamster. Journal of Nutrition, 139, 215–221. doi:10.3945/jn.108.099804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mayhew, T. M., Ohadike, C., Baker, P. N., Crocker, I. P., Mitchell, C., & Ong, S. S. (2003). Stereological investigation of placental morphology in pregnancies complicated by pre-eclampsia with and without intrauterine growth restriction. Placenta, 24, 219–226. doi:10.1053/plac.2002.0900.

    Article  CAS  PubMed  Google Scholar 

  • McCowan, L. M. E., George-Haddad, M., Stacey, T., & Thompson, J. M. D. (2007). Fetal growth restriction and other risk factors for stillbirth in a New Zealand setting. Australian and New Zealand Journal of Obstetrics and Gynaecology, 47, 450–456. doi:10.1111/j.1479-828X.2007.00778.x.

    Article  PubMed  Google Scholar 

  • McCowan, L. M. E., et al. (2013). Clinical prediction in early pregnancy of infants small for gestational age by customised birthweight centiles: Findings from a healthy nulliparous cohort. PLoS One. doi:10.1371/journal.pone.0070917.

    Google Scholar 

  • McDonald, S. D., Han, Z., Mulla, S., Beyene, J., & Grp, K. S. (2010). Overweight and obesity in mothers and risk of preterm birth and low birth weight infants: Systematic review and meta-analyses. British Medical Journal. doi:10.1136/bmj.c3428.

    Google Scholar 

  • Mele, J., Muralimanoharan, S., Maloyan, A., & Myatt, L. (2014). Impaired mitochondrial function in human placenta with increased maternal adiposity. The American Journal of Physiology—Endocrinology and Metabolism, 307, E419–E425. doi:10.1152/ajpendo.00025.2014.

    Article  CAS  PubMed  Google Scholar 

  • Regnault, T. R. H., de Vrijer, B., Galan, H. L., Wilkening, R. B., Battaglia, F. C., & Meschia, G. (2013). Umbilical uptakes and transplacental concentration ratios of amino acids in severe fetal growth restriction. Pediatric Research, 73, 602–611. doi:10.1038/pr.2013.30.

    Article  CAS  PubMed  Google Scholar 

  • Reynolds, C. M., Vickers, M. H., Harrison, C. J., Segovia, S. A., & Gray, C. (2014). High fat and/or high salt intake during pregnancy alters maternal meta-inflammation and offspring growth and metabolic profiles. Physiological Reports. doi:10.14814/phy2.12110.

    PubMed  PubMed Central  Google Scholar 

  • Roex, A., Nikpoor, P., van Eerd, E., Hodyl, N., & Dekker, G. (2012). Serial plotting on customised fundal height charts results in doubling of the antenatal detection of small for gestational age fetuses in nulliparous women. Australian and New Zealand Journal of Obstetrics and Gynaecology, 52, 78–82. doi:10.1111/j.1479-828X.2011.01408.x.

    Article  PubMed  Google Scholar 

  • Salihu, H. M., Mbah, A. K., Alio, A. P., Kornosky, J. L., Bruder, K., & Belogolovkin, V. (2009). Success of programming fetal growth phenotypes among obese women. Obstetrics and Gynecology, 114, 333–339. doi:10.1097/AOG.0b013e3181ae9a47.

    Article  PubMed  Google Scholar 

  • Simopoulos, A. P. (2011). Importance of the omega-6/omega-3 balance in health and disease: Evolutionary aspects of diet. World Review of Nutrition and Dietetics, 102, 10–21. doi:10.1159/000327785.

    Article  CAS  PubMed  Google Scholar 

  • Smart, K. F., Aggio, R. B., Van Houtte, J. R., & Villas-Boas, S. G. (2010). Analytical platform for metabolome analysis of microbial cells using methyl chloroformate derivatization followed by gas chromatography-mass spectrometry. Nature Protocols, 5, 1709–1729. doi:10.1038/nprot.2010.108.

    Article  CAS  PubMed  Google Scholar 

  • Stein, S. E. (1999). An integrated method for spectrum extraction and compound identification from gas chromatography/mass spectrometry data. Journal of the American Society for Mass Spectrometry, 10, 770–781. doi:10.1016/S1044-0305(99)00047-1.

    Article  CAS  Google Scholar 

  • Sumner, L. W., et al. (2007). Proposed minimum reporting standards for chemical analysis. Metabolomics, 3, 211–221. doi:10.1007/s11306-007-0082-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uauy, R., Hoffman, D. R., Peirano, P., Birch, D. G., & Birch, E. E. (2001). Essential fatty acids in visual and brain development. Lipids, 36, 885–895.

    Article  CAS  PubMed  Google Scholar 

  • Xia, J. G., & Wishart, D. S. (2011). Web-based inference of biological patterns, functions and pathways from metabolomic data using MetaboAnalyst. Nature Protocols, 6, 743–760. doi:10.1038/nprot.2011.319.

    Article  CAS  PubMed  Google Scholar 

  • Yang, Z. H., Miyahara, H., & Hatanaka, A. (2011). Chronic administration of palmitoleic acid reduces insulin resistance and hepatic lipid accumulation in KK-Ay Mice with genetic type 2 diabetes. Lipids in Health and Disease, 10, 120. doi:10.1186/1476-511X-10-120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, L. X., et al. (2014). Untargeted fatty acid profiles based on the selected ion monitoring mode. Analytica Chimica Acta, 839, 44–50. doi:10.1016/j.aca.2014.06.040.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to express their gratitude for support provided by the Vernon Jansen Unit and the Centre for Genomics, Proteomics and Metabolomics. Technical assistance was provided by Rachna Patel, Angelica Bernal, Minglan Li, Elizabeth McKenzie and Margaret Coe. Financial assistance was provided by Gravida: National Centre for Growth and Development (Project no. STF-13-24), Lotteries Health Research Fellowship, Faculty Development Research Funding (FDRF) and the Nutricia Research Foundation.

Author contributions

KS, PNB, CG and MHV designed research; KM and CJH conducted the research with support from KR in the biostatistical analysis; KS, CG and KM wrote manuscript; MHV, PNB, JLS, CMR, KR and SGV-B critically evaluated the manuscript.

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    Authors and Affiliations

    1. Liggins Institute, University of Auckland, Auckland, New Zealand

      Karen Mumme, Clint Gray, Clare M. Reynolds, Mark H. Vickers, Claudia J. Harrison, Joanna L. Stanley, Philip N. Baker & Karolina Sulek

    2. Gravida: National Centre for Growth and Development, Auckland, New Zealand

      Karen Mumme, Clint Gray, Clare M. Reynolds, Mark H. Vickers, Claudia J. Harrison, Joanna L. Stanley, Silas G. Villas-Bôas, Philip N. Baker & Karolina Sulek

    3. Department of Statistics, University of Auckland, Auckland, New Zealand

      Kathy Ruggiero

    4. School of Biological Sciences, University of Auckland, Auckland, New Zealand

      Silas G. Villas-Bôas

    5. The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3b, 6.6.24, 2200 N, Copenhagen, Denmark

      Karolina Sulek

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    1. Karen Mumme
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    Correspondence to Karolina Sulek.

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    KM, CG, CMR, MHV, CJH, JLS, KR, SGV-B, PNB, KS declare that they have no conflict of interest.

    Ethical approval

    All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. Animal procedures were approved by the Animal Ethics Committee of the University of Auckland (approval R1069). This article does not contain any studies with human participants performed by any of the authors.

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    Karen Mumme and Clint Gray have contributed equally.

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    Mumme, K., Gray, C., Reynolds, C.M. et al. Maternal-fetal hepatic and placental metabolome profiles are associated with reduced fetal growth in a rat model of maternal obesity. Metabolomics 12, 83 (2016). https://doi.org/10.1007/s11306-016-1014-9

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