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Published in: Reproductive Biology and Endocrinology 1/2015

Open Access 01-12-2015 | Research

Placental fibroblast growth factor 21 is not altered in late-onset preeclampsia

Authors: Marloes Dekker Nitert, Katherin Scholz-Romero, Marta H Kubala, H David McIntyre, Leonie K Callaway, Helen L Barrett

Published in: Reproductive Biology and Endocrinology | Issue 1/2015

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Abstract

Background

Preeclampsia (PE) is associated with alterations of placental function. The incidence of PE is higher in insulin resistant states. Women with PE have high circulating levels of the metabolic regulator fibroblast growth factor 21 (FGF21). FGF21 is synthesized in the placenta. The aim of this study was to compare the expression of FGF21, its receptors, downstream targets and transcriptional regulators in placental tissue from pregnancies with and without late-onset PE. Circulating FGF21 in maternal and cord blood was also studied.

Methods

mRNA expression was determined by semi-quantitative real-time PCR and normalized for cellular composition in 17 women with and 20 without PE. Protein expression was quantified by Western Blot. FGF21 levels were measured by ELISA in maternal and cord serum of ten mother-baby dyads per condition.

Results

Placental FGF21 mRNA and protein expression were similar in PE compared with control. Placental mRNA expression of the FGF receptors (1–4) and the co-receptor beta-Klotho was not different between the groups. There was no difference in the expression of the glucose transporters GLUT1, 3 or 4. PPAR-alpha but not PPAR-gamma expression was decreased in PE. Maternal FGF21 serum levels were not significantly different in PE. FGF21 was detected in cord blood of 6 infants (4 PE, 2 controls) but was undetectable in 14 infants.

Conclusions

Late-onset PE is not associated with major changes to the expression of FGF21, its receptors or metabolic targets.
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Literature
2.
go back to reference Bellamy L, Casas J-P, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ. 2007;335(7627):974.CrossRefPubMedCentralPubMed Bellamy L, Casas J-P, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ. 2007;335(7627):974.CrossRefPubMedCentralPubMed
3.
go back to reference Nerenberg K, Daskalopoulou SS, Dasgupta K. Gestational diabetes and hypertensive disorders of pregnancy as vascular risk signals: an overview and grading of the evidence. Can J Cardiol. 2014;30(7):765–773.CrossRefPubMed Nerenberg K, Daskalopoulou SS, Dasgupta K. Gestational diabetes and hypertensive disorders of pregnancy as vascular risk signals: an overview and grading of the evidence. Can J Cardiol. 2014;30(7):765–773.CrossRefPubMed
5.
go back to reference Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, et al. FGF-21 as a novel metabolic regulator. J Clin Invest. 2005;115(6):1627–35. doi:10.1172/JCI23606.CrossRefPubMedCentralPubMed Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, et al. FGF-21 as a novel metabolic regulator. J Clin Invest. 2005;115(6):1627–35. doi:10.1172/JCI23606.CrossRefPubMedCentralPubMed
6.
go back to reference Wente W, Efanov AM, Brenner M, Kharitonenkov A, Koster A, Sandusky GE, et al. Fibroblast growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes. 2006;55(9):2470–8. doi:10.2337/db05-1435.CrossRefPubMed Wente W, Efanov AM, Brenner M, Kharitonenkov A, Koster A, Sandusky GE, et al. Fibroblast growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes. 2006;55(9):2470–8. doi:10.2337/db05-1435.CrossRefPubMed
7.
go back to reference De Sousa-Coelho AL, Relat J, Hondares E, Perez-Marti A, Ribas F, Villarroya F, et al. FGF21 mediates the lipid metabolism response to amino acid starvation. J Lipid Res. 2013;54(7):1786.CrossRefPubMedCentralPubMed De Sousa-Coelho AL, Relat J, Hondares E, Perez-Marti A, Ribas F, Villarroya F, et al. FGF21 mediates the lipid metabolism response to amino acid starvation. J Lipid Res. 2013;54(7):1786.CrossRefPubMedCentralPubMed
8.
go back to reference Ge X, Chen C, Hui X, Wang Y, Lam KS, Xu A. Fibroblast growth factor 21 induces glucose transporter-1 expression through activation of the serum response factor/Ets-like protein-1 in adipocytes. J Biol Chem. 2011;286(40):34533–34541. doi:10.1074/jbc.M111.248591.CrossRefPubMedCentralPubMed Ge X, Chen C, Hui X, Wang Y, Lam KS, Xu A. Fibroblast growth factor 21 induces glucose transporter-1 expression through activation of the serum response factor/Ets-like protein-1 in adipocytes. J Biol Chem. 2011;286(40):34533–34541. doi:10.1074/jbc.M111.248591.CrossRefPubMedCentralPubMed
9.
go back to reference Mraz M, Bartlova M, Lacinova Z, Michalsky D, Kasalicky M, Haluzikova D, et al. Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity. Clin Endocrinol (Oxf). 2009;71(3):369–375. doi:10.1111/j.1365-2265.2008.03502.x.CrossRef Mraz M, Bartlova M, Lacinova Z, Michalsky D, Kasalicky M, Haluzikova D, et al. Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity. Clin Endocrinol (Oxf). 2009;71(3):369–375. doi:10.1111/j.1365-2265.2008.03502.x.CrossRef
10.
go back to reference Li S-M, Wang W-F, Zhou L-H, Ma L, An Y, Xu W-J et al. Fibroblast growth factor 21 expressions in white blood cells and sera of patients with gestational diabetes mellitus during gestation and postpartum. Endocrine. 2014:1–9. doi:10.1007/s12020-014-0309-8. Li S-M, Wang W-F, Zhou L-H, Ma L, An Y, Xu W-J et al. Fibroblast growth factor 21 expressions in white blood cells and sera of patients with gestational diabetes mellitus during gestation and postpartum. Endocrine. 2014:1–9. doi:10.1007/s12020-014-0309-8.
11.
go back to reference Ribas F, Villarroya J, Hondares E, Giralt M, Villarroya F. FGF21 expression and release in muscle cells: involvement of MyoD and regulation by mitochondria-driven signalling. Biochem J. 2014;463(2):191–199. doi:10.1042/BJ20140403.CrossRefPubMed Ribas F, Villarroya J, Hondares E, Giralt M, Villarroya F. FGF21 expression and release in muscle cells: involvement of MyoD and regulation by mitochondria-driven signalling. Biochem J. 2014;463(2):191–199. doi:10.1042/BJ20140403.CrossRefPubMed
12.
go back to reference Tan BK, Sivakumar K, Bari MF, Vatish M, Randeva HS. Lower cerebrospinal fluid/plasma fibroblast growth factor 21 (FGF21) ratios and placental FGF21 production in gestational diabetes. PLoS One. 2013;8(6):e65254. doi:10.1371/journal.pone.0065254.CrossRefPubMedCentralPubMed Tan BK, Sivakumar K, Bari MF, Vatish M, Randeva HS. Lower cerebrospinal fluid/plasma fibroblast growth factor 21 (FGF21) ratios and placental FGF21 production in gestational diabetes. PLoS One. 2013;8(6):e65254. doi:10.1371/journal.pone.0065254.CrossRefPubMedCentralPubMed
13.
go back to reference Stepan H, Kley K, Hindricks J, Kralisch S, Jank A, Schaarschmidt W, et al. Serum levels of the adipokine fibroblast growth factor-21 are increased in preeclampsia. Cytokine+. 2013;62(2):322–6. doi:10.1016/j.cyto.2013.02.019.PubMed Stepan H, Kley K, Hindricks J, Kralisch S, Jank A, Schaarschmidt W, et al. Serum levels of the adipokine fibroblast growth factor-21 are increased in preeclampsia. Cytokine+. 2013;62(2):322–6. doi:10.1016/j.cyto.2013.02.019.PubMed
14.
go back to reference Dekker Nitert M, Barrett HL, Kubala MH, Scholz Romero K, Denny KJ, Woodruff TM, et al. Increased placental expression of fibroblast growth factor 21 in gestational diabetes mellitus. J Clin Endocrinol Metab. 2014;99(4):E591–8. doi:10.1210/jc.2013-2581.CrossRefPubMed Dekker Nitert M, Barrett HL, Kubala MH, Scholz Romero K, Denny KJ, Woodruff TM, et al. Increased placental expression of fibroblast growth factor 21 in gestational diabetes mellitus. J Clin Endocrinol Metab. 2014;99(4):E591–8. doi:10.1210/jc.2013-2581.CrossRefPubMed
15.
go back to reference Yang C, Jin C, Li X, Wang F, McKeehan WL, Luo Y. Differential Specificity of Endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in Complex with KLB. PLoS One. 2012;7(3):e33870. doi:10.1371/journal.pone.0033870.CrossRefPubMedCentralPubMed Yang C, Jin C, Li X, Wang F, McKeehan WL, Luo Y. Differential Specificity of Endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in Complex with KLB. PLoS One. 2012;7(3):e33870. doi:10.1371/journal.pone.0033870.CrossRefPubMedCentralPubMed
16.
go back to reference Muise ES, Azzolina B, Kuo DW, El-Sherbeini M, Tan Y, Yuan X, et al. Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor gamma and altered metabolic states. Mol Pharmacol. 2008;74(2):403–412. doi:10.1124/mol.108.044826.CrossRefPubMed Muise ES, Azzolina B, Kuo DW, El-Sherbeini M, Tan Y, Yuan X, et al. Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor gamma and altered metabolic states. Mol Pharmacol. 2008;74(2):403–412. doi:10.1124/mol.108.044826.CrossRefPubMed
17.
go back to reference Hondares E, Rosell M, Gonzalez FJ, Giralt M, Iglesias R, Villarroya F. Hepatic FGF21 expression is induced at birth via PPARalpha in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab. 2010;11(3):206–212. doi:10.1016/j.cmet.2010.02.001.CrossRefPubMedCentralPubMed Hondares E, Rosell M, Gonzalez FJ, Giralt M, Iglesias R, Villarroya F. Hepatic FGF21 expression is induced at birth via PPARalpha in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab. 2010;11(3):206–212. doi:10.1016/j.cmet.2010.02.001.CrossRefPubMedCentralPubMed
19.
go back to reference Desoye G, Gauster M, Wadsack C. Placental transport in pregnancy pathologies. Am J Clin Nutr. 2011. doi:10.3945/ajcn.110.000851. Desoye G, Gauster M, Wadsack C. Placental transport in pregnancy pathologies. Am J Clin Nutr. 2011. doi:10.3945/ajcn.110.000851.
20.
go back to reference He P, Chen Z, Sun Q, Li Y, Gu H, Ni X. Reduced expression of 11beta-hydroxysteroid dehydrogenase type 2 in preeclamptic placentas is associated with decreased PPARgamma but increased PPARalpha expression. Endocrinology. 2013;155(1):299–309. doi:10.1210/en.2013-1350.CrossRefPubMed He P, Chen Z, Sun Q, Li Y, Gu H, Ni X. Reduced expression of 11beta-hydroxysteroid dehydrogenase type 2 in preeclamptic placentas is associated with decreased PPARgamma but increased PPARalpha expression. Endocrinology. 2013;155(1):299–309. doi:10.1210/en.2013-1350.CrossRefPubMed
21.
go back to reference Holdsworth-Carson SJ, Lim R, Mitton A, Whitehead C, Rice GE, Permezel M, et al. Peroxisome proliferator-activated receptors are altered in pathologies of the human placenta: gestational diabetes mellitus, intrauterine growth restriction and preeclampsia. Placenta. 2010;31(3):222–9. doi:10.1016/j.placenta.2009.12.009.CrossRefPubMed Holdsworth-Carson SJ, Lim R, Mitton A, Whitehead C, Rice GE, Permezel M, et al. Peroxisome proliferator-activated receptors are altered in pathologies of the human placenta: gestational diabetes mellitus, intrauterine growth restriction and preeclampsia. Placenta. 2010;31(3):222–9. doi:10.1016/j.placenta.2009.12.009.CrossRefPubMed
22.
go back to reference Rodie VA, Young A, Jordan F, Sattar N, Greer IA, Freeman DJ. Human placental peroxisome proliferator-activated receptor delta and gamma expression in healthy pregnancy and in preeclampsia and intrauterine growth restriction. J Soc Gynecol Investig. 2005;12(5):320–329. doi:10.1016/j.jsgi.2005.03.004.CrossRefPubMed Rodie VA, Young A, Jordan F, Sattar N, Greer IA, Freeman DJ. Human placental peroxisome proliferator-activated receptor delta and gamma expression in healthy pregnancy and in preeclampsia and intrauterine growth restriction. J Soc Gynecol Investig. 2005;12(5):320–329. doi:10.1016/j.jsgi.2005.03.004.CrossRefPubMed
23.
go back to reference Hay Jr WW. Placental-fetal glucose exchange and fetal glucose metabolism. Trans Am Clin Climatol Assoc. 2006;117:321–39. discussion 39–40.PubMedCentralPubMed Hay Jr WW. Placental-fetal glucose exchange and fetal glucose metabolism. Trans Am Clin Climatol Assoc. 2006;117:321–39. discussion 39–40.PubMedCentralPubMed
24.
go back to reference Xing AY, Challier JC, Lepercq J, Caüzac M, Charron MJ, Girard J, et al. Unexpected expression of glucose transporter 4 in villous stromal cells of human placenta. J Clin Endocrinol Metab. 1998;83(11):4097–4101.PubMed Xing AY, Challier JC, Lepercq J, Caüzac M, Charron MJ, Girard J, et al. Unexpected expression of glucose transporter 4 in villous stromal cells of human placenta. J Clin Endocrinol Metab. 1998;83(11):4097–4101.PubMed
25.
go back to reference Hauguel-de Mouzon S, Challier JC, Kacemi A, Cauzac M, Malek A, Girard J. The GLUT3 glucose transporter isoform is differentially expressed within human placental cell types. J Clin Endocrinol Metab. 1997;82(8):2689–2694. doi:10.1210/jcem.82.8.4147.PubMed Hauguel-de Mouzon S, Challier JC, Kacemi A, Cauzac M, Malek A, Girard J. The GLUT3 glucose transporter isoform is differentially expressed within human placental cell types. J Clin Endocrinol Metab. 1997;82(8):2689–2694. doi:10.1210/jcem.82.8.4147.PubMed
26.
go back to reference Janzen C, Lei MYY, Cho J, Sullivan P, Shin BC, Devaskar SU. Placental glucose transporter 3 (GLUT3) is up-regulated in human pregnancies complicated by late-onset intrauterine growth restriction. Placenta. 2013;34(11):1072–1078. doi:10.1016/j.placenta.2013.08.010.CrossRefPubMed Janzen C, Lei MYY, Cho J, Sullivan P, Shin BC, Devaskar SU. Placental glucose transporter 3 (GLUT3) is up-regulated in human pregnancies complicated by late-onset intrauterine growth restriction. Placenta. 2013;34(11):1072–1078. doi:10.1016/j.placenta.2013.08.010.CrossRefPubMed
27.
go back to reference Li K, Li L, Yang M, Liu H, Boden G, Yang G. The effects of fibroblast growth factor-21 knockdown and over-expression on its signaling pathway and glucose-lipid metabolism in vitro. Mol Cell Endocrinol. 2012;348(1):21–26. doi:10.1016/j.mce.2011.07.026.CrossRefPubMed Li K, Li L, Yang M, Liu H, Boden G, Yang G. The effects of fibroblast growth factor-21 knockdown and over-expression on its signaling pathway and glucose-lipid metabolism in vitro. Mol Cell Endocrinol. 2012;348(1):21–26. doi:10.1016/j.mce.2011.07.026.CrossRefPubMed
28.
go back to reference Rajakumar A, Brandon HM, Daftary A, Ness R, Conrad KP. Evidence for the functional activity of hypoxia-inducible transcription factors overexpressed in preeclamptic placentae. Placenta. 2004;25(10):763–769. doi:10.1016/j.placenta.2004.02.011.CrossRefPubMed Rajakumar A, Brandon HM, Daftary A, Ness R, Conrad KP. Evidence for the functional activity of hypoxia-inducible transcription factors overexpressed in preeclamptic placentae. Placenta. 2004;25(10):763–769. doi:10.1016/j.placenta.2004.02.011.CrossRefPubMed
29.
go back to reference Semba RD, Crasto C, Strait J, Sun K, Schaumberg DA, Ferrucci L. Elevated serum fibroblast growth factor 21 is associated with hypertension in community-dwelling adults. J Hum Hypertens. 2013;27(6):397–399. doi:10.1038/jhh.2012.52.CrossRefPubMedCentralPubMed Semba RD, Crasto C, Strait J, Sun K, Schaumberg DA, Ferrucci L. Elevated serum fibroblast growth factor 21 is associated with hypertension in community-dwelling adults. J Hum Hypertens. 2013;27(6):397–399. doi:10.1038/jhh.2012.52.CrossRefPubMedCentralPubMed
30.
go back to reference Yang SJ, Hong HC, Choi HY, Yoo HJ, Cho GJ, Hwang TG, et al. Effects of a three-month combined exercise programme on fibroblast growth factor 21 and fetuin-A levels and arterial stiffness in obese women. Clin Endocrinol (Oxf). 2011;75(4):464–9. doi:10.1111/j.1365-2265.2011.04078.x.CrossRef Yang SJ, Hong HC, Choi HY, Yoo HJ, Cho GJ, Hwang TG, et al. Effects of a three-month combined exercise programme on fibroblast growth factor 21 and fetuin-A levels and arterial stiffness in obese women. Clin Endocrinol (Oxf). 2011;75(4):464–9. doi:10.1111/j.1365-2265.2011.04078.x.CrossRef
31.
go back to reference Gallego-Escuredo JM, Gomez-Ambrosi J, Catalan V, Domingo P, Giralt M, Fruhbeck G, et al. Opposite alterations in FGF21 and FGF19 levels and disturbed expression of the receptor machinery for endocrine FGFs in obese patients. Int J Obes. 2015;39(1):121–9. doi:10.1038/ijo.2014.76.CrossRef Gallego-Escuredo JM, Gomez-Ambrosi J, Catalan V, Domingo P, Giralt M, Fruhbeck G, et al. Opposite alterations in FGF21 and FGF19 levels and disturbed expression of the receptor machinery for endocrine FGFs in obese patients. Int J Obes. 2015;39(1):121–9. doi:10.1038/ijo.2014.76.CrossRef
32.
go back to reference Stein S, Stepan H, Kratzsch J, Verlohren M, Verlohren H-J, Drynda K, et al. Serum fibroblast growth factor 21 levels in gestational diabetes mellitus in relation to insulin resistance and dyslipidemia. Metabolism. 2010;59(1):33–37. doi:10.1016/j.metabol.2009.07.003.CrossRefPubMed Stein S, Stepan H, Kratzsch J, Verlohren M, Verlohren H-J, Drynda K, et al. Serum fibroblast growth factor 21 levels in gestational diabetes mellitus in relation to insulin resistance and dyslipidemia. Metabolism. 2010;59(1):33–37. doi:10.1016/j.metabol.2009.07.003.CrossRefPubMed
33.
go back to reference Scioscia M, Gumaa K, Rademacher TW. The link between insulin resistance and preeclampsia: new perspectives. J Reprod Immunol. 2009;82(2):100–105. doi:10.1016/j.jri.2009.04.009.CrossRefPubMed Scioscia M, Gumaa K, Rademacher TW. The link between insulin resistance and preeclampsia: new perspectives. J Reprod Immunol. 2009;82(2):100–105. doi:10.1016/j.jri.2009.04.009.CrossRefPubMed
34.
go back to reference Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F, et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes. 2008;57(5):1246–1253. doi:10.2337/db07-1476.CrossRefPubMed Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F, et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes. 2008;57(5):1246–1253. doi:10.2337/db07-1476.CrossRefPubMed
35.
go back to reference Han SH, Choi SH, Cho BJ, Lee Y, Lim S, Park YJ, et al. Serum fibroblast growth factor-21 concentration is associated with residual renal function and insulin resistance in end-stage renal disease patients receiving long-term peritoneal dialysis. Metabolism. 2010;59(11):1656–1662. doi:10.1016/j.metabol.2010.03.018.CrossRefPubMed Han SH, Choi SH, Cho BJ, Lee Y, Lim S, Park YJ, et al. Serum fibroblast growth factor-21 concentration is associated with residual renal function and insulin resistance in end-stage renal disease patients receiving long-term peritoneal dialysis. Metabolism. 2010;59(11):1656–1662. doi:10.1016/j.metabol.2010.03.018.CrossRefPubMed
36.
go back to reference Mericq V, De Luca F, Hernandez MI, Peña V, Rossel K, Garcia M, et al. Serum fibroblast growth factor 21 levels are inversely associated with growth rates in infancy. Horm Res Paediatr. 2014;82(5):324–331.CrossRefPubMed Mericq V, De Luca F, Hernandez MI, Peña V, Rossel K, Garcia M, et al. Serum fibroblast growth factor 21 levels are inversely associated with growth rates in infancy. Horm Res Paediatr. 2014;82(5):324–331.CrossRefPubMed
Metadata
Title
Placental fibroblast growth factor 21 is not altered in late-onset preeclampsia
Authors
Marloes Dekker Nitert
Katherin Scholz-Romero
Marta H Kubala
H David McIntyre
Leonie K Callaway
Helen L Barrett
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Reproductive Biology and Endocrinology / Issue 1/2015
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/s12958-015-0006-3

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