Peroxisome proliferator-activated receptor-gamma (PPARγ) is down regulated in trophoblast cells of gestational diabetes mellitus (GDM) and in trophoblast tumour cells BeWo in vitro after stimulation with PPARγ agonists
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Julia Knabl
Abstract
Aims: Peroxisome proliferator-activated receptor-gamma (PPARγ) plays an important role in insulin metabolism, trophoblast differentiation and anti-inflammatory circuits. The aim of this study was to investigate the expression of PPARγ in the placenta of patients with gestational diabetes mellitus (GDM) and the regulation of PPARγ by its agonists in trophoblast tumour cells BeWo in vitro.
Methods: PPARγ expression in a total of 80 placentas (40 GDM/40 controls) was analysed by immunohistochemistry using the semi-quantitative immunoreactive score. Furthermore, a quantitative reverse transcription-polymerase chain reaction (PCR) was performed to determine the PPARγ mRNA-expression in both groups. We used a fused and a non-fused BeWo cell culture model for the stimulation with arachidonic acid and 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2). Afterwards PPARγ mRNA-expression was analysed by quantitative real-time PCR (RT-PCR) (TaqMan).
Results: Using immunohistochemistry we identified a decreased expression of PPARγ in the syncytiotrophoblast and the extravillous trophoblast of GDM placentas compared to normal controls. Furthermore, PPARγ mRNA-expression was reduced in GDM placentas. Stimulation of BeWo cells with arachidonic acid and 15d-PGJ2 caused a downregulation of PPARγ expression.
Conclusion: As PPARγ is down regulated by arachidonic acid and 15d-PGJ2, the reduced PPARγ expression in GDM placentas may be due to an altered concentration of fatty acid derivates.
Acknowledgments
The authors thank Christina Kuhn and Simone Hofmann for excellent technical support.
References
[1] AlSaleh A, Sanders TA, O’Dell SD. Effect of interaction between PPARG, PPARA and ADIPOQ gene variants and dietary fatty acids on plasma lipid profile and adiponectin concentration in a large intervention study. Proc Nutr Soc. 2012;71:141–53.10.1017/S0029665111003181Search in Google Scholar
[2] Arck P, Toth B, Pestka A, Jeschke U. Nuclear receptors of the peroxisome proliferator-activated receptor (PPAR) family in gestational diabetes: from animal models to clinical trials. Biol Reprod. 2010;83:168–76.10.1095/biolreprod.110.083550Search in Google Scholar
[3] Barlic J, Murphy PM. An oxidized lipid-peroxisome proliferator-activated receptor gamma-chemokine pathway in the regulation of macrophage-vascular smooth muscle cell adhesion. Trends Cardiovasc Med. 2007;17:269–74.10.1016/j.tcm.2007.09.004Search in Google Scholar
[4] Barnes-Powell LL. Infants of diabetic mothers: the effects of hyperglycemia on the fetus and neonate. Neonatal Netw. 2007;26:283–90.10.1891/0730-0832.26.5.283Search in Google Scholar
[5] Baumann MU, Deborde S, Illsley NP. Placental glucose transfer and fetal growth. Endocrine. 2002;19:13–22.10.1385/ENDO:19:1:13Search in Google Scholar
[6] Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002;53:409–35.10.1146/annurev.med.53.082901.104018Search in Google Scholar
[7] Bitsanis D, Ghebremeskel K, Moodley T, Crawford MA, Djahanbakhch O. Gestational diabetes mellitus enhances arachidonic and docosahexaenoic acids in placental phospholipids. Lipids. 2006;41:341–6.10.1007/s11745-006-5104-8Search in Google Scholar
[8] Bomba-Opon D, Wielgos M, Szymanska M, Bablok L. Effects of free fatty acids on the course of gestational diabetes mellitus. Neuro Endocrinol Lett. 2006;27:277–80.Search in Google Scholar
[9] Capobianco E, Jawerbaum A, Romanini MC, White V, Pustovrh C, Higa R, et al. 15-Deoxy-delta12,14-prostaglandin J2 and peroxisome proliferator-activated receptor gamma (PPARgamma) levels in term placental tissues from control and diabetic rats: modulatory effects of a PPARgamma agonist on nitridergic and lipid placental metabolism. Reprod Fertil Dev. 2005;17:423–33.10.1071/RD04067Search in Google Scholar
[10] Capobianco E, White V, Higa R, Martinez N, Jawerbaum A. Effects of natural ligands of PPARgamma on lipid metabolism in placental tissues from healthy and diabetic rats. Mol Hum Reprod. 2008;14:491–9.10.1093/molehr/gan039Search in Google Scholar
[11] Carpenter MW, Coustan DR. Criteria for screening tests for gestational diabetes. Am J Obstet Gynecol. 1982;144:768–73.10.1016/0002-9378(82)90349-0Search in Google Scholar
[12] Chen X, Scholl TO, Leskiw M, Savaille J, Stein TP. Differences in maternal circulating fatty acid composition and dietary fat intake in women with gestational diabetes mellitus or mild gestational hyperglycemia. Diabetes Care. 2010;33:2049–54.10.2337/dc10-0693Search in Google Scholar
[13] Ditsch N, Vrekoussis T, Lenhard M, Ruhl I, Gallwas J, Weissenbacher T, et al. Retinoid X receptor alpha (RXRalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma) expression in breast cancer: an immunohistochemical study. In Vivo. 2012;26:87–92.Search in Google Scholar
[14] Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell. 1995;83:803–12.10.1016/0092-8674(95)90193-0Search in Google Scholar
[15] Fournier T, Guibourdenche J, Handschuh K, Tsatsaris V, Rauwel B, Davrinche C, et al. PPARgamma and human trophoblast differentiation. J Reprod Immunol. 2011;90:41–9.10.1016/j.jri.2011.05.003Search in Google Scholar
[16] Fournier T, Handschuh K, Tsatsaris V, Evain-Brion D. Involvement of PPARgamma in human trophoblast invasion. Placenta. 2007;28(Suppl A):S76–81.10.1016/j.placenta.2006.12.006Search in Google Scholar
[17] Gil-Sanchez A, Demmelmair H, Parrilla JJ, Koletzko B, Larque E. Mechanisms involved in the selective transfer of long chain polyunsaturated fatty acids to the fetus. Front Genet. 2011;2:57.10.3389/fgene.2011.00057Search in Google Scholar
[18] Grummer R, Hohn HP, Mareel MM, Denker HW. Adhesion and invasion of three human choriocarcinoma cell lines into human endometrium in a three-dimensional organ culture system. Placenta. 1994;15:411–29.10.1016/0143-4004(94)90008-6Search in Google Scholar
[19] Haigh T, Chen C, Jones CJ, Aplin JD. Studies of mesenchymal cells from 1st trimester human placenta: expression of cytokeratin outside the trophoblast lineage. Placenta. 1999;20:615–25.10.1053/plac.1999.0441Search in Google Scholar PubMed
[20] Hanebutt FL, Demmelmair H, Schiessl B, Larque E, Koletzko B. Long-chain polyunsaturated fatty acid (LC-PUFA) transfer across the placenta. Clin Nutr. 2008;27:685–93.10.1016/j.clnu.2008.05.010Search in Google Scholar PubMed
[21] Hirano T, Higuchi T, Katsuragawa H, Inoue T, Kataoka N, Park KR, et al. CD9 is involved in invasion of human trophoblast-like choriocarcinoma cell line, BeWo cells. Mol Hum Reprod. 1999;5:168–74.10.1093/molehr/5.2.168Search in Google Scholar PubMed
[22] 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;31:222–9.10.1016/j.placenta.2009.12.009Search in Google Scholar PubMed
[23] Jansson T, Wennergren M, Illsley NP. Glucose transporter protein expression in human placenta throughout gestation and in intrauterine growth retardation. J Clin Endocrinol Metab. 1993;77:1554–62.Search in Google Scholar
[24] Jawerbaum A, Capobianco E, Pustovrh C, White V, Baier M, Salzberg S, et al. Influence of peroxisome proliferator-activated receptor gamma activation by its endogenous ligand 15-deoxy delta12,14 prostaglandin J2 on nitric oxide production in term placental tissues from diabetic women. Mol Hum Reprod. 2004;10:671–6.10.1093/molehr/gah090Search in Google Scholar
[25] Kersten S, Wahli W. Peroxisome proliferator activated receptor agonists. EXS. 2000;89:141–51.10.1007/978-3-0348-8393-1_9Search in Google Scholar
[26] Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely GB, Koble CS, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci USA. 1997;94:4318–23.10.1073/pnas.94.9.4318Search in Google Scholar
[27] Kubota N, Terauchi Y, Miki H, Tamemoto H, Yamauchi T, Komeda K, et al. PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell. 1999;4:597–609.10.1016/S1097-2765(00)80210-5Search in Google Scholar
[28] Kuhn DC, Botti JJ, Cherouny PH, Demers LM. Eicosanoid production and transfer in the placenta of the diabetic pregnancy. Prostaglandins. 1990;40:205–15.10.1016/0090-6980(90)90084-9Search in Google Scholar
[29] Lee CH, Olson P, Evans RM. Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology. 2003;144:2201–7.10.1210/en.2003-0288Search in Google Scholar PubMed
[30] Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995;270:12953–6.10.1074/jbc.270.22.12953Search in Google Scholar PubMed
[31] Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–8.10.1006/meth.2001.1262Search in Google Scholar PubMed
[32] Maes M, Mihaylova I, Kubera M, Bosmans E. Why fish oils may not always be adequate treatments for depression or other inflammatory illnesses: docosahexaenoic acid, an omega-3 polyunsaturated fatty acid, induces a Th-1-like immune response. Neuro Endocrinol Lett. 2007;28:875–80.Search in Google Scholar
[33] Metzger BE, Buchanan TA, Coustan DR, de Leiva A, Dunger DB, Hadden DR, et al. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. 2007;30(Suppl 2):S251–60.10.2337/dc07-s225Search in Google Scholar PubMed
[34] Min Y, Nam JH, Ghebremeskel K, Kim A, Crawford M. A distinctive fatty acid profile in circulating lipids of Korean gestational diabetics: a pilot study. Diabetes Res Clin Pract. 2006;73:178–83.10.1016/j.diabres.2006.01.003Search in Google Scholar PubMed
[35] Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell. 1998;93:229–40.10.1016/S0092-8674(00)81574-3Search in Google Scholar
[36] O’Moore-Sullivan TM, Prins JB. Thiazolidinediones and type 2 diabetes: new drugs for an old disease. Med J Aust. 2002;176:381–6.10.5694/j.1326-5377.2002.tb04461.xSearch in Google Scholar
[37] Orendi K, Gauster M, Moser G, Meiri H, Huppertz B. The choriocarcinoma cell line BeWo: syncytial fusion and expression of syncytium-specific proteins. Reproduction. 2010;140:759–66.10.1530/REP-10-0221Search in Google Scholar
[38] Ortega-Senovilla H, Schaefer-Graf U, Meitzner K, Abou-Dakn M, Graf K, Kintscher U, et al. Gestational diabetes mellitus causes changes in the concentrations of adipocyte fatty acid-binding protein and other adipocytokines in cord blood. Diabetes Care. 2011;34:2061–6.10.2337/dc11-0715Search in Google Scholar
[39] Powell TL, Jansson T, Illsley NP, Wennergren M, Korotkova M, Strandvik B. Composition and permeability of syncytiotrophoblast plasma membranes in pregnancies complicated by intrauterine growth restriction. Biochim Biophys Acta. 1999;1420:86–94.10.1016/S0005-2736(99)00096-6Search in Google Scholar
[40] Remmele W, Stegner HE. [Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue]. [In German]. Pathologe. 1987;8:138–40.Search in Google Scholar
[41] Ricote M, Huang JT, Welch JS, Glass CK. The peroxisome proliferator-activated receptor(PPARgamma) as a regulator of monocyte/macrophage function. J Leukoc Biol. 1999;66:733–9.10.1002/jlb.66.5.733Search in Google Scholar PubMed
[42] Sacks DB, Arnold M, Bakris GL, Bruns DE, Horvath AR, Kirkman MS, et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Clin Chem. 2011;57:e1–47.10.1373/clinchem.2010.161596Search in Google Scholar PubMed
[43] Schaefer-Graf UM, Meitzner K, Ortega-Senovilla H, Graf K, Vetter K, Abou-Dakn M, et al. Differences in the implications of maternal lipids on fetal metabolism and growth between gestational diabetes mellitus and control pregnancies. Diabet Med. 2011;28:1053–9.10.1111/j.1464-5491.2011.03346.xSearch in Google Scholar PubMed
[44] Schaiff WT, Barak Y, Sadovsky Y. The pleiotropic function of PPAR gamma in the placenta. Mol Cell Endocrinol. 2006;249:10–5.10.1016/j.mce.2006.02.009Search in Google Scholar PubMed
[45] Schopfer FJ, Lin Y, Baker PR, Cui T, Garcia-Barrio M, Zhang J, et al. Nitrolinoleic acid: an endogenous peroxisome proliferator-activated receptor gamma ligand. Proc Natl Acad Sci USA. 2005;102:2340–5.10.1073/pnas.0408384102Search in Google Scholar PubMed PubMed Central
[46] Semple RK, Chatterjee VK, O’Rahilly S. PPAR gamma and human metabolic disease. J Clin Invest. 2006;116:581–9.10.1172/JCI28003Search in Google Scholar PubMed PubMed Central
[47] Suwaki N, Masuyama H, Masumoto A, Takamoto N, Hiramatsu Y. Expression and potential role of peroxisome proliferator-activated receptor gamma in the placenta of diabetic pregnancy. Placenta. 2007;28:315–23.10.1016/j.placenta.2006.04.002Search in Google Scholar PubMed
[48] Toth B, Hornung D, Scholz C, Djalali S, Friese K, Jeschke U. Peroxisome proliferator-activated receptors: new players in the field of reproduction. Am J Reprod Immunol. 2007;58:289–310.10.1111/j.1600-0897.2007.00514.xSearch in Google Scholar PubMed
[49] Wadsack C, Hrzenjak A, Hammer A, Hirschmugl B, Levak-Frank S, Desoye G, et al. Trophoblast-like human choriocarcinoma cells serve as a suitable in vitro model for selective cholesteryl ester uptake from high density lipoproteins. Eur J Biochem. 2003;270:451–62.10.1046/j.1432-1033.2003.03394.xSearch in Google Scholar PubMed
[50] Warning JC, McCracken SA, Morris JM. A balancing act: mechanisms by which the fetus avoids rejection by the maternal immune system. Reproduction. 2011;141:715–24.10.1530/REP-10-0360Search in Google Scholar PubMed
[51] White V, Jawerbaum A, Sinner D, Pustovrh C, Capobianco E, Gonzalez E. Oxidative stress and altered prostanoid production in the placenta of streptozotocin-induced diabetic rats. Reprod Fertil Dev. 2002;14:117–23.10.1071/RD01032Search in Google Scholar
The authors stated that there are no conflicts of interest regarding the publication of this article.
©2014 by Walter de Gruyter Berlin Boston
Articles in the same Issue
- frontmatter
- Review articles
- Evaluation of the role of first-trimester obstetric ultrasound in the detection of major anomalies: a systematic review
- Austrian Newborn Screening Program: a perspective of five decades
- Original articles – Obstetrics
- Cervical strain determined by ultrasound elastography and its association with spontaneous preterm delivery
- Risk factors for unfavorable pregnancy outcome in women with adverse childhood experiences
- Peroxisome proliferator-activated receptor-gamma (PPARγ) is down regulated in trophoblast cells of gestational diabetes mellitus (GDM) and in trophoblast tumour cells BeWo in vitro after stimulation with PPARγ agonists
- Premature rupture of membranes at term in low risk women: how long should we wait in the “latent phase”?
- Ferrous bisglycinate 25 mg iron is as effective as ferrous sulfate 50 mg iron in the prophylaxis of iron deficiency and anemia during pregnancy in a randomized trial
- Neonatal serum magnesium concentrations are determined by total maternal dose of magnesium sulfate administered for neuroprotection
- Labor induction in nulliparous women with an unfavorable cervix: double balloon catheter versus dinoprostone
- Peripartum thromboprophylaxis before and after implementation of a uniform heparin protocol
- Original articles – Fetus
- Impact of sex on perinatal mortality and morbidity in twins
- Opinion paper
- Preeclampsia is caused by continuous sympathetic center excitation due to an enlarged pregnant uterus
- Original articles – Newborn
- Practical application of kangaroo mother care in preterm infants: clinical characteristics and safety of kangaroo mother care
- Survival and neonatal morbidity among extremely preterm born infants in relation to gestational age based on the last menstrual period or ultrasonographic examination
- Short communication
- Reference values of nuchal translucency thickness in a Brazilian population sample: experience from a single center
- Letters to the Editor
- Hepatic rupture: a rare but serious complication of HELLP syndrome
- Reply
- Reply to: hepatic rupture – a rare but serious complication of HELLP syndrome
- Congress Calendar
- Congress Calendar
Articles in the same Issue
- frontmatter
- Review articles
- Evaluation of the role of first-trimester obstetric ultrasound in the detection of major anomalies: a systematic review
- Austrian Newborn Screening Program: a perspective of five decades
- Original articles – Obstetrics
- Cervical strain determined by ultrasound elastography and its association with spontaneous preterm delivery
- Risk factors for unfavorable pregnancy outcome in women with adverse childhood experiences
- Peroxisome proliferator-activated receptor-gamma (PPARγ) is down regulated in trophoblast cells of gestational diabetes mellitus (GDM) and in trophoblast tumour cells BeWo in vitro after stimulation with PPARγ agonists
- Premature rupture of membranes at term in low risk women: how long should we wait in the “latent phase”?
- Ferrous bisglycinate 25 mg iron is as effective as ferrous sulfate 50 mg iron in the prophylaxis of iron deficiency and anemia during pregnancy in a randomized trial
- Neonatal serum magnesium concentrations are determined by total maternal dose of magnesium sulfate administered for neuroprotection
- Labor induction in nulliparous women with an unfavorable cervix: double balloon catheter versus dinoprostone
- Peripartum thromboprophylaxis before and after implementation of a uniform heparin protocol
- Original articles – Fetus
- Impact of sex on perinatal mortality and morbidity in twins
- Opinion paper
- Preeclampsia is caused by continuous sympathetic center excitation due to an enlarged pregnant uterus
- Original articles – Newborn
- Practical application of kangaroo mother care in preterm infants: clinical characteristics and safety of kangaroo mother care
- Survival and neonatal morbidity among extremely preterm born infants in relation to gestational age based on the last menstrual period or ultrasonographic examination
- Short communication
- Reference values of nuchal translucency thickness in a Brazilian population sample: experience from a single center
- Letters to the Editor
- Hepatic rupture: a rare but serious complication of HELLP syndrome
- Reply
- Reply to: hepatic rupture – a rare but serious complication of HELLP syndrome
- Congress Calendar
- Congress Calendar