The pleiotropic function of PPARγ in the placenta

doi:10.1016/j.mce.2006.02.009

Molecular and Cellular Endocrinology

Volume 249, Issues 1–2, 25 April 2006, Pages 10-15

https://doi.org/10.1016/j.mce.2006.02.009 Get rights and content

Abstract

At different stages of placental development the cytotrophoblasts differentiate into specialized cells that are vital for specific placental tasks. These types include the invasive trophoblasts, which are responsible for invasion of the placenta into the uterine wall, and syncytiotrophoblasts, which form a barrier between the maternal and fetal circulations, govern trans-placental transport of gas, nutrient and waste, and produce placental hormones. Recent research illuminated the role of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in the areas of adipocyte and macrophage biology, insulin action, bioenergetics and inflammation. It was somewhat surprising that PPARγ was also found to play a pivotal role in placental biology. In this review we summarize recent data, which show that PPARγ is expressed in the placenta, particularly in trophoblasts, and is essential for placental development, trophoblast invasion, differentiation of cytotrophoblasts into syncytium, and regulation of fat accumulation in trophoblasts. PPARγ may also play a role in modulating fetal membrane signals toward parturition. The data presented here underscore the need for a focused investigation of the unique aspects of PPARγ function in trophoblasts, which may have direct implications for the use of PPARγ ligands during pregnancy.

Introduction

Proper growth and differentiation of the placenta is essential for mammalian fetal development and the maintenance of pregnancy. During pregnancy the placenta must attach to and invade the uterine wall, and differentiate into structures that facilitate exchange of gas, nutrient and waste products between the maternal and fetal circulation. The placenta also imparts an anatomical and immunological barrier between the two systems, and provides hormonal signals for the maintenance of pregnancy. Many aspects of these processes are regulated by the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ), which functions as a heterodimer along with its partner, RXR. This review summarizes the central role of PPARγ in supporting mammalian feto-placental development. A detailed description of the molecular mechanisms PPARγ activity can be found elsewhere in excellent reviews, some of which are cited here.

Section snippets

The transcriptional activation function of PPARγ

PPARγ is one of three PPAR proteins (α, β/δ and γ, also termed NR1C1, NR1C2 or NR1C3, respectively) that belong to a family of ligand-activated nuclear hormone receptors (Desvergne and Wahli, 1999, Tan et al., 2005). PPARs regulate development and differentiation, and govern cellular bioenergetics by modulating fat and glucose metabolism and inflammatory response (reviewed in Kota et al., 2005, Lazar, 2005). Alternative promoters give rise to two major PPARγ isoforms, which differ in their AF1

Placental expression of PPARγ

PPARγ is expressed in the mouse placenta as early as embryonic day 8.5 (E8.5) (Barak et al., 1999) and in rats by E11 (Asami-Miyagishi et al., 2004). Murine PPARγ is expressed both in the spongiotrophoblast and in the labyrinth, which forms an interface between the maternal and fetal blood (Asami-Miyagishi et al., 2004, Barak et al., 1999, Kubota et al., 1999, Wang et al., 2004). Within the human placenta PPARγ is expressed predominantly in trophoblasts (Rodie et al., 2005, Schaiff et al., 2000

PPARγ pathways in placental development

In the absence of information on PPARγ deficiency in humans, the unexpected essential functions of PPARγ in placental development were gleaned from studies of gene-targeted mice. Ablation of PPARγ in mice leads to embryonic lethality at E10, a time when nutritional support to the developing embryo switches from the primary yolk sac to the placenta (Barak et al., 1999, Kubota et al., 1999). PPARγ-null placentas exhibit malformed labyrinth zone, with no permeation of fetal blood vessels and

Exposure to PPARγ ligands during pregnancy

Although the natural ligand for placental PPARγ is presently unknown, it could originate in the placenta, maternal serum, fetus or the amniotic fluid (Fig. 1). Waite et al. (2000) provided evidence for the presence of a PPARγ agonist in the serum of pregnant women. This agonist is heat stable, suggesting that it is not a protein but possibly a naturally occurring prostanoid or fatty acid, which are known to stimulate PPARγ activity (reviewed in Kota et al., 2005). Administration of the

Conclusion

PPARγ is essential for multiple functions of the placenta, including trophoblast differentiation, invasion and uptake of lipids that are important for fetal intrauterine development and as precursors for steroid hormone biosynthesis by trophoblasts. In addition, PPARγ agonists may decrease the risk of preterm delivery by suppressing the inflammatory response within the fetal membranes. Additional research that focuses on the mechanism of action, molecular targets, and functions of placental

Acknowledgements

This work was supported by NIH R01 HD044103 (to YB) and R01 ES11597 (to YS). We thank Lori Rideout for assistance with manuscript and figure preparation. While we are grateful to all researchers who contributed to this field, we are cognizant that not all manuscripts related to PPARγ and its role in the placenta could be cited here. We apologize for any relevant paper that was excluded from this review.

References (75)

R. Asami-Miyagishi et al.
Biochem. Biophys. Res. Commun.
(2004)
Y. Barak et al.
Mol. Cell.
(1999)
F.M. Campbell et al.
Placenta
(1998)
N.A. Cataldo et al.
Fertil. Steril.
(2001)
L.Y. Chan et al.
Fertil. Steril.
(2005)
A. Chawla et al.
Mol. Cell.
(2001)
I.P. Crocker et al.
Am. J. Pathol.
(2003)
G. Daoud et al.
Biochim. Biophys. Acta
(2005)
S.S. Davies et al.
J. Biol. Chem.
(2001)
L.R. Dunn-Albanese et al.
Am. J. Obstet. Gynecol.
(2004)

F. Yaris et al.

Reprod. Toxicol.

(2004)

Y. Zhu et al.

J. Biol. Chem.

(2000)

Y.J. Zhu et al.

J. Biol. Chem.

(2003)

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PPARγ is found to influence trophoblast syncytialization and differentiation through activation of GCM1 transcription factor leading to expression of hCG [15,16]. In context to trophoblast biology and placental development, the role of PPARβ/δ & PPARγ is very well known as they are involved in hCG synthesis, fatty acid uptake, lipid metabolism [14], and trophoblast growth [15–17], differentiation [18], and invasion [16], but the role of PPARα is still unexplored. Other than the role of PPARα in lipid metabolism, its role in tumor progression or suppression has also been observed in few studies [11,12].
The Peroxisome Proliferator-Activated Receptor-alpha (PPARα) is a member of the ligand-dependent nuclear receptor superfamily known for their crucial role in lipid metabolism. The expression and role of PPARα in trophoblast cells are not very well known. Trophoblast invasion is one of the most critical processes required for successful implantation of the developing embryo into the maternal endometrium. Defects in this process are associated with adverse pregnancy outcomes such as FGR(Fetal Growth Restriction), Preeclampsia, and choriocarcinoma. In this present study, we investigated the role of the ligand-activated transcription factor, Peroxisome proliferator-activated receptor (PPARα) in regulating trophoblast cell invasion using cell lines and explants-based models. Immunohistological localization of PPARα in human placental tissues showed a gestational variation with relatively low expression at term as compared to early trimester. PCR and Western Blot also confirmed this. Further to delineate the effect of PPAR alpha on trophoblast invasion, EVT derived HTR8/SVneo cell lines were stimulated with PPARα agonist, i.e., fenofibrate (FF). Fenofibrate stimulation led to an increased activation and nuclear translocation of PPARα, followed by reduced migration and invasion of these cells in a matrigel invasion assay (Boyden chamber). PPAR alpha stimulation also led to a reduced MMP-2/9 expression following our previous observation. Thus, we may conclude that PPARα to be playing a very important regulatory role in orchestrating the invasive trophoblast programme and hence it seems plausible for it to be associated with PE, which is often characterized by a shallow trophoblast invasion.
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Pregnancy is a critical time of vulnerability for the development of the fetal brain. Exposure to environmental pollutants at any point in pregnancy can negatively impact many aspects of fetal development, especially the organization and differentiation of the brain. The placenta performs a variety of functions that can help protect the fetus and sustain brain development. However, disruption of any of these functions can have negative impacts on both the pregnancy outcome and fetal neurodevelopment. This review presents current understanding of how environmental exposures, specifically to endocrine disrupting chemicals (EDCs), interfere with placental function and, in turn, neurodevelopment. Some of the key differences in placental development between animal models are presented, as well as how placental functions such as serving as a xenobiotic barrier and exchange organ, immune interface, regulator of growth and fetal oxygenation, and a neuroendocrine organ, could be vulnerable to environmental exposure. This review illustrates the importance of the placenta as a modulator of fetal brain development and suggests critical unexplored areas and possible vulnerabilities to environmental exposure.
Prenatal testosterone exposure induces insulin resistance, uterine oxidative stress and pro-inflammatory status in rats
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Prenatal androgen excess is considered one of the main causes of the development of polycystic ovary syndrome. In this study, we investigated the effect of prenatal hyperandrogenization (PH) on the physiology of the adult uterine tissue using a murine model of fetal programming caused by androgen excess in adult female rats. Pregnant rats were hyperandrogenized with testosterone and female offspring were studied when adult. Our results showed that PH leads to hyperglycemia and hyperinsulinemia. Consequently, PH developed insulin resistance and a systemic inflammatory state reflected by increased C-reactive protein. In the uterine tissue, levels of PPAR gamma—an important metabolic sensor in the endometrium—were found to be impaired. Moreover, PH induced a pro-inflammatory and an unbalanced oxidative state in the uterus reflected by increased COX-2, lipid peroxidation, and NF-κB. In summary, our results revealed that PH leads to a compromised metabolic state likely consequence of fetal reprogramming.
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Human chorionic gonadotropin (hCG) is one of the first hormonal messages produced by the placenta toward the mother. Detectable in maternal blood 2 days after implantation, hCG behaves like a superagonist of LH inducing the secretion of progesterone by the corpus luteum until the placenta itself acquires the ability to produce progesterone. hCG also has a role in quiescence of the myometrium and in local immune tolerance. Specific to humans, hCG is a complex glycoprotein composed of two highly glycosylated subunits. The α-subunit is identical to the pituitary gonadotrophin hormones (LH, FSH, TSH), contains two N-glycosylation sites, and is encoded by a single gene (CGA). The β-subunits are distinct in each of the gonadotropin hormones and confer receptor and biological specificity. hCGβ subunit is encoded by a cluster of genes (CGB), and the protein contains two sites of N-glycosylation and four sites of O-glycosylation. The expression of hCG and its glycosylation state vary with the stage of pregnancy, the source of production, and the pathology. The syncytiotrophoblast (ST) is the placental barrier between maternal and fetal blood that allows exchanges in nutrients and gases and also represents the endocrine tissue of the human placenta. Indeed, hCG is mainly secreted by the ST into maternal blood from about a week after fecundation reaching a peak around 8–10 weeks of gestation. Extravillous trophoblasts (EVTs), involved in chorionic villi anchoring, modulation of the uterine maternal immune system, and uterine artery remodeling, also secrete hCG. In particular, EVT produces hyperglycosylated forms of hCG (hCG-H) like in choriocarcinoma. In contrast to hCG, hCG-H is found elevated during early first trimester and then decreases, while hCG peaks. In addition to its endocrine role, hCG has autocrine and paracrine roles. It promotes the formation of the ST and angiogenesis through the LH/CG receptor but had no effect on trophoblast invasion. In contrast, hCG-H enhances trophoblast invasion and angiogenesis by interacting with the TGFβ receptor 2. hCG is largely used in antenatal screening and hCG-H represents a serum marker of implantation and early physiological trophoblast invasion. In conclusion, hCG is the main pregnancy hormone, whose maternal concentration and glycan structure change throughout pregnancy. Depending on its source of production, glycoforms of hCG display different biological activities and functions that are essential for pregnancy outcome.
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A finely-tuned interplay exists for the expression of the two ERs during syncytiotrophoblast development, with a prevalence of ERα in isolated cytotrophoblasts and of ERβ in mature syncytia [50]; therefore the BPA-induced upregulation of both ERs, may determine an unbalance of the syncytiotrophoblast development. In placenta, PPARγ induces cytotrophoblasts fusion and β-hCG release while inhibiting trophoblast invasion [26,27,51]. The induction of syncytin-1 expression by PPARγ may occur both indirectly, through GCM1 [26,27], the specific transcription factor of syncytiotrophoblast differentiation regulating also ERVDFRD-1 [52], and directly by interacting with a PPAR responsive element on the ERVW-1 gene [27].
Placenta is a target organ of Bisphenol A (BPA). To investigate possible effects on syncytiotrophoblast, the exchanging surface between mother and fetus, we exposed a trophoblast model (BeWo) to BPA concentrations occurring in humans (1 and 50 nM). We assessed the gene and protein expression of three human endogenous retroviral envelopes, specifically expressed in placenta (ERVW-1, ERVFRD-1 and ERV3-1), the secretion of β-hCG, the extent of trophoblast fusion and the activity of apoptosis markers (caspases 8, 3, 9 and PARP); additionally, the gene expression of transcription factors regulating HERV expression (i.e. GCM1, PPARγ, ERα and ERβ) was evaluated.
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At the Cutting EdgeThe pleiotropic function of PPARγ in the placenta

Abstract

Introduction

Section snippets

The transcriptional activation function of PPARγ

Placental expression of PPARγ

PPARγ pathways in placental development

Exposure to PPARγ ligands during pregnancy

Conclusion

Acknowledgements

Biochem. Biophys. Res. Commun.

Mol. Cell.

Placenta

Fertil. Steril.

Fertil. Steril.

Mol. Cell.

Am. J. Pathol.

Biochim. Biophys. Acta

J. Biol. Chem.

Am. J. Obstet. Gynecol.

Am. J. Obstet. Gynecol.

J. Biol. Chem.

Biochim. Biophys. Acta

Cell

J. Biol. Chem.

Prog. Lipid Res.

Reprod. Toxicol.

Placenta

Pharmacol. Res.

Mol. Cell.

Biochimie

J. Biol. Chem.

Cell

Cell

Placenta

Cell

Cell

Dev. Biol.

Placenta

J. Steroid Biochem. Mol. Biol.

Cell

Cell

Immunity

J. Biol. Chem.

Reprod. Toxicol.

J. Biol. Chem.

J. Biol. Chem.

At the Cutting Edge
The pleiotropic function of PPARγ in the placenta