Peroxisome proliferator-activated receptor (PPAR) isoforms are differentially expressed in peri-implantation porcine conceptuses

doi:10.1016/j.theriogenology.2017.06.013

Theriogenology

Volume 101, 1 October 2017, Pages 53-61

https://doi.org/10.1016/j.theriogenology.2017.06.013 Get rights and content

Highlights

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Greater PPARA mRNA expression in conceptuses was detected on Days 15–16 compared to Days 10–11.
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The greatest PPARD and PPARG mRNA expression was observed in filamentous conceptuses from Days 11–12.
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DNA binding activity of PPARD protein was higher in filamentous than spherical and tubular conceptuses.
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PPARD mRNA expression correlated with SLC2A1, PTGS2, and IL1B mRNA abundance.
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PPARG mRNA expression showed high correlation with PTGS2 mRNA expression.

Abstract

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of ligand-dependent transcription factors. PPARs are critical regulators of glucose homeostasis and lipid metabolism, and affect cell proliferation and differentiation. In the current study, we examined (1) the profiles of PPARA, PPARD, and PPARG mRNA expression and DNA binding activity in porcine conceptuses collected on Days 10–11 (spherical and tubular conceptuses), 11–12 (filamentous conceptuses), 13–14, and 15–16 (elongated conceptuses) of pregnancy, (2) the presence of PPARA, PPARD, and PPARG proteins in Days 10, 12, and 15 conceptuses. Moreover, we analyzed the abundance of retinoid X receptor (RXR; PPARs heterodimer partner) transcripts as well as the correlation between PPARs mRNA expression and the expression of genes important for and/or associated with elongation of porcine conceptuses: aromatase (CYP19A1), prostaglandin endoperoxide synthase 2 (PTGS2), glucose transporter 1 (SLC2A1), and interleukin 1B (IL1B). PPARA mRNA expression in conceptuses did not change during Days 10–14 of gestation, but was greater on Days 15–16 compared to Days 10–11 (P < 0.05). A considerable increase in PPARD and PPARG mRNA expression was observed in filamentous conceptuses from Days 11–12 compared to spherical and tubular conceptuses from Days 10–11 (P < 0.01), followed by a decrease on Days 13–14 and 15–16 (P < 0.05). PPARA, PPARD, and PPARG proteins were present in conceptus tissue demonstrating nuclear localization clearly visible on Days 12 and 15 of pregnancy. DNA binding activity of the PPARD isoform was greater in filamentous conceptuses from Days 11–12 than in spherical and tubular conceptuses from Days 10–11 (P < 0.01). Moreover, concentrations of active PPARD and PPARG proteins in nuclear fractions of conceptus tissue were greater on Days 11–12 compared to Days 13–14 and 15–16 of pregnancy (P < 0.05). RXRA, RXRD, and RXRG mRNA expression in conceptuses increased on Days 11–12 compared to Days 10–11 (P < 0.05). PPARD and PPARG mRNA expression showed strong positive correlations with PTGS2 mRNA expression (P < 0.0001). Additionally, PPARD gene expression correlated with SLC2A1 and IL1B mRNA expression (P < 0.01). Collectively, these results indicate that among all three PPARs expressed in peri-implantation porcine conceptuses, PPARD and PPARG may be involved in conceptus elongation before implantation.

Introduction

Peroxisome proliferator-activated receptors (PPARs) are members of a nuclear receptor superfamily of ligand-dependent transcription factors. Until now, three isoforms of PPAR named PPARA, PPARD and PPARG have been described, each encoded by a separate gene. For complete activation, PPARs must heterodimerize with retinoid X receptors (RXR) to form a PPAR/RXR complex that binds to a specific DNA sequence called a PPAR-response element in a target gene [1], [2]. Activity of PPARs can be regulated by a broad range of both natural and synthetic factors. Arachidonic acid and its metabolites are among the endogenous compounds, while synthetic ligands are represented mainly by fibrates, thiazolidinediones, and non-steroidal anti-inflammatory drugs [2], [3], [4].

PPARs are expressed in a broad range of tissues and control the expression of a wide array of genes mainly involved in the regulation of energy and glucose homeostasis, lipid metabolism, and cell proliferation and differentiation [1], [5], [6]. Increasing evidence suggests that PPARs are critical players in immune and inflammatory responses [1], [7], [8]. A role of PPAR isoforms has also been reported for female reproductive functions [9], [10], [11], [12]. Activation of PPARs was observed during steroidogenesis, tissue remodeling, and angiogenesis in the ovary [9], [13]. Spatiotemporal expression of PPARD and/or PPARG was detected in the endometrium of mice, rats, pigs, sheep and cattle [14], [15], [16], [17], [18], [19], indicating their involvement in the process of embryo implantation. In the porcine endometrium, PPARG mRNA expression was low until Day 15 of pregnancy; then, significantly increased and maintained high until Day 30. Endometrial PPARA and PPARD genes showed similar profiles of expression on Days 5–30 of pregnancy, with a decrease detected on Days 11–12 (the period of the maternal recognition of pregnancy) and 22 to 30 (the end of implantation) [19]. In mice, Ppard expression was markedly up-regulated in the stroma surrounding implanting blastocysts and was abundantly expressed in decidua during the post-implantation period [14]. Moreover, disruption of the Ppard or Pparg genes in this species was lethal to embryos due to placental dysfunction [20], [21], [22]. In the human placenta, PPARG was involved in hCG synthesis and trophoblast cell differentiation [23], [24], trophoblast invasion [25] and fatty acid uptake [26].

Pre-implantation mouse and bovine embryos express Ppard and PPARG, respectively [27], [28]. Moreover, the expression of PPARA, PPARD, and PPARG in ovine conceptuses changes along with the stage of conceptus development during the peri-implantation period [15]. Recent data clearly showed that PPARG is an essential regulator of ovine conceptus elongation, because inhibition of PPARG protein synthesis resulted in growth retardation and malformation of conceptuses on Day 14 of gestation [29]. In ruminants and pigs, elongation of conceptuses during the peri-implantation period is the process, which allows extensive contact between trophectoderm and maternal uterine epithelium [30], [31]. In contrast to sheep, there are no data available showing the presence of PPARs and their possible role in peri-implantation porcine conceptuses. Therefore, the current study was conducted to examine (1) the profiles of mRNA expression and DNA binding activity of PPARA, PPARD, and PPARG in porcine conceptuses collected on Days 10–16 of pregnancy, and (2) PPARA, PPARD, and PPARG protein localization in conceptuses of different morphology collected on Days 10 (spherical), 12 (filamentous), and 15 (elongated) of gestation. Moreover, we analyzed the abundance of RXR transcripts in conceptus samples as well as the correlation between expression levels of all three PPARs mRNA and the expression of genes important for and/or associated with the elongation of porcine conceptuses: aromatase (CYP19A1; cytochrome P450 family 19 subfamily A member 1), prostaglandin endoperoxide synthase 2 (PTGS2), glucose transporter 1 (SLC2A1) and interleukin 1B (IL1B).

Section snippets

Animals and sample collection

All procedures involving the use of animals were conducted in accordance with the national guidelines for agricultural animal care and were approved by the Animal Ethics Committee, University of Warmia and Mazury in Olsztyn, Poland.

Thirty-four crossbred gilts (Polish Landrace x Duroc) of similar genetic background from one commercial herd were used. Gilts that exhibited two estrous cycles of normal length were checked daily for the next estrus behavior with intact males. Then, gilts were bred

PPARA, PPARD, and PPARG mRNA expression

The mRNA expression of all three PPAR isoforms varied in developing conceptuses collected during the peri-implantation period (Fig. 1). PPARA mRNA expression in the porcine conceptuses did not change significantly on Days 10–14, but was greater on Days 15–16 compared to Days 10–11 (P < 0.05). A considerable increase in PPARD gene expression was observed in filamentous conceptuses from Days 11–12 of pregnancy compared to spherical and tubular conceptuses from Days 10–11 (P < 0.01), followed by a

Discussion

In the pig, blastocysts undergo a rapid transition from spherical to filamentous forms between Days 10 and 12 of pregnancy, achieving their final length until Day 16 [30], [31]. Conceptus transformation involves cellular hypertrophy and remodeling, migration of trophectoderm and extra-embryonic endoderm cells, reduction in blastocyst diameter, and an increased conceptus length and weight [31], [37]. Because activation of PPARs plays an important role in transport, cellular uptake, and

Conclusions

In summary, this is the first demonstration of the presence of all three PPAR isoforms in porcine peri-implantation conceptuses. The profiles of PPARD and PPARG mRNA expression and activity of protein to bind to specific DNA sequence as well as up-regulation of RXRs mRNA expression in peri-implantation conceptuses indicate important roles of PPAR isoforms in porcine conceptus elongation. This conclusion is supported by existence of the correlation between PPARD and PPARG mRNA expression and the

Competing interests

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Acknowledgements

The authors are grateful to Ms. Katarzyna Gromadzka-Hliwa and Mr. Jan Klos for technical assistance in the laboratory and Mr. Michal Blitek for help in sample collection.

This research was supported by the National Science Centre (grant 2013/11/B/NZ9/00806 to A. Blitek).

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Peroxisome proliferator–activated receptors must heterodimerize with RXR proteins for complete activation before binding to PPRE in a target gene. The mRNA expression of RXRs has been previously demonstrated in preimplantation embryos/conceptuses of cattle [41], sheep [15], and pig [26]. In the present study, RXRA and RXRB, but not RXRG, mRNA expression was observed in the trophoblast tissue.
Peroxisome proliferator–activated receptors (PPARs) are members of a nuclear receptor family of ligand-dependent transcription factors. Three isoforms of PPAR named PPARα, PPARβ/δ, and PPARγ have been described, each encoded by a separate gene: PPARA, PPARD, and PPARG, respectively. In the present study, we examined the profiles of PPAR and retinoid X receptor (RXR; PPAR heterodimer partner) mRNA expression and PPAR DNA binding activity in porcine trophoblast tissue collected on days 15, 20, 25, and 30 of pregnancy and in day-20 embryos. Placenta trophoblast cells isolated on day 25 of pregnancy were used to determine effects of (1) cytokines on PPAR and RXR mRNA expression and (2) PPAR agonists on prostaglandin (PG) E2 synthesis and the expression of genes involved in steroidogenesis, fatty acid binding, and PG transport, as well as on cell proliferation. The mRNA expression of PPARA and RXRB was greater in trophoblast tissue collected on days 25 and 30 of pregnancy compared with day 15 (P < 0.05), while DNA binding activity of PPARα decreased between day 15 and 25 (P < 0.05). Increased concentrations of PPARD and RXRA transcripts were observed in trophoblasts collected on day 20 compared to trophoblasts from days 15 and 30 (P < 0.05). Moreover, concentrations of DNA-bound PPARβ/δ and PPARγ proteins increased in day-30 trophoblasts compared to day 15 (P < 0.01) and day 20 (P < 0.05), respectively. On day 20 of gestation, the mRNA expression of PPARD, PPARG, and RXRA and protein levels of PPARα and PPARγ isoforms were greater in trophoblast than embryonic tissue (P < 0.01). Interleukin 1β and/or interferon γ, but not IL6 and leukemia inhibitory factor, upregulated PPAR and RXR mRNA expression in placenta trophoblast cells in vitro (P < 0.05). Rosiglitazone (a PPARγ agonist) stimulated prostaglandin E synthase mRNA expression in trophoblast cells and PGE2 accumulation in incubation medium (P < 0.05). Moreover, activation of PPAR isoforms differentially affected the expression of genes involved in steroidogenesis, fatty acid binding, and PG transport in studied cells. Finally, PPARα and PPARγ agonists stimulated trophoblast cell proliferation (P < 0.05), and this effect was abolished by the addition of a respective PPAR antagonist (P < 0.05). Overall, these results point to a role of PPAR isoforms in porcine placenta development and function.

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Peroxisome proliferator-activated receptor (PPAR) isoforms are differentially expressed in peri-implantation porcine conceptuses

Highlights

Abstract

Introduction

Section snippets

Animals and sample collection

PPARA, PPARD, and PPARG mRNA expression

Discussion

Conclusions

Competing interests

Acknowledgements

Pharmacol Res

Placenta

Prostagl Leukot Essent Fat Acids

Chem Biol

Trends Endocrinol Metab

Mol Cell

Mol Cell

Life Sci

Differentiation

Anim Reprod Sci

Anal Biochem

Placenta

Anim Reprod Sci

Domest Anim Endocrinol

Theriogenology

Peroxisome proliferator-activated receptors in female reproduction and fertility

PPAR Res

Peroxisome proliferator-activated receptors: nuclear control of metabolism

Endocr Rev

Nuclear hormone receptors enable macrophages and dendritic cells to sense their lipid environment and shape their immune response

Physiol Rev

Peroxisome proliferator-activated receptors (PPARs) and ovarian function – implications for regulating steroidogenesis, differentiation, and tissue remodeling

Reprod Biol Endocrinol

Peroxisome proliferator-activated receptors in reproductive tissues: from gametogenesis to parturition

J Endocrinol

Peroxisome proliferator-activated receptors: new players in the field of reproduction

Am J Reprod Immunol

Peroxisome proliferator-activated receptors in the regulation of female reproductive functions

Folia Histochem Cytobiol

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Genes Dev

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Reproduction

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