PPAR Research

PPAR Research / 2008 / Article
Special Issue

PPARs and RXRs in Male and Female Fertility and Reproduction

View this Special Issue

Review Article | Open Access

Volume 2008 |Article ID 723243 | https://doi.org/10.1155/2008/723243

Jichun Yang, Lihong Chen, Xiaoyan Zhang, Yunfeng Zhou, Dongjuan Zhang, Ming Huo, Youfei Guan, "PPARs and Female Reproduction: Evidence from Genetically Manipulated Mice", PPAR Research, vol. 2008, Article ID 723243, 8 pages, 2008. https://doi.org/10.1155/2008/723243

PPARs and Female Reproduction: Evidence from Genetically Manipulated Mice

Academic Editor: Pascal Froment
Received01 Jul 2007
Accepted06 Dec 2007
Published06 Apr 2008


Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors controlling many important physiological processes, including lipid and glucose metabolism, energy homeostasis, inflammation, as well as cell proliferation and differentiation. In the past decade, intensive study of PPARs has shed novel insight into prevention and treatment of dyslipidemia, insulin resistance, and type 2 diabetes. Recently, a large body of research revealed that PPARs are also functionally expressed in reproductive organs and various parts of placenta during pregnancy, which strongly suggests that PPARs might play a critical role in reproduction and development, in addition to their central actions in energy homeostasis. In this review, we summarize recent findings elucidating the role of PPARs in female reproduction, with particular focus on evidence from gene knockout and transgenic animal model study.

1. Introduction

Peroxisome proliferator-activated receptors (PPARs) are members of the ligand-activated nuclear hormone receptor superfamily of 49 members that participate in many physiological functions [1]. To date, three isotypes, designated as PPARα, PPARβ/δ, and PPARγ, have been identified in many species, including frogs, rodents, and humans [2, 3]. PPARα is highly expressed in liver, kidney, heart, skeletal muscle, and other tissues involving fatty acid oxidation and it had been demonstrated to be the central regulator of fatty acid β-oxidation, fatty acid (FA) transport, and lipoprotein synthesis in these tissues. Activation of PPARα by its natural or synthetic ligands enhances FA uptake and oxidation in liver, which is beneficial for ameliorating dyslipidemia [4, 5]. PPARγ is predominantly expressed in adipose tissue and is a key regulator of adipocyte differentiation and triglyceride storage, whereas PPARβ/δ is ubiquitously expressed in almost all tissues and believed to be involved in lipid metabolism [4, 6]. In contrast to intensive research into PPARγ and PPARα, little exists for PPARβ/δ. After binding by their endogenous ligands, such as 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2) and long-chain FAs, or exogenous synthetic agonists, such as thiazolidinediones (TZDs) and fibrates, PPARs will heterodimerize with another nuclear receptor called retinoid X receptor alpha (RXRα). The PPARs/RXRα heterodimer binds to a specific DNA sequence called PPAR-responsive element (PPRE) located in promoter regions of the target genes to initiate or silence gene transcription. A typical PPRE consists of a repeat AGGTCA separated by one nucleotide. However, activation of PPARs is far more complex than this, with complicated cross-talk among PPARs, RXRs, ligands, corepressors, coactivators, and many other factors [7, 8].

Because PPARs play key roles in regulating energy homeostasis, particularly FA oxidation and carbohydrate metabolism, numerous studies have been conducted in the past decade to develop synthetic PPAR agonists for therapeutic treatment of metabolic diseases, including dyslipidemia, insulin resistance, and type 2 diabetes. Long before being identified as PPARα agonists, fibrates were clinically prescribed for treatment of dyslipidemia. Subsequently, TZDs, structural analogues of fibrates, were shown to selectively activate PPARγ [7, 911]. To date, several TZDs, including pioglitazone and rosiglitazone, improve glycemic control in patients with type 2 diabetes or glucose intolerance via their insulin-sensitizing activity, mainly achieved by preventing FA uptake and adipose deposition in insulin-sensitive tissues such as liver, muscle, and pancreas [7, 911]. In addition, potent agonists for activation of multiple PPAR isotypes now in development, such as dual PPARα/γ agonists, have considerable promise for improving glycemic control with fewer side effects. As well, PPARβ/δ agonists are currently under development.

The nutrients glucose and FA and fuel sensors insulin and leptin have long been known to be critical in regulating female reproduction [1214]. During the onset of puberty, molecules such as leptin and neuropeptide Y might function as energy sensors and initiate reproduction processes under conditions of sufficient body energy storage [13, 15, 16]. Given the well-documented central roles of PPARs in energy homeostasis and because energy status is directly linked to reproduction [13, 14], it is reasonable to speculate that PPARs may play important roles in female reproduction. In fact, many recent studies have examined the potential role of PPARs in reproduction. In rodents, PPAR knockout mouse models have provided direct evidence of a critical role of PPARs in reproduction and placenta development (Table 1). PPARγ-null mouse fetuses were shown to die by embryonic day 10 because of failed formation of the vascular labyrinth [17, 18], and PPARβ/δ-null mice also exhibited abnormal placenta during development [19]. In contrast to PPARγ- and PPARβ/δ-null mice, PPARα-null mice displayed no placental abnormality but, rather, increased risk of maternal abortion and offspring neonatal mortality [20]. Subsequent studies involving RT-PCR, in situ hybridization, immunohistochemistry, and Northern and Western blot analysis further revealed all three PPAR isotypes are expressed in reproductive tissues such as testis (sperm), ovary (oocyte), as well as various parts of the placenta of rat, mouse, and human [12, 21, 22]. Importantly, pregnant rats given oral troglitazone showed significantly increased placental PPARγ expression as well as reduced mortality of fetuses by about 50% [23]. Loss-of-function mutations of PPARs have provided excellent models for studying the roles of PPARs in human reproduction and placenta development. To date, three groups of loss-of-function mutations of PPARγ have been described [6, 2426]. In one study, about 40% of female subjects with loss-of-function mutations of PPARγ had polycystic ovary syndrome (PCOS) [6], which has been believed to be associated with infertility in women. Consistent with these observations, administration of insulin-sensitizers TZDs and metformin improved ovulation function and fertility and enhanced growth hormone (GH) secretion in women with PCOS [27, 28]. Collectively, these findings imply an important role for PPARs in mammalian reproduction.

PPAR isotypeReproductive phenotypesReferences

PPARαKOMaternal abortion and neonatal death; altered ovarian estradiol productionYessoufou et al. [20], Lefebvre et al. [4]
TGDefect in mammary gland development; defect in lactation during pregnancyYang et al. [50]
PPARβ/δKOPlacental defects; frequent (>90%) midgestation lethality; placenta lipid accumulation defectsBarak et al. [19], Nadra et al. [57]
PPARγKOEmbryonic death at embryo day 10; embryonic lipid droplets lacking; placental malformed labyrinth zone; toxic milkBarak et al. [17], Kubota et al. [18], Wan et al. [71]
TGExacerbates mammary gland tumor developmentSaez et al. [73]

KO: global or tissue-specific knockout; TG: tissue-specific transgenic.

In this review, we discuss PPARs expression in female reproductive tissues and their roles in female reproduction, with a focus on genetically manipulated mice.

2. PPARs: Tissue Distribution in Female Reproductive System

2.1. Hypothalamic-Pituitary Axis

All three PPAR isotypes have been detected in the mouse pituitary gland [29]. PPARγ is highly expressed in normal human pituitary gland and in all normal pituitary secreting cell lines [30]. Because of its antiproliferative effects in pituitary cells, activation of PPARγ by TZDs inhibited the development of pituitary adenomas in mice and humans [31]. Despite its presence in the hypothalamic-pituitary axis, the precise roles of PPARγ in reproductive cells remain poorly understood. Although PPARγ expression is evident in pituitary tissue, TZD treatment failed to affect the in vitro secretion of ovine pituitary hormones, including prolactin (PRL), growth hormone (GH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH), and also no alteration of the LH secretion was observed in LbetaT2 cells, a murine gonadotropic pituitary tumor cell line [12].

2.2. Ovary

All three isotypes of PPAR are expressed in ovarian tissue. PPARα and PPARβ/δ are expressed primarily in the theca and stroma tissues [32], whereas PPARγ, more extensively studied, was detected in ovaries of mouse, rat, pig, sheep, cow, and human. In the ovaries of rodents and ruminants, PPARγ is highly expressed in granulosa cells, with lower expression in theca cells and the corpus luteum [12]. In humans, PPARγ was present in granulosa cells collected during oocyte aspiration from women undergoing treatment for in vitro fertilization [33]. Unlike the constant expression of PPARα and PPARβ/δ throughout follicular development and the ovarian cycle, the expression of PPARγ is downregulated in response to LH surge. PPARγ expression seems to be tightly regulated in the ovary, and its regulatory expression is the primary mechanism by which LH influences the activity of PPARγ [34].

2.3. Uterus and Placenta

Although all three PPAR isotypes are functionally expressed in uterus, they display different expression profiles with the development of placenta in pregnancy [3537]. In endometria of ewe, PPARα expression declines between day 7 and day 17 of pregnancy, whereas PPARβ/δ is constantly expressed at all developmental stages and PPARγ expression is erratically regulated. In addition, RXRs differ from that of PPARs, which suggests that different PPAR/RXR heterodimers might form and function distinctly as development proceeds [35]. All three PPAR isotypes have been reported in placenta in rodents and humans. PPARγ was the first to be detected in a human choriocarcinoma-derived JEG cell line by Northern blot analysis [34]. In human placenta, PPARγ is expressed in early and term villous trophoblasts and in extravillous trophoblasts in first-trimester placentas [21]. PPARγ was also detected in mouse placenta as early as embryonic day 8.5 [38] and in rat placenta by day 11 [23]. In mice, PPARγ is expressed in spongiotrophoblasts and in the vascular labyrinth that forms the interface between maternal and fetal circulation to control nutrient exchange [23]. In rodent placenta, PPARα and PPARβ/δ are present in the junctional zone, which has invasive and endocrine functions, and in the labyrinth, whereas in human placenta, they are in villous trophoblasts, particularly syncytiotrophoblasts [39]. However, in cultured villous trophoblasts of human term placenta, PPARα and PPARβ/δ transcript levels were higher in cytotrophoblasts than in syncytiotrophoblasts [40].

2.4. Mammary Gland

All three isotypes of PPAR are detected in rodent mammary gland and human breast cell lines [4144]. During pregnancy and lactation, the PPARα and γ mRNAs decreased while the PPARβ/δ mRNA remained relatively unchanged in mouse mammary gland [41].

3. PPARα and Female Reproduction

During pregnancy, placental transfer of FA and other nutrients from the mother to the fetus is crucial for adequate fetal growth and development, and PPARα might play a crucial role in this process because of its central role in FA transport and oxidation [4, 10, 39]. Recently, gemfibrozil and clofibrate, two PPARα agonists, were shown to downregulate human chorionic gonadotrophin and upregulate progesterone secretion in human trophoblasts, which suggests that activation of PPARα might be beneficial for the secretion of these hormones, so essential for maintaining pregnancy [45]. More recently, evidence for a key role of PPARα in placenta development was demonstrated by increased abortion rate (by 20%) in PPARα-null mice without diabetes [4, 20]. In PPARα-null mice with diabetes, the mean abortion rate was approximately 50%, as compared with 8.3% for wild-type mice. Moreover, PPARα-null mice showed higher neonatal mortality than wild-type mice: for mice without diabetes, the rate was 13.3% versus 5.1%, respectively, and for mice with diabetes, 78.9% versus 27.7% [20]. Thus, PPARα might have an important role in maternal-fetal nutrient exchange, and its deficiency could be deleterious to fetal development. This study further supported that tight control of blood glucose is beneficial for improving the fertility of diabetic women and, as clearly indicated in this study, abortion rate and neonatal mortality were increased in both wild-type and PPARα-null mice with diabetes.

Controversially, some other reports indicated that activation of PPARα might be deleterious to development of female reproductive cells. PPARα can bind to estrogen response elements and act as a competitive inhibitor of estrogen receptor [46, 47]. Activation of PPARα decreased the expression and activity of aromatase in granulosa cells [48], thus resulting in decreased estradio synthesis. More recently, treatment with the PPARα agonist fenofibrate decreased the level of aromatase in wild-type mice but enhanced it in PPARα-null mice [49]. A critical role for PPARα in mammary gland function was supported by a recent study in which transgenic mice expressing a constitutively activated PPARα form (VP16PPARα) in the stratified epithelia had a severe defect in mammary gland development and lactation during pregnancy, resulting in 100% neonate mortality [50]. Taken together, these observations reveal that PPARα plays an important role in mammalian female reproduction, but further research work is required to clarify its definite role and underlying molecular mechanism(s).

4.PPARβ/δ and Female Reproduction

PPARβ/δ is ubiquitously expressed in the ovary at a constant level during the estrous cycle and pseudopregnancy [51], which suggests that PPARβ/δ may be involved in normal ovarian function in theca, stroma, and luteal cells. One study showed that PPARβ/δ mRNA was almost absent on mouse embryo days 1–4 but was significantly expressed in the subluminal stroma surrounding blastocysts on day 5, just after embryo implantation. Subsequently, PPARβ/δ expression was increased in the decidua on days 6–8 [36, 52]. A similar process was observed in rat as well, intense PPARβ/δ immunostaining was observed in rat decidua under artificial decidualization but not in uninjected control horns [53]. These data suggest that PPARβ/δ expression at implantation sites requires an active blastocyst or analog and may play an essential role in blastocyst implantation.

A large body of research has indicated that PPARβ/δ mediates the important role of COX-2-derived prostaglandin I2 (prostacyclin, PGI2) in pregnancy. COX-2 knockout female mice displayed decreased fertility, in part due to deficiency of blastocyte implantation and decidualization [52, 54]. Treatment of these mice with a PGI2 analogue, carboprostacyclin, or the PPARβ/δ-selective agonist L-165041 restored implantation [52]. PGI2 is the most abundant prostaglandin at implantation sites where PPARβ/δ and COX-2 were colocalized and strongly upregulated during pregnancy in a similar manner [52]. As a potent endogenous PPARβ/δ ligand, PGI2 can act as a vasoactive agent to increase vascular permeability [55, 56] and blastocyst hatching [57], so the high expression of PPARβ/δ in the subluminal stroma at implantation sites might mediate this process, facilitating the implantation of the embryo [58]. This suggestion was further confirmed by placentas of PPARβ/δ-null mice displaying abnormal vascular development [19] and that giant-cell differentiation of placentas requires an intact PPARβ/δ signaling pathway [57].

In addition to the important roles of PPARβ/δ at implantation sites of the maternal body, the expression and function of PPARβ/δ in the embryo are of interest. Compared to the development of in vivo embryos, cultured embryos, such as in vitro fertilization (IVF) embryos, are retarded because they lack the protective environment of the maternal body [59]. Supplementing culture media with milepost, a stable analog of PGI2, enhanced mouse blastocyst hatching [60]. Recent work showed that preimplantation embryos express PPARβ/δ, which is essential for the enhancing effect of PGI2 and the spontaneous progression of the embryos. PGI2 promoted the development of wild-type embryos in vitro and enhanced their implantation potential but had no effect on PPARβ/δ-null embryos [61].

PPARβ/δ is expressed ubiquitously at higher levels during embryogenesis than in adulthood [62, 63]. In addition, homozygous loss of PPARβ/δ caused frequent embryonic lethality, but surviving PPARβ/δ-deficient offspring did not die postnatally, which suggests that the essential function of the receptor is restricted to the gestational period [19].

Given the roles of PPARβ/δ in embryo development and implantation, the activity of PPARβ/δ agonists under development should be carefully evaluated to avoid possible complications in pregnancy with their use.

5. PPARγ and Female Reproduction

After ovulation, the expression of PPARγ in the corpus luteum increases, otherwise the corpus luteum regresses and PPARγ expression decreases if no fertilization or embryo implantation occurs [64, 65]. Thus, PPARγ might play a role in fertility control. Indeed, mice with specific deletion of PPARγ in granulosa cells exhibited reduced fertility [66]. Luteal expression of PPARγ might be important for the pregnancy, possibly via maintaining production of progesterone to support implantation and gestation [67].

PPARγ-null embryos were shown to die by embryonic day 10 [17], as a result of placenta alteration and malformed vascular labyrinth due to PPARγ deficiency, which disrupts the interface between trophoblasts and the fetal endothelium and leads to embryonic myocardial thinning. A tetraploid-rescued mutant overcame the placenta defect for survival to term. Consistent with this observation, an RXRα-(PPARγ hetero-partner) or RXRα/RXRβ-null mutant exhibited a similar phenotype to that of PPARγ-null mice [17, 68]. The expression of Mucin 1 (MUC1), a PPARγ target gene, is lost in PPARγ-null mice, whereas its expression in wild-type mice can be upregulated by PPARγ agonist treatment. MUC1 expressed in the apical surface of the labyrinth helps in differentiation of trophoblast stem cells and invokes developmental and functional analogies between the placental blood sinuses and luminal epithelia [69].

During early term pregnancy, placental trophoblasts invade the uterine wall and establish the maternal-fetal exchange. PPARγ plays a dominant role in this process. The differentiation of the placenta is characterized by fusion of cytotrophoblasts into syncytiotrophoblasts, which are more resistant than cytotrophoblasts to hypoxic injury. Activation of PPARγ stimulates this differentiation process [21]. PPARγ agonists increase FA uptake and adipose accumulation in trophoblasts [70], and PPARγ-null or RXRα-null murine embryos show fewer lipid droplets than wild-type embryos [17, 68], which suggests an important role of PPARγ in providing sufficient nutrients for embryo development. Moreover, it is indicated in one latest study that PPARγ deletion in mammary gland resulted in the production of “toxic milk” containing elevated levels of inflammatory lipids, which results in inflammation, alopecia, and growth retardation in the nursing neonates [71]. Peroxisome proliferator-activated receptor-binding protein (PBP) serves as an anchor for recruiting PPAR mediator complexes, and is necessary for activation of PPARs. Moreover, specific knockout of PBP in mouse mammary gland resulted in a severe defect in mammary gland development, indeed the PBP-null mammary gland failed to produce milk for nursing neonates during lactation [72]. These studies clearly indicated that PPARγ/PPAR-binding protein expression are also vital for providing high-quality milk for nursing the neonates and protecting them from inflammatory lipids [71]. Interestingly and unexpectedly, constitutive expression of an active form of PPARγ (Vp16PPARγ) in mammary gland exacerbated mammary gland tumor development via enhanced Wnt signaling [73].

Proinflammatory proteins and cytokines are associated with term and preterm labor and stimulate uterine contraction [74]; PPARγ might be implicated in this process because of its ability to suppress inflammatory cytokine secretion [75]. The natural ligands of placental PPARγ may be present in maternal circulation, which could be naturally occurring prostanoids or FAs and some reproductive hormones. This hypothesis is supported by the observation that serum from pregnant women activated PPARγ expression in JEG-3 cells, while serum from nonpregnant women having no such effect [76].

In addition, as a target gene of PPARγ, another nuclear receptor, liver X receptor (LXR), participates in regulation of female reproduction. The two isforms, α and β, both act as transcription factors activated by binding of specific cholesterol metabolites [77]. LXRs play important roles in many metabolic pathways, such as cholesterol, lipid, and carbohydrate metabolism. In addition to these regulatory actions, LXRs affect reproductive function. Mice deficient in LXRα, LXRβ, or both showed decreased ability to conceive and fewer pups per litter as compared with wild-type mice [78]. As well, both LXRα and β are expressed in mouse oocytes and seem to affect ovarian function [78]. Lipid distribution in the uterus plays a critical role for its function. LXR prevents accumulation of cholesteryl esters in the mouse myometrium by controlling the expression of genes (ABCA1 and ABCG1) involved in cholesterol efflux and storage. As well, mice lacking LXRβ showed a contractile activity defect induced by oxytocin or PGF2α [79]. Taken together, gene knockout results suggest that PPARγ/LXR might participate in embryonic development by sensing changes in levels of nutrients, hormones, and/or other signals.

6. Conclusion

A large body of research has revealed that in addition to their central roles in regulating FA oxidation and glucose homeostasis, PPARs are highly expressed in reproductive tissues and placenta, so PPARs might also be key regulators of reproduction and development (Table 1). At the early stage of sexual maturation, PPARs might be activated in response to energy status and/or circulating hormones for involvement in maturation of reproductive cells. During gestation, PPARs are highly expressed in trophoblasts and directly involved in cytotrophoblast differentiation and function, possibly functioning as energy-signal sensors and transporters for nutrients and gases between maternal and fetus circulation to provide sufficient nutrients for development of the fetus (see Figure 1). Moreover, PPARs also play important roles in mammary gland development and maternal PPARs are vital for producing high-quality milk for nursing neonates. However, further research is required to address the following questions. (1) What are the natural ligands for activation of PPARs in reproduction and development, nutrients, sexual hormones, or other factors? (2) What are the underlying molecular mechanisms of PPAR activation in response to their natural ligands? Given the critical roles of all three PPAR isotypes in female reproduction, caution should be taken in the clinical use of PPARα and PPARγ agonists in young women.


The authors thank Dr. Jing Li and Dr. Dan Pu for their assistance in manuscript preparation. This work was supported by grants from the Natural Science Foundation of China (Grant no. NSFC 30670766, 30530340, 30771030) and the Ministry of Science and Technology of China (Grant no. 2006CB503907 to Y. Guan).


  1. X. Yang, M. Downes, R. Yu et al., “Nuclear receptor expression links the circadian clock to metabolism,” Cell, vol. 126, no. 4, pp. 801–810, 2006. View at: Publisher Site | Google Scholar
  2. M. Lehrke and M. A. Lazar, “The many faces of PPARγ,” Cell, vol. 123, no. 6, pp. 993–999, 2005. View at: Publisher Site | Google Scholar
  3. P. Balakumar, M. Rose, and M. Singh, “PPAR ligands: are they potential agents for cardiovascular disorders?” Pharmacology, vol. 80, no. 1, pp. 1–10, 2007. View at: Publisher Site | Google Scholar
  4. P. Lefebvre, G. Chinetti, J.-C. Fruchart, and B. Staels, “Sorting out the roles of PPARα in energy metabolism and vascular homeostasis,” Journal of Clinical Investigation, vol. 116, no. 3, pp. 571–580, 2006. View at: Publisher Site | Google Scholar
  5. S. W. Beaven and P. Tontonoz, “Nuclear receptors in lipid metabolism: targeting the heart of dyslipidemia,” Annual Review of Medicine, vol. 57, pp. 313–329, 2006. View at: Publisher Site | Google Scholar
  6. R. K. Semple, V. K. Chatterjee, and S. O'Rahilly, “PPARγ and human metabolic disease,” Journal of Clinical Investigation, vol. 116, no. 3, pp. 581–589, 2006. View at: Publisher Site | Google Scholar
  7. Y. Zhang and Y. Guan, “PPAR-γ agonists and diabetic nephropathy,” Current Diabetes Reports, vol. 5, no. 6, pp. 470–475, 2005. View at: Publisher Site | Google Scholar
  8. V. Zoete, A. Grosdidier, and O. Michielin, “Peroxisome proliferator-activated receptor structures: ligand specificity, molecular switch and interactions with regulators,” Biochimica et Biophysica Acta, vol. 1771, no. 8, pp. 915–925, 2007. View at: Publisher Site | Google Scholar
  9. B. Staels and J.-C. Fruchart, “Therapeutic roles of peroxisome proliferator-activated receptor agonists,” Diabetes, vol. 54, no. 8, pp. 2460–2470, 2005. View at: Publisher Site | Google Scholar
  10. Y. Guan, “Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome,” Journal of the American Society of Nephrology, vol. 15, no. 11, pp. 2801–2815, 2004. View at: Publisher Site | Google Scholar
  11. G. Wang, J. Wei, Y. Guan, N. Jin, J. Mao, and X. Wang, “Peroxisome proliferator-activated receptor-γ agonist rosiglitazone reduces clinical inflammatory responses in type 2 diabetes with coronary artery disease after coronary angioplasty,” Metabolism, vol. 54, no. 5, pp. 590–597, 2005. View at: Publisher Site | Google Scholar
  12. P. Froment, F. Gizard, D. Defever, B. Staels, J. Dupont, and P. Monget, “Peroxisome proliferator-activated receptors in reproductive tissues: from gametogenesis to parturition,” Journal of Endocrinology, vol. 189, no. 2, pp. 199–209, 2006. View at: Publisher Site | Google Scholar
  13. A. Cervero, F. Domínguez, J. A. Horcajadas, A. Quiñonero, A. Pellicer, and C. Simón, “The role of the leptin in reproduction,” Current Opinion in Obstetrics & Gynecology, vol. 18, no. 3, pp. 297–303, 2006. View at: Publisher Site | Google Scholar
  14. The ESHRE Capri Workshop Group, “Nutrition and reproduction in women,” Human Reproduction Update, vol. 12, no. 3, pp. 193–207, 2006. View at: Publisher Site | Google Scholar
  15. W. Kiess, W. F. Blum, and M. L. Aubert, “Leptin, puberty and reproductive function: lessons from animal studies and observations in humans,” European Journal of Endocrinology, vol. 138, no. 1, pp. 26–29, 1998. View at: Publisher Site | Google Scholar
  16. W. Kiess, A. Reich, K. Meyer et al., “A role for leptin in sexual maturation and puberty?” Hormone Research, vol. 51, supplement 3, pp. 55–63, 1999. View at: Publisher Site | Google Scholar
  17. Y. Barak, M. C. Nelson, E. S. Ong et al., “PPAR? is required for placental, cardiac, and adipose tissue development,” Molecular Cell, vol. 4, no. 4, pp. 585–595, 1999. View at: Publisher Site | Google Scholar
  18. N. Kubota, Y. Terauchi, H. Miki et al., “PPAR? mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance,” Molecular Cell, vol. 4, no. 4, pp. 597–609, 1999. View at: Publisher Site | Google Scholar
  19. Y. Barak, D. Liao, W. He et al., “Effects of peroxisome proliferator-activated receptor d on placentation, adiposity, and colorectal cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 1, pp. 303–308, 2002. View at: Publisher Site | Google Scholar
  20. A. Yessoufou, A. Hichami, P. Besnard, K. Moutairou, and N. A. Khan, “Peroxisome proliferator-activated receptor α deficiency increases the risk of maternal abortion and neonatal mortality in murine pregnancy with or without diabetes mellitus: modulation of T cell differentiation,” Endocrinology, vol. 147, no. 9, pp. 4410–4418, 2006. View at: Publisher Site | Google Scholar
  21. T. Fournier, V. Tsatsaris, K. Handschuh, and D. Evain-Brion, “PPARs and the placenta,” Placenta, vol. 28, no. 2-3, pp. 65–76, 2007. View at: Publisher Site | Google Scholar
  22. W. T. Schaiff, Y. Barak, and Y. Sadovsky, “The pleiotropic function of PPARγ in the placenta,” Molecular and Cellular Endocrinology, vol. 249, no. 1-2, pp. 10–15, 2006. View at: Publisher Site | Google Scholar
  23. R. Asami-Miyagishi, S. Iseki, M. Usui, K. Uchida, H. Kubo, and I. Morita, “Expression and function of PPARγ in rat placental development,” Biochemical and Biophysical Research Communications, vol. 315, no. 2, pp. 497–501, 2004. View at: Publisher Site | Google Scholar
  24. I. Barroso, M. Gurnell, V. E. F. Crowley et al., “Dominant negative mutations in human PPAR? associated with severe insulin resistance, diabetes mellitus and hypertension,” Nature, vol. 402, no. 6764, pp. 880–883, 1999. View at: Publisher Site | Google Scholar
  25. A. K. Agarwal and A. Garg, “A novel heterozygous mutation in peroxisome proliferator-activated receptor-γ gene in a patient with familial partial lipodystrophy,” Journal of Clinical Endocrinology & Metabolism, vol. 87, no. 1, pp. 408–411, 2002. View at: Publisher Site | Google Scholar
  26. R. A. Hegele, H. Cao, C. Frankowski, S. T. Mathews, and T. Leff, “PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy,” Diabetes, vol. 51, no. 12, pp. 3586–3590, 2002. View at: Publisher Site | Google Scholar
  27. D. Glintborg, R. K. Støving, C. Hagen et al., “Pioglitazone treatment increases spontaneous growth hormone (GH) secretion and stimulated GH levels in polycystic ovary syndrome,” Journal of Clinical Endocrinology & Metabolism, vol. 90, no. 10, pp. 5605–5612, 2005. View at: Publisher Site | Google Scholar
  28. E. Seli and A. J. Duleba, “Optimizing ovulation induction in women with polycystic ovary syndrome,” Current Opinion in Obstetrics & Gynecology, vol. 14, no. 3, pp. 245–254, 2002. View at: Publisher Site | Google Scholar
  29. A. L. Bookout, Y. Jeong, M. Downes, R. T. Yu, R. M. Evans, and D. J. Mangelsdorf, “Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network,” Cell, vol. 126, no. 4, pp. 789–799, 2006. View at: Publisher Site | Google Scholar
  30. F. Bogazzi, D. Russo, M. T. Locci et al., “Peroxisome proliferator-activated receptor (PPAR)? is highly expressed in normal human pituitary gland,” Journal of Endocrinological Investigation, vol. 28, no. 10, pp. 899–904, 2005. View at: Google Scholar
  31. A. P. Heaney, M. Fernando, and S. Melmed, “PPAR-γ receptor ligands: novel therapy for pituitary adenomas,” Journal of Clinical Investigation, vol. 111, no. 9, pp. 1381–1388, 2003. View at: Publisher Site | Google Scholar
  32. S. S. Lee, T. Pineau, J. Drago et al., “Targeted disruption of the a isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators,” Molecular and Cellular Biology, vol. 15, no. 6, pp. 3012–3022, 1995. View at: Google Scholar
  33. C. M. Komar, “Peroxisome proliferator-activated receptors (PPARs) and ovarian function—implications for regulating steroidogenesis, differentiation, and tissue remodeling,” Reproductive Biology and Endocrinology, vol. 3, p. 41, 2005. View at: Publisher Site | Google Scholar
  34. J. Banerjee and C. M. Komar, “Effects of luteinizing hormone on peroxisome proliferator-activated receptor γ in the rat ovary before and after the gonadotropin surge,” Reproduction, vol. 131, no. 1, pp. 93–101, 2006. View at: Publisher Site | Google Scholar
  35. L. Cammas, P. Reinaud, N. Bordas, O. Dubois, G. Germain, and G. Charpigny, “Developmental regulation of prostacyclin synthase and prostacyclin receptors in the ovine uterus and conceptus during the peri-implantation period,” Reproduction, vol. 131, no. 5, pp. 917–927, 2006. View at: Publisher Site | Google Scholar
  36. N.-Z. Ding, C.-B. Teng, H. Ma et al., “Peroxisome proliferator-activated receptor d expression and regulation in mouse uterus during embryo implantation and decidualization,” Molecular Reproduction and Development, vol. 66, no. 3, pp. 218–224, 2003. View at: Publisher Site | Google Scholar
  37. E. Lord, B. D. Murphy, J. A. Desmarais, S. Ledoux, D. Beaudry, and M.-F. Palin, “Modulation of peroxisome proliferator-activated receptor δ and γ transcripts in swine endometrial tissue during early gestation,” Reproduction, vol. 131, no. 5, pp. 929–942, 2006. View at: Publisher Site | Google Scholar
  38. A. Cutando and J. A. Gil-Montoya, “The dental patient with hemostatic disorders. A review of hemostasia physiopathology for dental professionals,” Medicina Oral, vol. 4, no. 3, pp. 485–493, 1999. View at: Google Scholar
  39. Q. Wang, H. Fujii, and G. T. Knipp, “Expression of PPAR and RXR isoforms in the developing rat and human term placentas,” Placenta, vol. 23, no. 8-9, pp. 661–671, 2002. View at: Publisher Site | Google Scholar
  40. G. Daoud, L. Simoneau, A. Masse, E. Rassart, and J. Lafond, “Expression of cFABP and PPAR in trophoblast cells: effect of PPAR ligands on linoleic acid uptake and differentiation,” Biochimica et Biophysica Acta, vol. 1687, no. 1–3, pp. 181–194, 2005. View at: Publisher Site | Google Scholar
  41. J. M. Gimble, G. M. Pighetti, M. R. Lerner et al., “Expression of peroxisome proliferator activated receptor mRNA in normal and tumorigenic rodent mammary glands,” Biochemical and Biophysical Research Communications, vol. 253, no. 3, pp. 813–817, 1998. View at: Publisher Site | Google Scholar
  42. K. M. Suchanek, F. J. May, W. Jae Lee, N. A. Holman, and S. J. Roberts-Thomson, “Peroxisome proliferator-activated receptor β expression in human breast epithelial cell lines of tumorigenic and non-tumorigenic origin,” The International Journal of Biochemistry & Cell Biology, vol. 34, no. 9, pp. 1051–1058, 2002. View at: Publisher Site | Google Scholar
  43. K. M. Suchanek, F. J. May, J. A. Robinson et al., “Peroxisome proliferator-activated receptor a in the human breast cancer cell lines MCF-7 and MDA-MB-231,” Molecular Carcinogenesis, vol. 34, no. 4, pp. 165–171, 2002. View at: Publisher Site | Google Scholar
  44. D. Bonofiglio, S. Aquila, S. Catalano et al., “Peroxisome proliferator-activated receptor-? activates p53 gene promoter binding to the nuclear factor-?B sequence in human MCF7 breast cancer cells,” Molecular Endocrinology, vol. 20, no. 12, pp. 3083–3092, 2006. View at: Publisher Site | Google Scholar
  45. F. Hashimoto, Y. Oguchi, M. Morita et al., “PPARa agonists clofibrate and gemfibrozil inhibit cell growth, down-regulate hCG and up-regulate progesterone secretions in immortalized human trophoblast cells,” Biochemical Pharmacology, vol. 68, no. 2, pp. 313–321, 2004. View at: Publisher Site | Google Scholar
  46. H. Keller, F. Givel, M. Perroud, and W. Wahli, “Signaling cross-talk between peroxisome proliferator-activated receptor/retinoid X receptor and estrogen receptor through estrogen response elements,” Molecular Endocrinology, vol. 9, no. 7, pp. 794–804, 1995. View at: Publisher Site | Google Scholar
  47. S. B. Nuñez, J. A. Medin, O. Braissant et al., “Retinoid X receptor and peroxisome proliferator-activated receptor activate an estrogen responsive gene independent of the estrogen receptor,” Molecular and Cellular Endocrinology, vol. 127, no. 1, pp. 27–40, 1997. View at: Publisher Site | Google Scholar
  48. T. Lovekamp-Swan, A. M. Jetten, and B. J. Davis, “Dual activation of PPARα and PPARγ by mono-(2-ethylhexyl) phthalate in rat ovarian granulosa cells,” Molecular and Cellular Endocrinology, vol. 201, no. 1-2, pp. 133–141, 2003. View at: Publisher Site | Google Scholar
  49. K. Toda, T. Okada, C. Miyaura, and T. Saibara, “Fenofibrate, a ligand for PPARα, inhibits aromatase cytochrome P450 expression in the ovary of mouse,” Journal of Lipid Research, vol. 44, no. 2, pp. 265–270, 2003. View at: Publisher Site | Google Scholar
  50. Q. Yang, R. Kurotani, A. Yamada, S. Kimura, and F. J. Gonzalez, “Peroxisome proliferator-activated receptor α activation during pregnancy severely impairs mammary lobuloalveolar development in mice,” Endocrinology, vol. 147, no. 10, pp. 4772–4780, 2006. View at: Publisher Site | Google Scholar
  51. C. M. Komar and T. E. Curry Jr., “Localization and expression of messenger RNAs for the peroxisome proliferator-activated receptors in ovarian tissue from naturally cycling and pseudopregnant rats,” Biology of Reproduction, vol. 66, no. 5, pp. 1531–1539, 2002. View at: Publisher Site | Google Scholar
  52. H. Lim, R. A. Gupta, W.-G. Ma et al., “Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARd,” Genes & development, vol. 13, no. 12, pp. 1561–1574, 1999. View at: Google Scholar
  53. N.-Z. Ding, X-H. Ma, H-L. Diao, L-B. Xu, and Z-M. Yang, “Differential expression of peroxisome proliferator-activated receptor δ at implantation sites and in decidual cells of rat uterus,” Reproduction, vol. 125, no. 6, pp. 817–825, 2003. View at: Publisher Site | Google Scholar
  54. H. Lim, B. C. Paria, S. K. Das et al., “Multiple female reproductive failures in cyclooxygenase 2-deficient mice,” Cell, vol. 91, no. 2, pp. 197–208, 1997. View at: Publisher Site | Google Scholar
  55. C. Wheeler-Jones, R. Abu-Ghazaleh, R. Cospedal, R. A. Houliston, J. Martin, and I. Zachary, “Vascular endothelial growth factor stimulates prostacyclin production and activation of cytosolic phospholipase A2 in endothelial cells via p42/p44 mitogen-activated protein kinase,” FEBS Letters, vol. 420, no. 1, pp. 28–32, 1997. View at: Publisher Site | Google Scholar
  56. T. Murohara, J. R. Horowitz, M. Silver et al., “Vascular endothelial growth factor/vascular permeability factor enhances vascular permeability via nitric oxide and prostacyclin,” Circulation, vol. 97, no. 1, pp. 99–107, 1998. View at: Google Scholar
  57. K. Nadra, S. I. Anghel, E. Joye et al., “Differentiation of trophoblast giant cells and their metabolic functions are dependent on peroxisome proliferator-activated receptor ß/d,” Molecular and Cellular Biology, vol. 26, no. 8, pp. 3266–3281, 2006. View at: Publisher Site | Google Scholar
  58. A. Psychoyos, “Uterine receptivity for nidation,” Annals of the New York Academy of Sciences, vol. 476, no. 1, pp. 36–42, 1986. View at: Publisher Site | Google Scholar
  59. K. Hardy, “Cell death in the mammalian blastocyst,” Molecular Human Reproduction, vol. 3, no. 10, pp. 919–925, 1997. View at: Publisher Site | Google Scholar
  60. J.-C. Huang, W.-S. A. Wun, J. S. Goldsby, I. C. Wun, S. M. Falconi, and K. K. Wu, “Prostacyclin enhances embryo hatching but not sperm motility,” Human Reproduction, vol. 18, no. 12, pp. 2582–2589, 2003. View at: Publisher Site | Google Scholar
  61. J.-C. Huang, W.-S. A. Wun, J. S. Goldsby, I. C. Wun, D. Noorhasan, and K. K. Wu, “Stimulation of embryo hatching and implantation by prostacyclin and peroxisome proliferator-activated receptor δ activation: implication in IVF,” Human Reproduction, vol. 22, no. 3, pp. 807–814, 2006. View at: Publisher Site | Google Scholar
  62. O. Braissant, F. Foufelle, C. Scotto, M. Dauça, and W. Wahli, “Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-α, -β, and -γ in the adult rat,” Endocrinology, vol. 137, no. 1, pp. 354–366, 1996. View at: Publisher Site | Google Scholar
  63. O. Braissant and W. Wahli, “Differential expression of peroxisome proliferator-activated receptor-α, -β, and -γ during rat embryonic development,” Endocrinology, vol. 139, no. 6, pp. 2748–2754, 1998. View at: Publisher Site | Google Scholar
  64. B. Löhrke, T. Viergutz, S. K. Shahi et al., “Detection and functional characterisation of the transcription factor peroxisome proliferator-activated receptor ? in lutein cells,” Journal of Endocrinology, vol. 159, no. 3, pp. 429–439, 1998. View at: Publisher Site | Google Scholar
  65. T. Viergutz, B. Loehrke, R. Poehland, F. Becker, and W. Kanitz, “Relationship between different stages of the corpus luteum and the expression of the peroxisome proliferator-activated receptor γ protein in bovine large lutein cells,” Journal of Reproduction and Fertility, vol. 118, no. 1, pp. 153–161, 2000. View at: Publisher Site | Google Scholar
  66. Y. Cui, K. Miyoshi, E. Claudio et al., “Loss of the peroxisome proliferation-activated receptor ? (PPAR?) does not affect mammary development and propensity for tumor formation but leads to reduced fertility,” Journal of Biological Chemistry, vol. 277, no. 20, pp. 17830–17835, 2002. View at: Publisher Site | Google Scholar
  67. D. I. Lebovic, M. Kir, and C. L. Casey, “Peroxisome proliferator-activated receptor-γ induces regression of endometrial explants in a rat model of endometriosis,” Fertility and Sterility, vol. 82, supplement 3, pp. 1008–1013, 2004. View at: Publisher Site | Google Scholar
  68. V. Sapin, P. Dollé, C. Hindelang, P. Kastner, and P. Chambon, “Defects of the chorioallantoic placenta in mouse RXRα null fetuses,” Developmental Biology, vol. 191, no. 1, pp. 29–41, 1997. View at: Publisher Site | Google Scholar
  69. T. Shalom-Barak, J. M. Nicholas, Y. Wang et al., “Peroxisome proliferator-activated receptor ? controls Muc1 transcription in trophoblasts,” Molecular and Cellular Biology, vol. 24, no. 24, pp. 10661–10669, 2004. View at: Publisher Site | Google Scholar
  70. U. Elchalal, R. G. Humphrey, S. D. Smith, C. Hu, Y. Sadovsky, and D. M. Nelson, “Troglitazone attenuates hypoxia-induced injury in cultured term human trophoblasts,” American Journal of Obstetrics and Gynecology, vol. 191, no. 6, pp. 2154–2159, 2004. View at: Publisher Site | Google Scholar
  71. Y. Wan, A. Saghatelian, L.-W. Chong, C.-L. Zhang, B. F. Cravatt, and R. M. Evans, “Maternal PPARγ protects nursing neonates by suppressing the production of inflammatory milk,” Genes & Development, vol. 21, no. 15, pp. 1895–1908, 2007. View at: Publisher Site | Google Scholar
  72. Y. Jia, C. Qi, Z. Zhang, Y. T. Zhu, S. M. Rao, and Y.-J. Zhu, “Peroxisome proliferator-activated receptor-binding protein null mutation results in defective mammary gland development,” Journal of Biological Chemistry, vol. 280, no. 11, pp. 10766–10773, 2005. View at: Publisher Site | Google Scholar
  73. E. Saez, J. Rosenfeld, A. Livolsi et al., “PPAR? signaling exacerbates mammary gland tumor development,” Genes & Development, vol. 18, no. 5, pp. 528–540, 2004. View at: Publisher Site | Google Scholar
  74. R. L. Goldenberg, J. C. Hauth, and W. W. Andrews, “Intrauterine infection and preterm delivery,” The New England Journal of Medicine, vol. 342, no. 20, pp. 1500–1507, 2000. View at: Publisher Site | Google Scholar
  75. G. Pascual, A. L. Fong, S. Ogawa et al., “A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-?,” Nature, vol. 437, no. 7059, pp. 759–763, 2005. View at: Publisher Site | Google Scholar
  76. L. L. Waite, E. C. Person, Y. Zhou, K.-H. Lim, T. S. Scanlan, and R. N. Taylor, “Placental peroxisome proliferator-activated receptor-γ is up-regulated by pregnancy serum,” Journal of Clinical Endocrinology & Metabolism, vol. 85, no. 10, pp. 3808–3814, 2000. View at: Publisher Site | Google Scholar
  77. M. Lehrke, G. Pascual, C. K. Glass, and M. A. Lazar, “Gaining weight: the keystone symposium on PPAR and LXR,” Genes & Development, vol. 19, no. 15, pp. 1737–1742, 2005. View at: Publisher Site | Google Scholar
  78. K. R. Steffensen, K. Robertson, J.-Å. Gustafsson, and C. Y. Andersen, “Reduced fertility and inability of oocytes to resume meiosis in mice deficient of the LXR genes,” Molecular and Cellular Endocrinology, vol. 256, no. 1-2, pp. 9–16, 2006. View at: Publisher Site | Google Scholar
  79. K. Mouzat, M. Prod'homme, D. H. Volle et al., “Oxysterol nuclear receptor LXRß regulates cholesterol homeostasis and contractile function in mouse uterus,” Journal of Biological Chemistry, vol. 282, no. 7, pp. 4693–4701, 2007. View at: Publisher Site | Google Scholar

Copyright © 2008 Jichun Yang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles