# PPARs and Female Reproduction: Evidence from  Genetically Manipulated Mice

Authors: Jichun Yang; Lihong Chen; Xiaoyan Zhang; Yunfeng Zhou; Dongjuan Zhang; Ming Huo; Youfei Guan
Journal: PPAR Research
 (2008-01-06)

---

## Abstract

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.


---

## Body

## 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, 9–11]. 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, 9–11]. 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 [12–14]. 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, 24–26]. 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.Table 1
Studies of reproductive phenotypes of female PPARα,
PPARβ/δ,
and PPARγ-null or transgenic mice.
PPAR isotypeReproductive  phenotypesReferencesPPARαKOMaternal 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 [35–37]. 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 [41–44]. During pregnancy and lactation, the PPARα and γ mRNAs
decreased while the PPARβ/δ mRNA remained relatively unchanged in mouse mammary
gland [41].


## 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 [35–37]. 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 [41–44]. 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 (Table1). 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.Figure 1
Schematic presentation of regulatory roles of PPARs in reproduction and development.



---

*Source: 723243-2008-04-06.xml*