PPARγ Functions in the Placenta and Trophoblasts: Comparison
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The increasing incidence of pregnancy complications, particularly gestational diabetes mellitus (GDM) and preeclampsia (PE), is a cause for concern, as they can result in serious health consequences for both mothers and infants. The pathogenesis of these complications is still not fully understood, although it is known that the pathologic placenta plays a crucial role. Studies have shown that PPARγ, a transcription factor involved in glucose and lipid metabolism, may have a critical role in the etiology of these complications.

  • PPARγ
  • rosiglitazone
  • trophoblast
  • placenta
  • gestational diabetes mellitus
  • preeclampsia
  • pregnancy

1. Introduction

Pregnancy can lead to complications that pose serious risks to both the mother and infant during pregnancy, labor, and postpartum. These complications typically arise from conditions unique to pregnancy. Alarmingly, there has been a 16.4% increase in the incidence of pregnancy complications between 2014 and 2018, with gestational diabetes mellitus (GDM) increasing by 16.6% and preeclampsia (PE) increasing by 19% [1]. Although it is recognized that the pathologic placenta is the root cause of many pregnancy complications, the exact mechanism is not yet fully understood. Recent clinical studies have suggested that genetic analysis, such as Peroxisome proliferator-activated receptor-γ (PPARγ) as a transcription factor, can offer a novel approach to diagnosis and prediction [2]. PPARγ is crucial for metabolism homeostasis, adipocyte differentiation, and the immune system. Research has revealed significant associations between certain PPARγ gene variations and PE, underscoring the importance of PPARγ in the development of this condition. Notably, PE is more prevalent in women with hyperglycemia, a well-known risk factor [3,4,5][3][4][5]. Women with diabetes are at least twice as likely to develop PE, with around 50% of diabetic pregnancies experiencing hypertensive disorders of pregnancy (HDP), particularly those with pre-existing diabetes and poor glycemic control [6,7,8,9][6][7][8][9]. Considering the therapeutic potential of PPARγ agonists, which are FDA-approved for Type 2 Diabetes Mellitus, it becomes evident that these agents hold promise for preeclampsia treatment, particularly in patients with risk factors such as hyperglycemia.

2. Peroxisome Proliferator-Activated Receptor-γ

The Peroxisome Proliferator-Activated Receptor-γ (PPARγ) is a PPAR subfamily member consisting of two isoforms. PPARγ1 is encoded by mRNA PPARγ1, PPARγ3, and PPARγ4, while PPARγ2 is translated from mRNA PPARγ2 [10]. PPARγ1 is broadly expressed in various tissues including adipose tissue, the liver, colon, heart, epithelial cells, and skeletal muscle, and is also found in immune cells such as monocytes/macrophages, dendritic cells, and T lymphocytes [11]. On the other hand, PPARγ2 contains 28 additional amino acids and is primarily found in adipose tissue. Both isoforms are highly expressed in reproductive organs such as the placenta, testis, and ovary [12].
PPARγ is a ligand-dependent transcription factor, meaning it can be regulated by agonists and antagonists. It acts as a sensor for different fatty acid types, also known as a lipid sensor. In addition to endogenous ligands, synthetic ligands are widely used in clinical practice and in vitro studies to modulate PPARγ [13,14][13][14]. A summary of reported PPARγ ligands is provided in Table 1.
Table 1.
Natural and synthetic ligands of PPARγ *.

Agonists

Antagonists

Natural Ligand

Synthetic Ligand

Natural Ligand

Synthetic Ligand

Unsaturated fatty acid ** [15]

GW1929 [16]

Betulinic acid [17]

SR-202 [18]

Oxidized LDL [19]

TZD ***

NFκB [20]

BADGE [21]

EETs [22]

FMOC-L-Leucine [23]

Fetuin A [20]

LG100641 [24]

15d-PGJ2 [25]

INT131 [26]

  

PD068235 [27]

Azelaoyl phosphatidylcholine [28]

Farglitazar (GI262570) [29]

  

T0070907 [30]

9-oxoODE [31]

S26948 [32]

  

GW9662 [33]

13-oxoODE [34]

AZ 242 [35]

    

15-HETE [36]

LG100754 [37]

    

13-HODE [36]

      
* Partial ligands of PPARγ such as telmisartan [38], Irbesartan [39], metaglidasen [40], and non-TZD partial agonist (nTZDpa) [41] are not included. ** poly-unsaturated FAs γ-linolenic (18:3), eicosatrienoic acid (C20:3), dihomo-γ-linolenic (20:3), arachidonic acid (C20:4), and eicosapentaenoic acid (C20:5). *** rosiglitazone, pioglitazone, troglitazone, ciglitazone [21], RWJ-241947 [42], NC-2100 [43], and KRP-297 [44].
PPARγ, in addition to its well-established roles in lipid metabolism and adipocyte differentiation, has also been shown to be essential in regulating insulin resistance, glucose metabolism, immunity, as well as cell biology, including cell differentiation [45,46,47][45][46][47]. The TZD family comprises FDA-approved drugs used for treating Type 2 Diabetes Mellitus [13]. Beyond its function in immunology and maintaining energy homeostasis, PPARγ is also indispensable for the early development of the conceptus as early as E10. Its critical role in development seems to be particularly important in the placenta [48]. This revisewarch primarily focuses on the function of PPARγ in trophoblast differentiation and invasion, as well as its relationship with pregnancy complications, including GDM and PE.

3. PPARγ Functions in the Placenta and Trophoblasts

PPARγ is highly expressed in human placentas, particularly in syncytiotrophoblasts, cytotrophoblasts, and extravillous trophoblasts (EVTs) [49,50][49][50]. Its expression in the placenta is associated with infant birth weight. Placentas from small-for-gestational-age (SGA) infants were found to have lower expression of PPARγ, whereas placentas from average-for-gestational-age and large-for-gestational-age infants showed a nearly 2-fold higher expression of PPARγ compared with that from SGA infants [51]. These findings suggest that PPARγ may play a role in regulating fetal growth and development in the placenta.
Recent in vitro studies have shown that PPARγ is associated with trophoblast migration and invasion, although its exact role in these processes appears to be paradoxical. Some studies have reported that PPARγ inhibits trophoblast invasion in human primary cultures of EVTs [52,53,54][52][53][54]. One proposed mechanism is through the repression of pregnancy-associated plasma protein A, which reduces insulin-like growth factor (IGF) availability and limits trophoblast invasion [55,56][55][56]. Additionally, heme oxygenase-1 (HO-1) has been reported to negatively regulate trophoblast motility through the up-regulation of PPARγ [57]. Furthermore, PPARγ has been shown to inhibit trophoblast migration through its interaction with endocrine gland-derived vascular endothelial growth factor (EG-VEGF), a placental angiogenic factor [58]. Some studies have also reported that rosiglitazone, a PPARγ agonist, blocked lipopolysaccharide (LPS)-induced invasion in human first-trimester trophoblast cell lines [59].
However, more recent studies have suggested that PPARγ may promote trophoblast migration. Activated PPARγ/RXRα heterodimer by IL-17 was found to promote proliferation, migration, and invasion in HTR8/SVneo, a trophoblast cell line [60]. Furthermore, pioglitazone, which increases PPARγ expression, was shown to stimulate EVT migration by promoting IGF signaling [56]. In addition, mutations on the ligand-binding domain of PPARγ have been found to significantly suppress migration in the primary villous cytotrophoblasts [61]. These findings suggest that the role of PPARγ in trophoblast migration and invasion may be complex, and further research is needed to fully understand its mechanisms and effects in these processes.
PPARγ has also been identified as a regulator of trophoblast differentiation. In the BeWo cell model, blocking PPARγ activity has been shown to induce cell proliferation but suppress the differentiation [62]. In human placenta explants, PPARγ/RXRα heterodimers have been found to promote cytotrophoblast differentiation into syncytiotrophoblasts [63], which is a key event in placental development. In PPARγ-deficient mouse placentas, diminished expression of several trophoblast differentiation markers, such as Tpbpα and Mash2, as well as the abnormal spatial expression of glial cell missing 1 (GCM1), a transcription factor important for syncytiotrophoblast differentiation, were observed [64]. In addition, oral administration of troglitazone, a PPARγ agonist, was found to enhance cytotrophoblast differentiation into syncytiotrophoblasts [65]. PPARγ also promotes the differentiation of syncytiotrophoblasts, but not trophoblast giant cells (TGCs) in the mouse labyrinth, which is the region of the placenta where nutrient exchange occurs [66]. On the other hand, rosiglitazone, another PPARγ agonist, has been reported to reduce TGC differentiation while inducing GCM1 expression [67], suggesting that the role of PPARγ in trophoblast differentiation may be complex and dependent on the specific cell type. Further research is needed to fully elucidate the mechanisms and effects of PPARγ in trophoblast differentiation.

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