{"paper_id":"e4243951-3c36-4530-bf0e-10823a86f0d7","body_text":"Peroxisome\nproliferator-activated receptors (PPARs) are major regulators of lipid and\nglucose metabolism, inflammation,\nand angiogenesis [ 1 – 6 ] that allow adaptation of the mother to the nutritional\nand perfusion requirements of the fetus [ 3 ,  7 ,  8 ]. PPARs, members of the nuclear hormone receptor\nsuperfamily, are ligand-activated transcription factors. The PPAR amino acid\nsequence can be divided into five modular domains: A/B, C, D, E, and F. Domain\nE is the ligand binding domain (LBD) and contains a ligand-dependent transcriptional\nactivation function (AF-2). Domain C is the DNA binding domain, formed of two\ntypical zinc fingers. PPARs activate DNA direct repeat response elements \nby binding as heterodimers with retinoic acid receptor (RXR) partners [ 9 ]. There are three PPAR isotypes, PPAR α ,\nPPAR γ ,\nand PPAR β / δ , that are highly conserved across species, with mouse, rat, and human sequences sharing >80% amino acid homology [ 6 ,  10 ]. The conserved expression of different PPAR and RXR isotypes\nin both rat and human placentas [ 11 ] suggests that these receptors play\nfunctional roles in placental lipid transfer and homeostasis. PPAR α \nhas a wide distribution and is prominent in tissues with high metabolic rates\nsuch as liver, heart, skeletal muscle, and kidney and in steroidogenic organs\nsuch as the adrenals [ 12 ]. PPAR γ  has three isoforms (PPAR γ 1,\n γ 2,\nand  γ 3)\nand is expressed in brown and white adipose tissue, large intestine, to a\nlesser extent in immune cells (monocytes, macrophages, Peyer’s patches of the\ndigestive tract), the mucosa of colon and cecum, and placental trophoblasts [ 13 –  16 ]. PPAR β / δ  is distributed in all tissues tested\nwith particularly high expression in placenta and large intestine [ 8 ,  17 ,  18 ]. PPAR α  and PPAR γ \nare involved in adipocyte differentiation, lipid metabolism, insulin action,\nand in the regulation of inflammatory responses [ 1 ,  5 ,  16 ], particularly involving the macrophage [ 19 ]. PPAR β / δ  is known to be involved in lipid\nmetabolism and inflammation, as well as keratinocyte differentiation and wound\nhealing [ 5 ,  20 ,  21 ].\nThe PPAR system is intimately involved\nin cardiovascular disease, obesity, as well as pregnancy-specific diseases [ 6 ,  22 ]. Over the past decade studies have\nshown that all three PPAR isotypes are expressed in human placental trophoblast\ncells [ 11 ] and that they are involved in the\nregulation of pregnancy physiology and its clinical complications. Physiological\nand pathophysiological conditions that modulate the PPAR system [ 22 –  35 ] influence the risk and course of preeclampsia (PE),\ngestational diabetes mellitus (GDM), or intrauterine growth restriction (IUGR) [ 36 –  53 ]. Some of these diseases and factors involving the PPAR\nsystem are summarized in \nTables  1  and  2 .\nIn early pregnancy, immediately after embryonic\nimplantation, major maternal physiologic changes occur in the cardiovascular,\nhepatic, and endocrine systems with resultant anatomical and metabolic\nmodifications that serve to promote maternal immune tolerance of the conceptus\nand to provide the fetus with its increased nutritional needs [ 54 ,  55 ]. Metabolic changes (including increased availability of\nglucose, low density lipoprotein, and fatty acids) increased insulin resistance and altered amino acid\nmetabolism, immunologic, and hematologic changes (including an increase in\nplasma volume). Establishment of a thrombophilic state and extensive placental\nand decidual angiogenesis are observed in pregnancy, and these changes require\na complex activation of regulating mediators [ 56 – 58 ].\nPregnancy complications result when\nthe mother and/or fetus fail to adapt to these new metabolic, angiogenic, and\nthrombogenic challenges. Women with preexisting compromise to their vascular homeostasis,\nsuch as underlying hypertension, diabetes mellitus, or metabolic syndrome, have\na significantly increased risk of developing pregnancy complications (see  Table 2 ). Placenta-associated complications also can lead to impaired growth or fetal\ndemise [ 59 ,  60 ]. These placental conditions share vasculopathological\nmechanisms in common with atherosclerosis and represent early markers for\nmaternal risk of cardiovascular disease [ 61 ,  62 ] and hypertension [ 61 , 63 ,  64 ]. Curiously, a prior history of preeclampsia appears to\nconfer protection against the future development of endometriosis and some\ncancers [ 65 ,  66 ].\nPPARs\ncan be activated by natural ligands, like prostaglandins (PGs), fatty acids,\nand their derivatives, as well as by synthetic ligands. PPAR medications have\nbeen developedand discovered to be relatively safe drugs with\nbenefits in multiple disease states including diabetes and\ncardiovascular disease [ 67 ]. Fibrate drugs used to treat\nhyperlipidemia, and thiazolidinedione drugs used to treat type 2 diabetes are potent and\nrelatively specific ligand activators of PPAR α  and  γ , respectively,\nand are widely used clinically [ 68 ,  69 ]. A number of naturally-occurring PPAR ligands have been identified,\nincluding long-chain fatty acids (C16 and greater), eicosanoids such as 8(S)-HETE\n(PPAR α )\nand 9-and13-HODE (PPAR γ ), and PGs such as\nPGA 1, which binds to PPAR α ,\nPPAR β / δ ,\nand 15-deoxy-delta 12,14 -prostaglandin\nJ 2 (15dPGJ 2 ), which in turn binds to PPAR γ \n[ 70 –  72 ]. Both the expression of PPAR and the production of their\npotential ligands are altered during pregnancy and its related diseases. We\npostulate that pathologic diversion of fatty-acid metabolism away from the\nproduction of eicosanoid ligands in preeclampsia and gestational diabetes might\nbe corrected using synthetic ligands.\n\nIn first trimester, human placental\nbed biopsies, PPAR- γ  is expressed predominantly in\ninvasive trophoblasts, whereas in the second-trimester PPAR γ \nis expressed in the columns of anchoring villi and cytotrophoblasts [ 73 ,  74 ]. In the third trimester, PPAR γ \nprincipally localizes to extravillous cytotrophoblasts (EVCT) and villous syncytiotrophoblasts\n[ 75 ], where it appears to regulate placental hormone\nproduction and secretion. Although the focus of this review is to summarize findings\non PPAR/RXR heterodimers in human placentation, much of the direct evidence for\na role of these receptors in trophoblast invasion and placental development has\nemerged from studies in knockout mouse models. This topic is reviewed\ncomprehensively in Schaiff et al. [ 3 ], and is summarized briefly here and\nin  Table 3  [ 76 – 81 ].\nPPAR γ /RXR α  heterodimers play a key regulatory\nrole in murine placental development. PPAR γ  deficiency was shown to interfere\nwith terminal trophoblast differentiation and placental vascularization [ 78 ]; embryos without this gene\nshow massive placental defects that can be rescued by restoration of\nthe trophoblast PPAR γ  gene via tetraploid chimeras [ 15 ]. Deletion\nof RXR α  and RXR β  also leads to embryo lethality [ 15 ,  81 ,  83 ]. Both PPAR-interacting protein (PRIP) and nuclear\nreceptor-activating protein 250 (RAP250) encode nuclear receptor coactivators\nthat associate with PPARs, RXRs, and other nuclear receptor proteins. Genetic\ndisruption of PRIP or RAP250 in mouse models results in embryonic lethality at\npostconception days 11.5 and 13.5, respectively [ 79 ,  80 ]. Placentas of PRIP (−/−) and RAP250 (−/−) embryos\nexhibited dramatically reduced spongiotrophoblast and labyrinth layers as well\nas failure of blood vessel maturation in the region bordering the\nspongiotrophoblast [ 79 ,  80 ].\nIn addition to placentation per se, PPAR γ \nappears to play an important role in the uterine preparation for embryonic\nimplantation. Peeters et al. demonstrated that PPAR γ \nligands reduced the production of the endometrial angiogenic factor VEGF, and postulated\nthat this pathway might influence early embryonic vascularization [ 84 ]. By contrast, PPAR γ \nagonists induce angiogenesis in cardiac myofibroblasts, smooth muscle cells,\nand macrophages [ 85 –  87 ]. Recent preliminary data by our lab and others suggest\nthat the PPAR γ \nsystem also stimulates VEGF expression in trophoblast (JEG-3) cells (Depoix et\nal., unpublished).\nThe functional role of PPAR γ  activity\nis well studied in trophoblast physiology ( Table 4 ). PPAR γ \nagonists inhibit invasion of cultured EVCT isolated from human first-trimester\nplacenta, whereas PPAR γ  antagonists promoted EVCT invasion\nand repressed the PPAR γ  agonist-mediated effects [ 78 ]. PPAR γ  controls mucin (MUC)-1 transcription\nand regulates maternal-fetal transport in mouse models [ 88 ]. Moreover, PPAR γ  and RXR α  play a role in human chorionic\ngonadotropin (hCG) expression, trophoblast differentiation, and regulation of\nfatty acid transport and storage in human placental trophoblasts [ 89 ,  90 ]. PPAR γ  diminishes leptin-induced\ninflammatory responses in the human placenta [ 91 ] and inhibits PAPP-A expression [ 92 ].\nRegulation of PPAR γ \nin human placental tissues is thought to occur through natural ligands (e.g.,\n15dPGJ2, 9-HODE, 13-HODE, and 15-HETE) through direct binding to the receptor’s\nligand binding pocket [ 11 ,  100 ]. These ligands are likely to be synthesized locally within\nthe placenta. Furthermore, crosstalk between the mitogen-activated protein\nkinase (MAPK) p38 and PPAR γ  occurs within cultured trophoblast\ncells [ 101 ]. PPAR γ  decreases IGFII secretion and is thought\nto inhibit trophoblast invasion via the PAPP-A cascade [ 92 ].\nIn\nyoung PPAR α  knock out mice, no major phenotypic differences\nof gross pathology of internal organs were described [ 76 ,  102 ]. However, disturbance of the Th1/Th2 T-lymphocyte ratio,\nrather than placental malformation, is thought to be responsible for an increased\nabortion rate (20%) in PPAR α  null mice. During normal pregnancy Th1\ncytokines are downregulated and Th2 cytokines are upregulated [ 103 ].\nThe third distinct PPAR, PPAR β / δ \nalso is essential for placentation as demonstrated in PPAR β / δ \nknockout mice ( Table 3 ) [ 77 ], and is involved in the regulation of implantation in other\nanimal models [ 17 ,  104 ,  105 ]. The implantation of cultured embryos is enhanced by\nPPAR β / δ \nactivation and this receptor even has been postulated as a novel therapeutic\ntarget to improve clinical IVF outcomes [ 104 ]. PPAR β / δ  is induced during decidualization of\nthe implantation site and requires close contact with the blastocyst. PPAR β / δ \nnull mice die between 9.5 to 10.5 embryonic days due to abnormal cell-cell\ncommunication at the placental-decidual interface [ 8 ].\nTogether these data suggest that PPARs\nare required not only for trophoblast invasion and differentiation but also for\nestablishment of the placental maternal-fetal transport.\n\nBased on its regulatory functions and\nknown eicosanoid ligands, PPAR γ  has emerged as an excellent candidate\nto play a role in the regulation of maternal metabolism, maintenance of uterine\nquiescence, and onset of labor by regulating proinflammatory cytokines and\nprostaglandins ( Table 4 ). Normal pregnancy is accompanied by changes in lipid\nand glucose metabolism, but further dysregulation of these pathways can lead to\npregnancy complications such as PE or GDM. Hence, PPAR regulators of these\nmetabolic pathways might be expected to be important in human pregnancy.\nSome of our initial studies in this\nfield were designed to screen for potential activators of PPAR γ \nin the circulation of pregnant women. Human choriocarcinoma JEG-3 cells were\ntransfected with peroxisome-proliferator responsive reporter plasmids; and pooled\nsera from pregnant and nonpregnant women were added to the cell culture medium [ 73 ]. Peroxisome proliferator responsive\nelement (PPRE) luciferase reporter activation was dramatically increased by\nsera from pregnant women compared to nonpregnant women (Figures  1 \n and 2 ). We\nshowed that PPAR γ  (and to some extent PPAR α )\nactivity is increased from the earliest stages of pregnancy ( Figure 2 ). The\nfindings suggested that circulating PPAR γ -activating factors, presumably\neicosanoids, were present throughout the course of gestation. We hypothesized\nthat activation of PPAR γ  by sera of pregnant women is a\nregulatory adaptation of the maternal organism to increased lipid and glucose\nloading in pregnancy [ 73 ].\nIt also has been hypothesized that\nPPAR γ \nactivation regulates uterine quiescence by influencing Nuclear Factor-Kappa B\n(NF κ B)\nand cyclooxygenase (COX-2) expression [ 96 ,  97 ,  106 ]. Reciprocal expression of PPAR γ \nand (COX)-2 in human term placenta suggests a role of the PPAR system in the\ninitiation of labor [ 98 ]. Under conditions of high PPAR γ \nexpression, antiinflammatory actions dominate; however, with onset of labor\nPPAR γ \nlevels drop and COX-2 concomitantly increases in the fetal membranes [ 98 ]. Elevated COX-2 activity in the human amnion is observed\nin the settings of term and idiopathic preterm labor, contributing to the\ngeneration of uterotonic prostaglandins (PGs), which are known to participate\nin parturition [ 107 ]. PPAR γ  ligands have been shown to antagonize\nNF- κ B\nactivation and reduce inflammatory cytokine gene expression (IL-1 β ,\nIL-6, IL-10 and TNF- α ) and COX-2 [ 108 ]. Both natural (e.g., 15dPGJ2) and synthetic ligands\n(e.g., troglitazone) were shown to have anti-inflammatory effects in human\ngestational tissues, significantly decreasing basal and LPS-stimulated PGE 2  and PGF 2 α  release from placenta and amnion [ 108 ]. PGF 2 α \n, also a marker of oxidative stress, is\nincreased in women with preeclampsia [ 109 ]. Given the inflammatory changes observed\nin pregnancy-specific diseases, a potential role of PPAR agonist treatment has\nbeen entertained for the treatment of PE, GDM, and other pregnancy-specific\ndiseases such as the prevention of preterm labor [ 96 ].\nPPAR α  and  β / δ  also play a role in maintaining\npregnancy and parturition. PPAR α  and  β / δ  are expressed in the amnion,\nchoriodecidua, and villous placental tissues. Data from PPAR α  knockout\nmice suggest that PPAR α  maintains pregnancy by stimulating a\nTh2 cytokine response [ 76 ]. In normal pregnancy, expression of PPAR α \ndeclines in the choriodecidua with the onset of labor [ 99 ]. By contrast, PPAR β / δ \nexpression, which is temporally upregulated between the first and third\ntrimester of pregnancy [ 99 ], increases further in the amnion coincidental\nwith the onset of labor [ 99 ].\nFew studies have elucidated substantial\nrisk of PPAR agonists during pregnancy in animal models, but these drugs carry a\n“C” classification from the FDA. For example, rosiglitazone\ndid not damage blastocyst development in vitro or harm mouse fetuses when given\nduring murine pregnancy\n[ 110 ]. While the use of\nrosiglitazone during pregnancy is generally considered to be safe [ 110 ]; more data need\nto be acquired before these drugs can be recommended.\n\nFailure of metabolic adaptation to\npregnancy can result in pregnancy-specific complications such as PE and GDM. We\nand others have postulated that angiogenic factors and cytokines that lead to\npathological gestational changes are likely to be regulated by the PPAR system ( Table 5 ).\nPE is a multifactorial,\npregnancy-related disorder that is defined by new-onset hypertension and\nproteinuria after 20 weeks of gestation [ 117 ]. PE is a common cause of maternal and\ninfant morbidity and mortality worldwide, and is responsible for about 20% of\npregnancy-related maternal deaths in the US [ 118 ]. Women with PE have increased insulin\nresistance as well as hypertriglyceridemia relative to normal pregnant women [ 119 ]. To date, no effective treatment has been found that either\nprevents or reverses the development of the disease. Modern concepts of PE\npathophysiology invoke a two-stage process. The first stage is believed to be\ninitiated by impaired trophoblast invasion and abnormal uterine vessel\nremodeling. The second stage is postulated to result from circulating factors\nclaimed to be derived from the ischemic placenta that stimulate an inflammatory\nactivation of maternal vascular endothelial cells. PE presents clinically in\nthe second or third trimester, however, fundamental inflammatory and angiogenic\nbiomarkers in the serum are detectable as early as the first trimester in women\nwith PE. Elevated concentrations of IL-2, TNF α , and sVEGFR-1 and reduced concentrations\nof PlGF, IGFBP-1, and HLA-G in the maternal serum precede the clinical\nmanifestations of PE [ 119 – 123 ].\nWhile the cause of PE remains unknown,\nseveral environmental and genetic risk factors have been identified ( Table 2 ).\nRelevant to this review are hypertension, diabetes, and high (>29) body mass\nindex (BMI) [ 47 ,  124 , 125 ]. Black race also appears to be a risk factor for PE [ 126 ] although this may be confounded by increased rates of\nthe above risk factors. Key inflammatory and angiogenic pathways involved in\nthe pathogenesis of PE are regulated by the PPAR system, which itself is\ninfluenced by environmental and genetic factors. We believe that exogenous and endogenous\nlipid regulators of PPAR play a role in maternal metabolism and\nimmune functionin normal and pathological pregnancies. For example,\ndietary factors and physical activity that modulate the PPAR system have been\nshown to reduce the risk and course of PE ( Table 2 ).\nSimilarly, genetic variations in the\nPPAR γ \ngene have been proposed to modify the risk of PE. For example, the Pro467Leu\nmutation of PPAR γ  [ 127 – 129 ] is a dominant negative mutant resulting from a C-to-T\ntransition in exon 6. A report of two individuals (one woman, one man) with\nthis mutation showed that they developed type 2 diabetes at young ages (26 and\n27 years at diagnosis), as well as early hypertension (37 and 27 years at\ndiagnosis). Intriguingly, the woman had two pregnancies, both of which were\ncomplicated by severe PE. The Pro12Ala polymorphism occurs in PPAR γ 2\n[ 130 ], a second isoform of PPAR γ  that is expressed mainly in adipose\ntissue. This mutation is the result of a C-to-G transversion in exon B. This is\nby far the most studied allelic variation in any PPAR, and occurs at a rate of\nabout 12% in the Caucasian US population. While the resulting\nphenotype is highly diverse and even apparently contradictory, it appears that\nthe penetrance of this mutation is influenced by other genetic, environmental,\nethnic, and gender differences. The studies generally agree that the presence\nof the Ala\nallele is associated with increased BMI, an independent risk factor for PE.\nThus, this polymorphism is a candidate affecting pregnancy outcome. Preliminary data of a study on the PPAR\ngene variations (in PPAR gene) showed no association with PE or severity of PE in\na Finnish population [ 131 ]. Further studies on the association\nof PPAR  α ,  β , and  γ  gene variations of mothers and offspring and\npregnancy-specific diseases need to be performed in different ethnic\npopulations.\nPE is marked by hyperlipidemia, and is\ncharacterized by a state of oxidative stress. Circulating lipids in PE women are\nmore highly oxidized, and oxidized low-density lipoproteins (oxLDLs), in\nparticular, are highly elevated [ 132 ]. Given the circulating plasma lipid disturbances in PE,\nour group performed experiments comparing sera from normal and PE\npatients. We found that serum from women with severe PE had reduced\nlevels of PPAR activating lipids compared with serum of parity and\ngestational age-matched women and also diminished the expression of PPAR γ \nin trophoblast cells (Figures  1 \n and 3 ) [ 111 ]. The reduction of transcriptional\nactivity observed in preeclamptic women’s sera was shown for PPAR γ \nand PPAR α ,\nhowever not for PPAR β / δ  or RXR. The reduction in potential\ncirculating PPAR activatorswas observed weeks and sometimes months\nbefore the onset of maternal symptoms and clinicaldiagnosis of PE\n[ 133 ]. Our results are consistent with other clinical evidence that antiinflammatory\nregulation is challenged and further compromised in the maternal syndrome of\nPE. Normal pregnancy manifests as a physiologic inflammatory state postulated\nto be tolerated to serve the nutritional needs of the fetus, whereas, in PE\nregulatory inflammatory mechanisms are excessively amplified, leading to\nvascular damage in the mother [ 133 ]. In this “hyperinflammatory” state\nof PE [ 134 ], the cytokines TNF α \nand IL-1 β \nwhich are typically controlled by the NF- κ B pathway in a negative-feedback\nloop with PPAR, are elevated [ 26 ,  60 ,  119 ]. Elevated inflammatory parameters in PE accompany\naltered levels of PG metabolites and circulating fatty acids. As noted, PG metabolites as well as fatty acids are\nimportant ligands of the PPAR system [ 135 ]. PG metabolism is altered\nduring normal pregnancy with levels of vasorelaxants suchas prostacyclin\nincreasing, whereas vasoconstrictive prostaglandin levelstend to be\nsuppressed [ 136 ]. Failure of these alterations have\nbeen suggested to lead to pregnancy complications (e.g., PE) [ 137 ]. For example, PGF 2 α ,\nwhich itself is stimulated by factorsin the plasma of women with PE\n[ 138 ], can inhibit PPAR γ  effects [ 135 ]. Levels of circulating free fatty acids are in the normal range duringmost of pregnancy,\nbut rise dramatically during the final weeks of pregnancy and drop\nprecipitously at term [ 136 ]. In PE these levels are increased from\n20 weeks’ gestation [ 133 ,  139 ]. We postulate that altered PG metabolism in this setting\n[ 138 ] results in decreased PPAR γ  ligation and subsequent cytokine\nactivation. If this proposal is supported by more data, the use of PPAR ligands\nmight be proposed to ameliorate symptoms such as hypertension and inflammation.\nUnfortunately, at present, the mechanism and site of this salutary of PPAR\nligand effect remain unknown in pregnancy, confounded by PPAR expression in\nmany cell types, including endothelial cells.\nDuring normal\npregnancy, maternal lipid, and glucose metabolism is profoundly altered\n[ 140 ]. The developing fetus uses\nglucose as its predominant energy source, which puts a continuous\ndemand on the mother to provide this substrate [ 141 ]. This constant need for glucose\nresults in frequent hypoglycemia and postprandial hyperglycemia during normal\npregnancy [ 141 ]. Problems with energy metabolism such as GDM\nare not uncommon and are often observed in susceptible women at this time. GDM\nis defined as any degreeof glucose intolerance with onset or first\nrecognition during pregnancy. In women with GDM, defective  β -cells\nfunction cannot adequately compensate for free fatty acid-mediated insulin\nresistance [ 142 ]. As elsewhere in our society, the\nincidence of obesity, diabetes, and gestational diabetes mellitus are\nincreasing in the pregnant population [ 143 ]. In the United\nStates, the incidence of obesity among pregnant women ranges from\n18.5% to 38.3% [ 144 ]; obesity comprises a major risk factor for GDM [ 145 ]. Morphological changes have been\nidentified in the syncytiotrophoblast, cytotrophoblast, trophoblastic basement\nmembrane, and fetal vessels within the placentae of these cases [ 146 ]. GDM is associated with several severe\nneonatal complications (such as macrosomia, brachial plexus palsy, premature\ndelivery, IUGR, and intrauterine death) and maternal birth injuries also are\ncommon [ 125 ,  147 ]. Furthermore, GDM has emerged as a risk factor for the\ndevelopment of diabetes mellitus type 2 (DM2) and cardiovascular disease in\nlater life and shares a number of epidemiologic, pathophysiologic, and genetic\ncharacteristics with DM2 [ 148 ]. GDM also has detrimental effects on the postnatal\ninfants [ 149 ].\nThe PPAR system regulates the\nmetabolic and pathways involved in the establishment of GDM. PPAR-agonists\nhave antidiabetogenic, antiinflammatory, and antioxidant effects, which are all\npotentially beneficial in the treatment of GDM [ 5 ].\nEnvironmental factors, such as diet\nand exercise and genetic factors influence PPAR α ,  γ  activity [ 130 ,  150 ] as well as the risk for insulin resistance and GDM\n( Table 2 ). Exercise activity initiated prepregnancy was shown to reduce the\nrisk of GDM and its complications [ 40 ,  41 ,  44 ,  151 , 152 ]. Nutritional counseling, moderate physical exercise,\nweight loss, and diet are successful therapies in some women with GDM,\nimproving glycemic control, reducing the incidence of LGA infants, and decreasing\nthe need for cesarean deliveries for cephalopelvic disproportion [ 41 ,  153 ].\nCandidate genes for GDM risk include\nTNF α ,\n β 3\nadrenoreceptor (ADRB3), and PPAR α  and  γ . The PPAR γ \nPro12Ala polymorphism was not associated with increased insulin resistance in\nTurkish women with GDM, however it was associated with weight gain [ 112 ]. The PPAR γ \ncoactivator-1alpha (PGC-1) polymorphism also failed to be associated with the development\nof GDM [ 154 ]. More studies on the association of various\ngenetic PPAR α  and  γ  variants and GDM in different ethnic\npopulations will be of interest.\n15dPGJ 2  is a potent antiinflammatory\nagent that represses the expression of a number of inflammatory\ngenes and regulating factors including the transcription factor NF- κ B\n[ 33 ,  108 ]. The concentration of 15dPGJ 2  was reduced in\nplacentae from diabetic rats ( Table 5 ) [ 95 ]. Placental 15dPGJ 2  was noted to be diminished\nin women with gestational and pregestational diabetes when compared to\ncontrols, whereas levels of nitric oxide (a stimulator of placental\ninvasiveness, differentiation, and proliferation) were higher in term placental\nexplants from diabetic patients when compared to controls [ 113 ]. As PPAR γ  can\nprevent nitric oxide overproduction in placenta from pregestational diabetic\nwomen [ 113 ], it may have the potential to improve\nfetal outcome in this condition.\nSulfonylurea\nagents including gliumepiride and glibenclamide exhibit PPAR γ  activity [ 155 ]. A randomized controlled trial to test\nthe effectiveness and safety of the sulfonylurea agent glyburide in the\nmanagement of women with GDM showed similar efficacy to insulin treatment [ 156 ]. Both the insulin- and\nglyburide-treated women were able to achieve satisfactory glucose control and\nhad similar perinatal outcome [ 156 ].\nTrophoblast research has emphasized\nthe similarities between the proliferative, migratory, andinvasive\nproperties of placental cells and those of cancer cells [ 157 ]. PPAR γ , PPAR β / δ , and RXR appear to be linked to gestational\ntrophoblastic neoplasms, conditions associated with malignant trophoblast\nbehavior [ 114 ]. PPAR γ  agonists inhibit invasion of normal\nextravillous cytotrophoblast isolated from human first-trimester placenta, and PPAR\nactivity has been shown to be downregulated in trophoblastic diseases including\nhydatidiform mole and choriocarcinoma [ 114 ].\nPPAR γ \nhas an effect on fetal and placental size influencing intrauterine growth. In an\nintrauterine growth restriction (IUGR) model, glucocorticoids inhibited fetal\nand placental growth partly by suppression of PPAR γ \nin the labyrinth zone of the placenta [ 158 ]. Activation of PPAR γ \nin the labyrinth trophoblasts is hypothesized to induce angiogenic factors and stimulate\nthe growth of fetal blood vessels, thereby promoting placental growth. However, treatment of pregnant mice with\nrosiglitazone led to reduced thickness of the spongiotrophoblast layer and the\nsurface area of labyrinthine vasculature, and it altered expression of proteins\nimplicated in placental development [ 159 ].\nIn vitro\nand in vivo experiments\nas well as animal models studies suggest a link between the PPAR system and\ngestational duration, preterm labor, and birth weight\n[ 116 ]. Variations in the PPAR genes influence other pregnancy-related mechanisms\nincluding birth weight and gestational duration. In an Irish population, the\nPPAR γ  Ala12\nallele was associated with shorter gestational duration [ 116 ].\nPPAR ligands regulate apoptotic\nmechanisms involved in rupture of the fetal membranes and may play a role in\npreterm delivery, a condition associated with increased risk of neonatal sepsis\nand newborn trauma [ 160 ]. 15d-PGJ 2 induced morphological\ncharacteristics of apoptosis within 2 hours in an amniotic cell line [ 160 ]. In addition, ciglitizone also induced apoptosis,\nwhereas rosiglitazone had no effect on cell viability [ 160 ]. Prevention of apoptosis may have therapeutic potential\nin preterm labor and premature rupture of the membranes and necessitates further\ninvestigations.\nInterestingly, PPAR α  deficiency\nis associated with miscarriage, neonatal mortality, and a shift from Th2 to a\nTh1 cytokine phenotype [ 76 ]. Th1 predominant immunity is closely associated with inflammation,\nendothelial dysfunction, and pregnancy complications. For example, interferon γ \nis significantly reduced in the spleens of PPAR α  null mice [ 76 ]. Twenty percent of PPAR α  knockout mice aborted, and offspring\nof PPAR- α  null\nmice exhibited increased neonatal mortality (13.3%). However the mechanism\nwhereby PPAR α  induces\na Th2 phenotype shift remains to be determined. PPAR γ \nligands also were shown to decrease production of inflammatory ligands in\nactivated macrophages and T cells and to induce a shift from Th1 to Th2 cytokine\nphenotype [ 161 ,  162 ].\n\nPPARs are involved in trophoblast\ninvasion, placental development, parturition, and pregnancy-specific diseases,\nparticularly PE and GDM. The role of the PPAR system in pregnancy under\nphysiologic and pathologic conditions has remained partly unclear due to lack\nof knowledge about endogenous PPAR ligands. Pharmacological ligand research is\nahead of the identification of physiologic ligands. Partially characterized\ninflammatory, angiogenic, and metabolic disturbances in pregnancy-related\ndiseases suggest that these synthetic PPAR agonists may be of potential use in\nthese conditions. Ongoing basic studies have elucidated the metabolic, antiinflammatory,\nand angiogenic benefits of PPAR α / β / δ  and PPAR γ / β / δ  dual agonists and PPAR pan agonists\nfor treatment purposes. However, some experimental and clinical data have\nuncovered unfortunate side effects of PPAR ligands, including cancer\nprogression and increased cardiac event rates. New generations of PPAR modulators\nare under development and these promise to be more receptor-specific, and\nhopefully will activate only a specific subset of target genes and metabolic\npathways to reduce untoward side effects. The potential role of PPARs in\nregulation of inflammation and angiogenesis is intriguing and warrants further\nstudies. We submit that PPAR agonists may become beneficial drugs for\npregnancy-specific diseases, once their risks have been fully evaluated.","source_license":"CC-BY-4.0","license_restricted":false}