Nuclear Receptors of the Peroxisome Proliferator-Activated Receptor (PPAR) Family in Gestational Diabetes: From Animal Models to Clinical Trials1

Arck, Petra C.; Tóth, Bettina; Pestka, Aurelia; Jeschke, Udo

doi:10.1095/biolreprod.110.083550

Cited by 53 publications

(30 citation statements)

References 107 publications

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“…This disease is characterized by impaired glucose tolerance during pregnancy, affecting 2-8% of all pregnancies (Arck et al, 2010), a figure that has risen by 50% in the last 20 years (Ferrara, 2007). Along with other complications, gestational diabetes mellitus can result in the development of type II diabetes mellitus in both mother and child.…”

Section: Gestational Diabetes Mellitusmentioning

confidence: 99%

“…PPAR-g is a major regulator of both glucose and lipid metabolism through its involvement in the regulation of adipogenesis and intracellular insulin signalling processes that ultimately controls glucose homeostasis (Tontonoz et al, 1994). In gestational diabetes, PPAR-g expression is often dysregulated, leading to changes in insulin sensitivity profiles (Arck et al, 2010). Furthermore, a recent study has suggested that the PPAR-g variants, Pro 12 Ala and C1431T, and their haplotypes may play a role in the susceptibility of developing gestational diabetes (Heude et al, 2011), further demonstrating their potential as biomarkers for disease and possible therapeutic targets for translational medicine.…”

Section: Gestational Diabetes Mellitusmentioning

confidence: 99%

“…Thiazolidinediones such as rosiglitazone activate PPAR-g in order to improve insulin sensitivity profile; however, the thiazolidinediones currently on the market are first-generation, nonspecific agonists of PPAR-g, resulting in the deleterious side effects (Kung and Henry, 2012) that have caused their limited usage and in some cases have been withdrawn from the market (Mutalik, 2011). While there has yet to be an assessment of the risks associated with thiazolidinedione administration during pregnancy and a safety profile remains to be established (Arck et al, 2010), there is hope on the horizon in terms of modulators of PPAR-g activity. The new development of highly targeted selective PPAR-g modulators (SPPARgMs) and dual PPAR-g/PPAR-a agonists (Kung and Henry, 2012) has led to the re-emergence of PPAR-g as a potential therapeutic target.…”

Section: Ppar-g As a Therapeutic Targetmentioning

confidence: 99%

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PPAR‐γ – a possible drug target for complicated pregnancies

McCarthy

Delany

Kenny

et al. 2013

British J Pharmacology

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Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors expressed in trophoblasts, which regulate both cell differentiation and proliferation. In recent years, evidence has linked PPARs to playing an integral role in pregnancy; specifically, PPAR-b and PPAR-g have been shown to play an integral role in placentation, with PPAR-g additionally serving to regulate trophoblast differentiation. Recent evidence has shown that PPAR-g expression is altered in many complications of pregnancy such as intrauterine growth restriction (IUGR), preterm birth, pre-clampsia and gestational diabetes. Thus, at present, accumulating evidence from the literature suggests both a pivotal role for PPAR-g in the progression of a healthy pregnancy and the possibility that PPAR-g may act as a therapeutic target in complicated pregnancies. This review aims to provide a succinct and comprehensive assessment of the role of PPAR-g in normal pregnancy and pregnancy complications, and finally its potential as a therapeutic target in the treatment and/or prevention of adverse pregnancy outcomes. AbbreviationsET-1, endothelin-1; HO-1, heme oxygenase-1; ICAM-1, intercellular adhesion molecule-1; IKK, IkB kinase; RXR, retinoid X receptor; SO, superoxide; TXA2, thromboxane A2; VCAM-1, vascular adhesion molecule-1

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Section: Gestational Diabetes Mellitusmentioning

confidence: 99%

Section: Gestational Diabetes Mellitusmentioning

confidence: 99%

Section: Ppar-g As a Therapeutic Targetmentioning

confidence: 99%

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PPAR‐γ – a possible drug target for complicated pregnancies

McCarthy

Delany

Kenny

et al. 2013

British J Pharmacology

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“…PPAR together with its heterodimer binding partner retinoid X receptor  (RXR) are involved in cell proliferation, cell differentiation, and organogenesis [8]. RXR is upregulated in extravillous trophoblast in recurrent miscarriages in humans [9].…”

Section: Introductionmentioning

confidence: 99%

PPARgamma Expression is Diminished in Macrophages of Recurrent Miscarriage Placentas

Kolben¹,

Rogatsch²,

Vattai³

et al. 2018

Preprint

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PPAR belongs to the group of nuclear receptors which is expressed in the trophoblast and together with other factors is responsible for the maintenance of pregnancy. Apart from that PPAR is also a main factor for macrophage polarization. The aim of this study was to investigate the combined expression pattern and frequency of PPAR under physiological circumstances and in spontaneous and recurrent miscarriages in the trophoblast and in maternal macrophages of the decidua. Human placental tissues of the first trimester (15 physiologic pregnancies, 15 spontaneous abortion & 16 recurrent miscarriage placentas) were analyzed for expression of the nuclear receptor PPAR. Expression changes were evaluated by immunohistochemistry and RT-PCR in trophoblast and in maternal macrophages of the decidua. Maternal macrophages were identified by double immunofluorescence using CD68 as marker for macrophages. The intermediate villous trophoblast revealed a significantly lower PPAR expression in spontaneous and recurrent abortion. Maternal macrophages express PPAR. Their number is significantly enhanced in the decidua of spontaneous miscarriages whereas in recurrent miscarriages maternal macrophages seem to express PPAR only in very few cases. PPAR is associated with an M2 polarization state that is common for decidual macrophages. The lack of PPAR in recurrent miscarriage decidual macrophages seems to be associated with a specific inflammatory response against the fetus.

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“…An important group of PPAR agonists are prostaglandins that belong to the eicosanoids (Forman et al 1995, Kliewer et al 1997. PPAR agonists can be used in the treatment of type II diabetes mellitus and for patients suffering from polycystic ovary syndrome (Arck et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Retinoid X receptor α and retinoids are key regulators in apoptosis of trophoblasts of patients with recurrent miscarriages

Pestka

Tóth²,

Kühn³

et al. 2011

Journal of Molecular Endocrinology

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The retinoid X receptor a (RXRa) is a nuclear hormone receptor that is able to bind other nuclear receptors in a heterodimeric complex, thereby activating gene transcription. Recently, we identified enhanced expression of RXRa in extravillous trophoblasts (EVT) and villous trophoblasts (VT) of miscarried placentas. In addition, an increased number of apoptotic EVT was present in miscarried placentas. In this study, on the basis of immunocytochemical analysis, western blots, and quantitative real-time reverse transcription PCR, we could demonstrate a reduced expression of RXRa in choriocarcinoma cell lines and in human VTs after stimulation with the retinoids 9-cis-retinoic acid and all-transretinoic acid and the prostaglandin 15-deoxy-D 12,14 -prostaglandin J 2 . Furthermore, a simultaneous expression of RXRa and the apoptotic marker M30 CytoDEATH in EVT of miscarried placentas from the first trimester was shown. In EVT of control placentas from legal termination of pregnancies, no co-expression of RXRa and M30 could be detected. A likely conclusion is that RXRa plays an important role in the induction of apoptosis. Downregulation of RXRa, as observed in the tested choriocarcinoma cells and trophoblasts, might serve as a protection against apoptosis and miscarriage. In conclusion, RXRa represents a potential target in the treatment of recurrent miscarriages.

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Nuclear Receptors of the Peroxisome Proliferator-Activated Receptor (PPAR) Family in Gestational Diabetes: From Animal Models to Clinical Trials1

Cited by 53 publications

References 107 publications

PPAR‐γ – a possible drug target for complicated pregnancies

PPAR‐γ – a possible drug target for complicated pregnancies

PPARgamma Expression is Diminished in Macrophages of Recurrent Miscarriage Placentas

Retinoid X receptor α and retinoids are key regulators in apoptosis of trophoblasts of patients with recurrent miscarriages

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