Differentiation of Trophoblast Giant Cells and Their Metabolic Functions Are Dependent on Peroxisome Proliferator-Activated Receptor β/δ

ABSTRACT Mutation of the nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) severely affects placenta development, leading to embryonic death at embryonic day 9.5 (E9.5) to E10.5 of most, but not all, PPARβ/δ-null mutant embryos. While very little is known at present about the pathway governed by PPARβ/δ in the developing placenta, this paper demonstrates that the main alteration of the placenta of PPARβ/δ-null embryos is found in the giant cell layer. PPARβ/δ activity is in fact essential for the differentiation of the Rcho-1 cells in giant cells, as shown by the severe inhibition of differentiation once PPARβ/δ is silenced. Conversely, exposure of Rcho-1 cells to a PPARβ/δ agonist triggers a massive differentiation via increased expression of 3-phosphoinositide-dependent kinase 1 and integrin-linked kinase and subsequent phosphorylation of Akt. The links between PPARβ/δ activity in giant cells and its role on Akt activity are further strengthened by the remarkable pattern of phospho-Akt expression in vivo at E9.5, specifically in the nucleus of the giant cells. In addition to this phosphatidylinositol 3-kinase/Akt main pathway, PPARβ/δ also induced giant cell differentiation via increased expression of I-mfa, an inhibitor of Mash-2 activity. Finally, giant cell differentiation at E9.5 is accompanied by a PPARβ/δ-dependent accumulation of lipid droplets and an increased expression of the adipose differentiation-related protein (also called adipophilin), which may participate to lipid metabolism and/or steroidogenesis. Altogether, this important role of PPARβ/δ in placenta development and giant cell differentiation should be considered when contemplating the potency of PPARβ/δ agonist as therapeutic agents of broad application.

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The mechanism of mouse egg-cylinder morphogenesis in vitro

Development ◽

10.1242/dev.61.1.277 ◽

1981 ◽

Vol 61 (1) ◽

pp. 277-287

Author(s):

A. J. Copp

Keyword(s):

Giant Cell ◽

Cell Formation ◽

Cell Movement ◽

Giant Cells ◽

Cell Number ◽

Dependent Change ◽

Morphogenesis In Vitro ◽

Trophoblast Giant Cells

The number of trophoblast giant cells in outgrowths of mouse blastocysts was determined before, during and after egg-cylinder formation in vitro. Giant-cell numbers rose initially but reached a plateau 12 h before the egg cylinder appeared. A secondary increase began 24 h after egg-cylinder formation. Blastocysts whose mural trophectoderm cells were removed before or shortly after attachment in vitro formed egg cylinders at the same time as intact blastocysts but their trophoblast outgrowths contained fewer giant cells at this time. The results support the idea that egg-cylinder formation in vitro is accompanied by a redirection of the polar to mural trophectoderm cell movement which characterizes blastocysts before implantation. The resumption of giant-cell number increase in trophoblast outgrowths after egg-cylinder formation may correspond to secondary giant-cell formation in vivo. It is suggested that a time-dependent change in the strength of trophoblast cell adhesion to the substratum occurs after blastocyst attachment in vitro which restricts the further entry of polar cells into the outgrowth and therefore results in egg-cylinder formation.

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Peroxisome Proliferator-Activated Receptor γ and Its Role in Adipocyte Homeostasis and Thiazolidinedione-Mediated Insulin Sensitization

Molecular and Cellular Biology ◽

10.1128/mcb.00677-17 ◽

2018 ◽

Vol 38 (10) ◽

Cited By ~ 9

Author(s):

Qiong A. Wang ◽

Fang Zhang ◽

Lei Jiang ◽

Risheng Ye ◽

Yu An ◽

...

Keyword(s):

Whole Body ◽

Peroxisome Proliferator ◽

Metabolic Homeostasis ◽

Short Term ◽

Peroxisome Proliferator Activated Receptor ◽

Fat Depots ◽

Metabolic Functions ◽

Sensitizing Effect

ABSTRACT Adipose tissue is a dynamic organ that makes critical contributions to whole-body metabolic homeostasis. Although recent studies have revealed that different fat depots have distinct molecular signatures, metabolic functions and adipogenic mechanisms, peroxisome proliferator-activated receptor γ (PPARγ) is still widely viewed as the master regulator of adipogenesis and critical for maintaining mature adipocyte function. Using an inducible, adipocyte-specific knockout system, we explored the role of PPARγ in mature adipocytes in vivo . Short-term PPARγ deficiency in adipocytes reduces whole-body insulin sensitivity, but adipocytes are viable both in vitro and in vivo . However, after exposure to a high-fat diet, even short-term PPARγ deficiency leads to rapid adipocyte death. When mature adipocytes are depleted of both PPARγ and CCAAT-enhancer-binding protein α (C/EBPα), they are rapidly depleted of lipids and undergo adipocyte death, both in vitro and in vivo . Surprisingly, although thiazolidinediones (TZDs; PPARγ agonists) are thought to act mainly on PPARγ, PPARγ in adipocytes is not required for the whole-body insulin-sensitizing effect of TZDs. This offers new mechanistic aspects of PPARγ/TZD action and its effect on whole-body metabolic homeostasis.

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Reprogramming the Cell Cycle for Endoreduplication in Rodent Trophoblast Cells

Molecular Biology of the Cell ◽

10.1091/mbc.9.4.795 ◽

1998 ◽

Vol 9 (4) ◽

pp. 795-807 ◽

Cited By ~ 125

Author(s):

Alasdair MacAuley ◽

James C. Cross ◽

Zena Werb

Keyword(s):

Cell Cycle ◽

Cell Differentiation ◽

Giant Cell ◽

Mitotic Cycle ◽

Mitotic Cell ◽

Giant Cells ◽

Cyclin B ◽

Helix Loop Helix ◽

Trophoblast Giant Cells ◽

Cycle Regulation

Differentiation of trophoblast giant cells in the rodent placenta is accompanied by exit from the mitotic cell cycle and onset of endoreduplication. Commitment to giant cell differentiation is under developmental control, involving down-regulation of Id1and Id2, concomitant with up-regulation of the basic helix-loop-helix factor Hxt and acquisition of increased adhesiveness. Endoreduplication disrupts the alternation of DNA synthesis and mitosis that maintains euploid DNA content during proliferation. To determine how the mammalian endocycle is regulated, we examined the expression of the cyclins and cyclin-dependent kinases during the transition from replication to endoreduplication in the Rcho-1 rat choriocarcinoma cell line. We cultured these cells under conditions that gave relatively synchronous endoreduplication. This allowed us to study the events that occur during the transition from the mitotic cycle to the first endocycle. With giant cell differentiation, the cells switched cyclin D isoform expression from D3 to D1 and altered several checkpoint functions, acquiring a relative insensitivity to DNA-damaging agents and a coincident serum independence. The initiation of S phase during endocycles appeared to involve cycles of synthesis of cyclins E and A, and termination of S was associated with abrupt loss of cyclin A and E. Both cyclins were absent from gap phase cells, suggesting that their degradation may be necessary to allow reinitiation of the endocycle. The arrest of the mitotic cycle at the onset of endoreduplication was associated with a failure to assemble cyclin B/p34cdk1complexes during the first endocycle. In subsequent endocycles, cyclin B expression was suppressed. Together these data suggest several points at which cell cycle regulation could be targeted to shift cells from a mitotic to an endoreduplicative cycle.

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Peroxisome Proliferator–Activated Receptor γ Regulates Angiotensin II–Stimulated Phosphatidylinositol 3-Kinase and Mitogen-Activated Protein Kinase in Blood Vessels In Vivo

Hypertension ◽

10.1161/01.hyp.0000196728.05488.c3 ◽

2006 ◽

Vol 47 (1) ◽

pp. 102-108 ◽

Cited By ~ 44

Author(s):

Karim Benkirane ◽

Émilie C. Viel ◽

Farhad Amiri ◽

Ernesto L. Schiffrin

Keyword(s):

Angiotensin Ii ◽

Protein Kinase ◽

Blood Vessels ◽

Mitogen Activated Protein Kinase ◽

Peroxisome Proliferator ◽

Phosphatidylinositol 3 Kinase ◽

Peroxisome Proliferator Activated Receptor ◽

Mitogen Activated Protein ◽

Phosphatidylinositol 3

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Peroxisome proliferator-activated receptor (PPAR)-γ ligand inhibits the progression of pancreatic fibrosis in vivo and profibrogenic action in pancreatic myofibroblast

Gastroenterology ◽

10.1016/s0016-5085(01)80545-x ◽

2001 ◽

Vol 120 (5) ◽

pp. A111-A111

Author(s):

K SHIMIZU ◽

S HISADA ◽

K SHIRATORI ◽

M KOBAYASHI ◽

N HAYASHI

Keyword(s):

Pancreatic Fibrosis ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ

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Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

Nature Communications ◽

10.1038/s41467-021-22106-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

KyeongJin Kim ◽

Jin Ku Kang ◽

Young Hoon Jung ◽

Sang Bae Lee ◽

Raffaela Rametta ◽

...

Keyword(s):

Fatty Liver ◽

Whole Body ◽

Acid Oxidation ◽

Chow Diet ◽

Peroxisome Proliferator ◽

Obese Mice ◽

Ph Domain ◽

Peroxisome Proliferator Activated Receptor

AbstractIncreased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

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The lipid-lowering drug fenofibrate combined with si-HOTAIR can effectively inhibit the proliferation of gliomas

BMC Cancer ◽

10.1186/s12885-021-08417-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Wei Zhu ◽

Hongyang Zhao ◽

Fenfen Xu ◽

Bin Huang ◽

Xiaojing Dai ◽

...

Keyword(s):

Noncoding Rna ◽

Glioma Cells ◽

Lipid Lowering ◽

Fibric Acid Derivative ◽

Peroxisome Proliferator ◽

Glioma Invasion ◽

Peroxisome Proliferator Activated Receptor ◽

Lncrna Hotair

Abstract Background Fenofibrate is a fibric acid derivative known to have a lipid-lowering effect. Although fenofibrate-induced peroxisome proliferator-activated receptor alpha (PPARα) transcription activation has been shown to play an important role in the malignant progression of gliomas, the underlying mechanisms are poorly understood. Methods In this study, we analyzed TCGA database and found that there was a significant negative correlation between the long noncoding RNA (lncRNA) HOTAIR and PPARα. Then, we explored the molecular mechanism by which lncRNA HOTAIR regulates PPARα in cell lines in vitro and in a nude mouse glioma model in vivo and explored the effect of the combined application of HOTAIR knockdown and fenofibrate treatment on glioma invasion. Results For the first time, it was shown that after knockdown of the expression of HOTAIR in gliomas, the expression of PPARα was significantly upregulated, and the invasion and proliferation ability of gliomas were obviously inhibited. Then, glioma cells were treated with both the PPARα agonist fenofibrate and si-HOTAIR, and the results showed that the proliferation and invasion of glioma cells were significantly inhibited. Conclusions Our results suggest that HOTAIR can negatively regulate the expression of PPARα and that the combination of fenofibrate and si-HOTAIR treatment can significantly inhibit the progression of gliomas. This introduces new ideas for the treatment of gliomas.

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The Novel Role of PGC1α in Bone Metabolism

International Journal of Molecular Sciences ◽

10.3390/ijms22094670 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4670

Author(s):

Cinzia Buccoliero ◽

Manuela Dicarlo ◽

Patrizia Pignataro ◽

Francesco Gaccione ◽

Silvia Colucci ◽

...

Keyword(s):

Bone Metabolism ◽

Osteoblastic Differentiation ◽

In Vivo Studies ◽

Peroxisome Proliferator ◽

Sirtuin 3 ◽

Peroxisome Proliferator Activated Receptor ◽

Increased Risk

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a protein that promotes transcription of numerous genes, particularly those responsible for the regulation of mitochondrial biogenesis. Evidence for a key role of PGC1α in bone metabolism is very recent. In vivo studies showed that PGC1α deletion negatively affects cortical thickness, trabecular organization and resistance to flexion, resulting in increased risk of fracture. Furthermore, in a mouse model of bone disease, PGC1α activation stimulates osteoblastic gene expression and inhibits atrogene transcription. PGC1α overexpression positively affects the activity of Sirtuin 3, a mitochondrial nicotinammide adenina dinucleotide (NAD)-dependent deacetylase, on osteoblastic differentiation. In vitro, PGC1α overexpression prevents the reduction of mitochondrial density, membrane potential and alkaline phosphatase activity caused by Sirtuin 3 knockdown in osteoblasts. Moreover, PGC1α influences the commitment of skeletal stem cells towards an osteogenic lineage, while negatively affects marrow adipose tissue accumulation. In this review, we will focus on recent findings about PGC1α action on bone metabolism, in vivo and in vitro, and in pathologies that cause bone loss, such as osteoporosis and type 2 diabetes.

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Protein Kinase A/CREB Signaling Prevents Adriamycin-Induced Podocyte Apoptosis via Upregulation of Mitochondrial Respiratory Chain Complexes

Molecular and Cellular Biology ◽

10.1128/mcb.00181-17 ◽

2017 ◽

Vol 38 (1) ◽

Cited By ~ 10

Author(s):

Kewei Xie ◽

Mingli Zhu ◽

Peng Xiang ◽

Xiaohuan Chen ◽

Ayijiaken Kasimumali ◽

...

Keyword(s):

Protein Kinase ◽

Protein Kinase A ◽

Respiratory Chain ◽

Mitochondrial Respiratory Chain ◽

Peroxisome Proliferator ◽

Respiratory Chain Complexes ◽

Peroxisome Proliferator Activated Receptor ◽

Kinase A ◽

Mitochondrial Respiratory

ABSTRACT Previous work showed that the activation of protein kinase A (PKA) signaling promoted mitochondrial fusion and prevented podocyte apoptosis. The cAMP response element binding protein (CREB) is the main downstream transcription factor of PKA signaling. Here we show that the PKA agonist 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate–cyclic AMP (pCPT-cAMP) prevented the production of adriamycin (ADR)-induced reactive oxygen species and apoptosis in podocytes, which were inhibited by CREB RNA interference (RNAi). The activation of PKA enhanced mitochondrial function and prevented the ADR-induced decrease of mitochondrial respiratory chain complex I subunits, NADH-ubiquinone oxidoreductase complex (ND) 1/3/4 genes, and protein expression. Inhibition of CREB expression alleviated pCPT-cAMP-induced ND3, but not the recovery of ND1/4 protein, in ADR-treated podocytes. In addition, CREB RNAi blocked the pCPT-cAMP-induced increase in ATP and the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1-α). The chromatin immunoprecipitation assay showed enrichment of CREB on PGC1-α and ND3 promoters, suggesting that these promoters are CREB targets. In vivo, both an endogenous cAMP activator (isoproterenol) and pCPT-cAMP decreased the albumin/creatinine ratio in mice with ADR nephropathy, reduced glomerular oxidative stress, and retained Wilm's tumor suppressor gene 1 (WT-1)-positive cells in glomeruli. We conclude that the upregulation of mitochondrial respiratory chain proteins played a partial role in the protection of PKA/CREB signaling.

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