98 Peroxisome proliferator-activated receptor-gamma (PPARG) is dispensable for bovine blastocyst formation

2021 ◽  
Vol 33 (2) ◽  
pp. 156
Author(s):  
A. C. Quiroga ◽  
C. de Frutos ◽  
E. Zurita ◽  
P. Bermejo-Álvarez
Keyword(s):  
Embryo Development ◽  
Developmental Stages ◽  
Peroxisome Proliferator ◽  
Blastocyst Formation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Signalling Molecules ◽  
Lipid Signalling ◽  
Peroxisome Proliferator Activated Receptors ◽  
Rule Out ◽  
Bovine Blastocyst

Prostaglandins (PGs) are lipid signalling molecules that play critical roles in gestation by promoting corpus luteus maintenance or luteolysis, and have been suggested to play other roles in early pregnancy, including embryo–maternal crosstalk. The signalling roles of PGs and other lipids are often mediated by peroxisome proliferator-activated receptors (PPARs), transcription factors that regulate the expression of other genes through PPAR-responsive elements. PPARG is a PPAR expressed by bovine pre-implantation embryos whose inhibition by morpholino intrauterine infusion has been reported to impair embryo development. As this approach causes PPARG depletion in both conceptus and uterus, it is unknown whether PPARG-mediated signalling in the embryo is required for embryo development. The objective of this study was to determine whether PPARG is required for blastocyst formation. For that aim, we have evaluated embryo development in PPARG knockout (KO) bovine embryos generated by CRISPR-Cas9 technology. Invitro matured oocytes were allocated in two groups: one was injected with mRNA encoding for Cas9 and sgRNA against PPARG to generate KO embryos (C+G, n=191) and the other was injected with mRNA alone (C, n=148), serving as a microinjection control generating only wild-type embryos. Following fertilization, embryos were allowed to develop to Day 8 blastocysts invitro. No differences were found in cleavage and blastocyst rates between both groups (cleavage 78.5±3.4 vs. 78.4±4.2; Day 7 blastocyst 17.3±3.9 vs. 10.8±2.9; Day 8 blastocyst 20.4±6.2 vs. 16.9±4.7; C+G vs. C; mean±s.e.m.; ANOVA P>0.05). Blastocysts of the C+G group were genotyped by clonal sequencing to determine which embryos in the C+G group were KO (i.e. harboured only frame-disrupting, KO alleles). Twenty-eight out of the 32 blastocysts analysed were edited (87.5%), of which 6 (18.8%) were KO. These results show that PPARG is not required for blastocyst formation, because KO embryos develop to that stage, but do not rule out a possible role in further developmental stages.

scholarly journals Wnt/β-catenin Pathway-Mediated PPARδ Expression during Embryonic Development Differentiation and Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 1854
Author(s):  
Tabinda Sidrat ◽  
Zia-Ur Rehman ◽  
Myeong-Don Joo ◽  
Kyeong-Lim Lee ◽  
Il-Keun Kong
Keyword(s):  
Embryonic Development ◽  
Transcriptional Activation ◽  
Target Gene ◽  
Developmental Stages ◽  
Embryonic Stem ◽  
Hereditary Diseases ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Stem Cell Regulation ◽  
Early Developmental

The Wnt/β-catenin signaling pathway plays a crucial role in early embryonic development. Wnt/β-catenin signaling is a major regulator of cell proliferation and keeps embryonic stem cells (ESCs) in the pluripotent state. Dysregulation of Wnt signaling in the early developmental stages causes several hereditary diseases that lead to embryonic abnormalities. Several other signaling molecules are directly or indirectly activated in response to Wnt/β-catenin stimulation. The crosstalk of these signaling factors either synergizes or opposes the transcriptional activation of β-catenin/Tcf4-mediated target gene expression. Recently, the crosstalk between the peroxisome proliferator-activated receptor delta (PPARδ), which belongs to the steroid superfamily, and Wnt/β-catenin signaling has been reported to take place during several aspects of embryonic development. However, numerous questions need to be answered regarding the function and regulation of PPARδ in coordination with the Wnt/β-catenin pathway. Here, we have summarized the functional activation of the PPARδ in co-ordination with the Wnt/β-catenin pathway during the regulation of several aspects of embryonic development, stem cell regulation and maintenance, as well as during the progression of several metabolic disorders.

scholarly journals Peroxisome Proliferator-Activated Receptor Delta: A Conserved Director of Lipid Homeostasis through Regulation of the Oxidative Capacity of Muscle

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-7 ◽  
Author(s):  
Pieter de Lange ◽  
Assunta Lombardi ◽  
Elena Silvestri ◽  
Fernando Goglia ◽  
Antonia Lanni ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Oxidative Capacity ◽  
Whole Body ◽  
Lipid Homeostasis ◽  
Peroxisome Proliferator ◽  
Transcriptional Program ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisome Proliferator Activated Receptors ◽  
Metabolic Action

The peroxisome proliferator-activated receptors (PPARs), which are ligand-inducible transcription factors expressed in a variety of tissues, have been shown to perform key roles in lipid homeostasis. In physiological situations such as fasting and physical exercise, one PPAR subtype, PPARδ, triggers a transcriptional program in skeletal muscle leading to a switch in fuel usage from glucose/fatty acids to solely fatty acids, thereby drastically increasing its oxidative capacity. The metabolic action of PPARδ has also been verified in humans. In addition, it has become clear that the action of PPARδ is not restricted to skeletal muscle. Indeed, PPARδ has been shown to play a crucial role in whole-body lipid homeostasis as well as in insulin sensitivity, and it is active not only in skeletal muscle (as an activator of fat burning) but also in the liver (where it can activate glycolysis/lipogenesis, with the produced fat being oxidized in muscle) and in the adipose tissue (by incrementing lipolysis). The main aim of this review is to highlight the central role for activated PPARδ in the reversal of any tendency toward the development of insulin resistance.

scholarly journals Association with Coregulators Is the Major Determinant Governing Peroxisome Proliferator-activated Receptor Mobility in Living Cells

2006 ◽  
Vol 282 (7) ◽  
pp. 4417-4426 ◽  
Author(s):  
Cicerone Tudor ◽  
Jérôme N. Feige ◽  
Harikishore Pingali ◽  
Vidya Bhushan Lohray ◽  
Walter Wahli ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Molecular Mechanisms ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Living Cells ◽  
Correlation Spectroscopy ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisome Proliferator Activated Receptors

The nucleus is an extremely dynamic compartment, and protein mobility represents a key factor in transcriptional regulation. We showed in a previous study that the diffusion of peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors regulating major cellular and metabolic functions, is modulated by ligand binding. In this study, we combine fluorescence correlation spectroscopy, dual color fluorescence cross-correlation microscopy, and fluorescence resonance energy transfer to dissect the molecular mechanisms controlling PPAR mobility and transcriptional activity in living cells. First, we bring new evidence that in vivo a high percentage of PPARs and retinoid X receptors is associated even in the absence of ligand. Second, we demonstrate that coregulator recruitment (and not DNA binding) plays a crucial role in receptor mobility, suggesting that transcriptional complexes are formed prior to promoter binding. In addition, association with coactivators in the absence of a ligand in living cells, both through the N-terminal AB domain and the AF-2 function of the ligand binding domain, provides a molecular basis to explain PPAR constitutive activity.

Prenatal androgen excess alters the uterine peroxisome proliferator-activated receptor (PPAR) system

2019 ◽  
Vol 31 (8) ◽  
pp. 1401
Author(s):  
Silvana R. Ferreira ◽  
Leandro M. Vélez ◽  
Maria F. Heber ◽  
Giselle A. Abruzzese ◽  
Alicia B. Motta
Keyword(s):  
Fetal Programming ◽  
Female Offspring ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Androgen Excess ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisome Proliferator Activated Receptors ◽  
Pg E2 ◽  
Prenatal Androgen

It is known that androgen excess induces changes in fetal programming that affect several physiological pathways. Peroxisome proliferator-activated receptors (PPARs) α, δ and γ are key mediators of female reproductive functions, in particular in uterine tissues. Thus, we aimed to study the effect of prenatal hyperandrogenisation on the uterine PPAR system. Rats were treated with 2mg testosterone from Day 16 to 19 of pregnancy. Female offspring (PH group) were followed until 90 days of life, when they were killed. The PH group exhibited an anovulatory phenotype. We quantified uterine mRNA levels of PPARα (Ppara), PPARδ (Ppard), PPARγ (Pparg), their regulators peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a) and nuclear receptor co-repressor 1 (Ncor1) and cyclo-oxygenase (COX)-2 (Ptgs2), and assessed the lipid peroxidation (LP) index and levels of glutathione (GSH) and prostaglandin (PG) E2. The PH group showed decreased levels of all uterine PPAR isoforms compared with the control group. In addition, PGE2 and Ptgs2 levels were increased in the PH group, which led to a uterine proinflammatory environment, as was LP, which led to a pro-oxidant status that GSH was not able to compensate for. These results suggest that prenatal exposure to androgen excess has a fetal programming effect that affects the gene expression of PPAR isoforms, and creates a misbalanced oxidant–antioxidant state and a proinflammatory status.

Triterpenoids from Hibiscus sabdariffa L. with PPARδ/γ Dual Agonist Action: In Vivo, In Vitro and In Silico Studies

Planta Medica ◽  
2019 ◽  
Vol 85 (05) ◽  
pp. 412-423 ◽  
Author(s):  
Abraham Giacoman-Martínez ◽  
Francisco Alarcón-Aguilar ◽  
Alejandro Zamilpa ◽  
Sergio Hidalgo-Figueroa ◽  
Gabriel Navarrete-Vázquez ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Messenger Ribonucleic Acid ◽  
Transporter Protein ◽  
Agonist Action ◽  
Fatty Acid Transporter ◽  
Peroxisome Proliferator Activated Receptors ◽  
Glucose Transporter Type 4 ◽  
Dual Agonist

Abstract Hibiscus sabdariffa is a medicinal plant consumed as a diuretic and anti-obesity remedy. Several pharmacological studies have shown its beneficial effects in metabolism. Peroxisome proliferator-activated receptors δ and γ may play a role in the actions of H. sabdariffa. These nuclear receptors regulate lipid and glucose metabolism and are therapeutic targets for type 2 diabetes. This research aimed to perform a phytochemical study guided by a bioassay from H. sabdariffa to identify compounds with peroxisome proliferator-activated receptor δ and peroxisome proliferator-activated receptor γ agonist activity, supported by messenger ribonucleic acid expression, molecular docking, lipid accumulation, and an antihyperglycemic effect. An oral glucose tolerance test in mice with the aqueous extract of H. sabdariffa and the dichloromethane extract of H. sabdariffa was performed. The dichloromethane extract of H. sabdariffa exhibited an antihyperglycemic effect. The dichloromethane extract of H. sabdariffa was fractioned, and four fractions were evaluated in 3T3-L1 adipocytes on peroxisome proliferator-activated receptor δ, peroxisome proliferator-activated receptor γ, fatty acid transporter protein, and glucose transporter type 4 messenger ribonucleic acid expression. Fraction F3 exhibited peroxisome proliferator-activated receptor δ/γ dual agonist activity, and a further fractionation yielded two subfractions, F3-1 and F3-2, which also increased peroxisome proliferator-activated receptor δ and peroxisome proliferator-activated receptor γ expression. Subfractions were analyzed by GC/MS. The main compounds identified in F3-1 were linoleic acid, oleic acid, and palmitic acid, while in F3-2, the main compounds identified were α-amyrin and lupeol. These molecules were subjected to molecular docking analysis. α-Amyrin and lupeol showed the highest affinity. Moreover, both produced an increase in peroxisome proliferator-activated receptor δ, peroxisome proliferator-activated receptor γ, fatty acid transporter protein, and glucose transporter type 4 expression. Additionally, α-amyrin and lupeol decreased lipid accumulation in 3T3-L1 adipocytes and blood glucose in mice. Until now, α-amyrin and lupeol have not been reported with activity on peroxisome proliferator-activated receptors. This study provides evidence that α-amyrin and lupeol possess antidiabetic effects through a peroxisome proliferator-activated receptor δ/γ dual agonist action.

scholarly journals Obesogens, stem cells and the maternal programming of obesity

2010 ◽  
Vol 2 (1) ◽  
pp. 3-8 ◽  
Author(s):  
B. Blumberg
Keyword(s):  
Adipose Tissue ◽  
Developmental Stages ◽  
Chemical Exposure ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Global Epidemic ◽  
Multipotent Stromal Cell ◽  
Diet And Exercise ◽  
Adipose Tissue Development ◽  
Lipid Balance

Obesity and metabolic syndrome diseases have exploded into a global epidemic. Consumption of calorie-dense food and diminished physical activity are the generally accepted causes for obesity. But, could environmental factors expose preexisting genetic differences or exacerbate the root causes of diet and exercise? The environmental obesogen model proposes that chemical exposure during critical developmental stages influences subsequent adipogenesis, lipid balance and obesity. Obesogens are chemicals that stimulate adipogenesis and fat storage or alter the control of metabolism, appetite and satiety to promote weight gain. Tributyltin (TBT) is a high-affinity agonistic ligand for the retinoid X receptor (RXR) and peroxisome proliferator activated receptor gamma (PPARγ). RXR-PPARγ signaling is a key component in adipogenesis and the function of adipocytes; activation of this heterodimer increases adipose mass in rodents and humans. Thus, inappropriate activation of RXR-PPARγ can directly alter adipose tissue homeostasis. TBT exposure promoted adipocyte differentiation, modulated adipogenic genes and increased adiposity in mice after in utero exposure. These results suggest that organotin exposure is a previously unappreciated risk factor for the development of obesity and related disorders. Based on the observed effects of TBT on adipogenesis, we hypothesized that organotin exposure during prenatal adipose tissue development would create an environment that led to more adipocytes. We observed that the multipotent stromal cell compartment was altered by prenatal TBT exposure leading to an increased number of preadipocytes. This increase in the number of preadipocytes could correspondingly increase the steady state number of adipocytes in the adult, which could favor the development of obesity over time.

scholarly journals Control of human carnitine palmitoyltransferase II gene transcription by peroxisome proliferator-activated receptor through a partially conserved peroxisome proliferator-responsive element

2003 ◽  
Vol 369 (3) ◽  
pp. 721-729 ◽  
Author(s):  
María J. BARRERO ◽  
Nuria CAMARERO ◽  
Pedro F. MARRERO ◽  
Diego HARO
Keyword(s):  
Consensus Sequence ◽  
Carnitine Palmitoyltransferase ◽  
Proximal Promoter ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisome Proliferator Activated Receptors ◽  
Responsive Element ◽  
Carnitine Palmitoyltransferase Ii ◽  
Half Site

The expression of several genes involved in fatty acid metabolism is regulated by peroxisome proliferator-activated receptors (PPARs). To gain more insight into the control of carnitine palmitoyltransferase (CPT) gene expression, we examined the transcriptional regulation of the human CPT II gene. We show that the 5′-flanking region of this gene is transcriptionally active and binds PPARα in vivo in a chromatin immunoprecipitation assay. In addition, we characterized the peroxisome proliferator-responsive element (PPRE) in the proximal promoter of the CPT II gene, which appears to be a novel PPRE. The sequence of this PPRE contains one half-site which is a perfect consensus sequence (TGACCT) but no clearly recognizable second half-site (CAGCAC); this part of the sequence contains only one match to the consensus, which seems to be irrelevant for the binding of PPARα. As expected, other members of the nuclear receptor superfamily also bind to this element and repress the activation mediated by PPARα, thus showing that the interplay between several nuclear receptors may regulate the entry of fatty acids into the mitochondria, a crucial step in their metabolism.

scholarly journals Peroxisome Proliferator-Activated Receptor Subtype- and Cell-Type-Specific Activation of Genomic Target Genes upon Adenoviral Transgene Delivery

2006 ◽  
Vol 26 (15) ◽  
pp. 5698-5714 ◽  
Author(s):  
Ronni Nielsen ◽  
Lars Grøntved ◽  
Hendrik G. Stunnenberg ◽  
Susanne Mandrup
Keyword(s):  
Target Genes ◽  
Receptor Subtype ◽  
Peroxisome Proliferator ◽  
Cell Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Molecular Events ◽  
Adenoviral Delivery ◽  
Cell Type Specific ◽  
Peroxisome Proliferator Activated Receptors ◽  
The Individual

ABSTRACT Investigations of the molecular events involved in activation of genomic target genes by peroxisome proliferator-activated receptors (PPARs) have been hampered by the inability to establish a clean on/off state of the receptor in living cells. Here we show that the combination of adenoviral delivery and chromatin immunoprecipitation (ChIP) is ideal for dissecting these mechanisms. Adenoviral delivery of PPARs leads to a rapid and synchronous expression of the PPAR subtypes, establishment of transcriptional active complexes at genomic loci, and immediate activation of even silent target genes. We demonstrate that PPARγ2 possesses considerable ligand-dependent as well as independent transactivation potential and that agonists increase the occupancy of PPARγ2/retinoid X receptor at PPAR response elements. Intriguingly, by direct comparison of the PPARs (α, γ, and β/δ), we show that the subtypes have very different abilities to gain access to target sites and that in general the genomic occupancy correlates with the ability to activate the corresponding target gene. In addition, the specificity and potency of activation by PPAR subtypes are highly dependent on the cell type. Thus, PPAR subtype-specific activation of genomic target genes involves an intricate interplay between the properties of the subtype- and cell-type-specific settings at the individual target loci.

scholarly journals Peroxisome Proliferator-Activated Receptors and Hepatitis C Virus-Induced Insulin Resistance

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-6 ◽  
Author(s):  
Francesco Negro
Keyword(s):  
Insulin Resistance ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Insulin Signalling ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Insulin Resistant ◽  
Peroxisome Proliferator Activated Receptors ◽  
Chronic Hepatitis C Patients

Insulin resistance and type 2 diabetes are associated with hepatitis C virus infection. A wealth of clinical and experimental data suggests that the virus is directly interfering with the insulin signalling in hepatocytes. In the case of at least one viral genotype (the type 3a), insulin resistance seems to be directly mediated by the downregulation of the peroxisome proliferator-activated receptorγ. Whether and how this interaction may be manipulated pharmacologically, in order to improve the responsiveness to antivirals of insulin resistant chronic hepatitis C, patients remain to be fully explored.

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