Placental glycogen stores and fetal growth: insights from genetic mouse models

Tunster, Simon James; Watson, Erica D.; Fowden, Abigail L.; Burton, Graham J.

doi:10.1530/rep-20-0007

Cited by 51 publications

(65 citation statements)

References 143 publications

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“…In accordance with that, it has been shown that lipid droplets formation and glycogen storage are crucial for proper trophoblast function and that p38 MAPK pathway controls the invasiveness capability of trophoblastic cells 69–71 . Genes that are upregulated in clusters 1,2,3 to the highest level in OSKM reprogrammable cells are related to Wnt signaling (p≤0.008), IGF-1 pathway (p≤0.01) and cardiocyte differentiation (p≤0.0004), while cluster 4 is enriched with genes involve in BMP signaling pathway (p≤0.0001).…”

Section: Resultssupporting

confidence: 68%

Comparative Parallel Multi-Omics Analysis During the Induction of Pluripotent and Trophectoderm States

Jaber¹,

Radwan²,

Loyfer

et al. 2020

Preprint

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Following fertilization, totipotent cells divide to generate two compartments in the early embryo: the inner cell mass (ICM) and trophectoderm (TE). It is only at the 32-64 -cell stage when a clear segregation between the two cell-types is observed, suggesting a T-shaped model of specification. Here, we examine whether the acquisition of these two states in vitro by nuclear reprogramming share similar dynamics/trajectories. We conducted a comparative parallel multi-omics analysis on cells undergoing reprogramming to Induced pluripotent stem cells (iPSCs) and induced trophoblast stem cells (TSCs), and examined their transcriptome, methylome, chromatin accessibility and activity and genomic stability. Our analysis revealed that cells undergoing reprogramming to pluripotency and TSC state exhibit specific trajectories from the onset of the process, suggesting V-shaped model. Using these analyses, not only we could describe in detail the various trajectories toward the two states, we also identified previously unknown stage-specific reprogramming markers as well as markers for faithful reprogramming and reprogramming blockers. Finally, we show that while the acquisition of the TSC state involves the silencing of embryonic programs by DNA methylation, during the acquisition of pluripotency these specific regions are initially open but then retain inactive by the elimination of the histone mark, H3K27ac.

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Section: Resultssupporting

confidence: 68%

Comparative Parallel Multi-Omics Analysis During the Induction of Pluripotent and Trophectoderm States

Jaber¹,

Radwan²,

Loyfer

et al. 2020

Preprint

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“…A number of transcriptional regulators have been implicated in regulating GlyT development and/or function [1]. We hypothesised that the transition from a predominantly glycogenic state to a glycogenolytic state during late gestation is driven by a down-regulation of genes encoding glycogenesis pathway enzymes (Fig 4) and a coincident upregulation of genes encoding glycogenolysis pathway enzymes (Fig 5).…”

Section: Temporal Expression Of Glycogenesis and Glycogenolysis Pathway Genesmentioning

confidence: 99%

“…In addition to facilitating nutrient transport from mother to fetus, the placenta also stores glucose as glycogen. Aberrant placental glycogen storage is often associated with fetal growth restriction (FGR) in mouse models [1], and in humans, elevated placental glycogen has been reported in diabetic pregnancies and pre-eclampsia [2][3][4][5][6]. However, the normal physiological role of placental glycogen stores remains unclear [reviewed in 1,7].…”

Section: Introductionmentioning

confidence: 99%

“…Aberrant placental glycogen storage is often associated with fetal growth restriction (FGR) in mouse models [1], and in humans, elevated placental glycogen has been reported in diabetic pregnancies and pre-eclampsia [2][3][4][5][6]. However, the normal physiological role of placental glycogen stores remains unclear [reviewed in 1,7]. The most widely accepted hypothesis is that placental glycogen represents a readily mobilised source of glucose to support fetal growth during late gestation [8,9].…”

Section: Introductionmentioning

confidence: 99%

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Characterising the dynamics of placental glycogen stores in the mouse

Roberts

Tunster

2020

Placenta

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Introduction:The placenta performs a range of functions to support fetal growth. In addition to facilitating nutrient transport, the placenta also stores glucose as glycogen, which is thought to maintain fetal glucose supply during late gestation. However, evidence to support such a role is currently lacking. Similarly, our understanding of the dynamics of placental glycogen metabolism in normal mouse pregnancy is limited.Methods: We quantified the placental glycogen content in wild type C57BL/6JOlaHsd mouse placentas from mid (E12.5) to late (E18.5) gestation, alongside characterising the temporal expression pattern of genes encoding glycogenesis and glycogenolysis pathway enzymes. To assess the potential of the placenta to produce glucose, we investigated the spatiotemporal expression of glucose 6-phosphatase by qPCR and in situ hybridisation. Separate analyses were undertaken for placentas of male and female conceptuses to account for potential sexual dimorphism.Results: Placental glycogen stores peak at E15.5, having increased over 5-fold from E12.5, before declining by a similar extent at E18.5. Glycogen stores were 17% higher in male placentas than in females at E15.5. Expression of glycogen branching enzyme (Gbe1) was reduced ~40% towards term. Expression of the glucose 6-phosphatae isoform G6pc3 was enriched in glycogen trophoblast cells and increased towards term.Discussion: Reduced expression of Gbe1 suggests a decline in glycogenesis, and specifically, glycogen branching towards term. Expression of G6pc3 by glycogen trophoblasts is consistent with an ability to produce and release glucose from glycogen stores. However, the ultimate destination of the glucose generated from placental glycogen remains to be elucidated. Highlights Placental glycogen stores peak at embryonic day 15.5 and decline 4-fold by E18.5  Expression of glycogen branching enzyme Gbe1 declines ~40% from E12.5  The glucose phosphatase isoform G6pc3 is expressed in the mouse placenta  G6pc3 expression is enriched in glycogen trophoblast cells  G6pc3 expression in glycogen cells is consistent with glucose production *Highlights *Manuscript References Click here to download Manuscript + References: 4 -GlyT Paper Text.docx Click here to view linked References

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“…The close proximity of glycogen trophoblasts to the vasculature suggests glycogen may exist as a source of glucose for the rapid portion of fetal growth in late gestation. 49,50 Therefore, the excess glycogen deposition, considered an indicator of developmental disturbance 49,50 , could have aided in maintaining fetal growth in the setting of IRAP deficiency.…”

Section: Irap Deficiency Perturbs Placental Development At Late Gestamentioning

confidence: 99%

Insulin-regulated aminopeptidase deficiency impairs cardiovascular adaptations and placental development during pregnancy

et al. 2020

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Insulin-regulated aminopeptidase (IRAP), an enzyme that cleaves vasoactive peptides including oxytocin and vasopressin, is suggested to play a role in pregnancy and the onset of preeclampsia. Our aim was to examine the contribution of IRAP to arterial pressure regulation and placental development during pregnancy in mice. Mean arterial pressure and heart rate were measured via radiotelemetry in 12-week-old female wildtype and IRAP knockout mice. Females were time-mated with males of the same genotype. Placentae were collected at embryonic day 18.5 for histological analysis. Basal heart rate was ~40 bpm lower in IRAP knockout females compared to wildtype females. The increase in heart rate across gestation was greater in IRAP knockout females than wildtype females. Neither basal nor gestational mean arterial pressure was different between wildtype and IRAP knockout females. Urine output and water intake of IRAP knockout mice were ~45% less than wildtype mice at late gestation. IRAP deficiency had no effect on fetal weight. Morphological assessment of placentae revealed that IRAP deficiency was associated with reduced labyrinth surface area and accumulation of glycogen in the junctional zone. Our data demonstrates that IRAP deficiency alters maternal fluid handling and impairs placental labyrinth expansion at late gestation, indicating that IRAP contributes to the normal adaptions to pregnancy

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Placental glycogen stores and fetal growth: insights from genetic mouse models

Cited by 51 publications

References 143 publications

Comparative Parallel Multi-Omics Analysis During the Induction of Pluripotent and Trophectoderm States

Comparative Parallel Multi-Omics Analysis During the Induction of Pluripotent and Trophectoderm States

Characterising the dynamics of placental glycogen stores in the mouse

Insulin-regulated aminopeptidase deficiency impairs cardiovascular adaptations and placental development during pregnancy

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