Placental lipid processing in response to a maternal high-fat diet and diabetes in rats

Louwagie, Eli J.; Larsen, Tricia D.; Wachal, Angela L.; Baack, Michelle

doi:10.1038/pr.2017.288

Cited by 27 publications

(25 citation statements)

References 39 publications

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“…Dams that received streptozotocin but did not manifest a fasting blood glucose level ≥ 200 mg/dl were excluded from the study. While in our model all pregnant dams developed physiologic hyperlipidemia of pregnancy, diabetes increased serum triglycerides ∼2 fold, diet ∼3 fold, and the combination ∼5 fold higher than controls leading to corresponding hyperinsulinemia in offspring (30,(32)(33)(34). Thus, our model of late gestation diabetes plus HF diet translates to poorly controlled gestational diabetes or Type 2 diabetes in the developing offspring with exposure to glucolipotoxicity and fetal hyperinsulinemia.…”

Section: Animal Model Characteristicsmentioning

confidence: 86%

“…We previously demonstrated that combination exposed offspring (P1) are exposed to high levels of circulating maternal glucose and lipids which incite insulin and C-peptide overproduction in the offspring (30)(31)(32)(33)(34). This triad of maternal hyperglycemia and hyperlipidemia and fetal hyperinsulinemia causes insulin resistance with attendant downregulation of growth hormone receptors and less PI3K/AKT activation to drive a glycolysis-togluconeogenesis switch (33,(41)(42)(43).…”

Section: Downregulated Fgfr2/pi3k/akt Activation Underlies Metabolic mentioning

confidence: 99%

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Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways That Regulate Cardiac Metabolism and Cell Fate in Newborn Rat Hearts

et al. 2020

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Background: Children born to diabetic or obese mothers have a higher risk of heart disease at birth and later in life. Using chromatin immunoprecipitation sequencing, we previously demonstrated that late-gestation diabetes, maternal high fat (HF) diet, and the combination causes distinct fuel-mediated epigenetic reprogramming of rat cardiac tissue during fetal cardiogenesis. The objective of the present study was to investigate the overall transcriptional signature of newborn offspring exposed to maternal diabetes and maternal H diet. Methods: Microarray gene expression profiling of hearts from diabetes exposed, HF diet exposed, and combination exposed newborn rats was compared to controls. Functional annotation, pathway and network analysis of differentially expressed genes were performed in combination exposed and control newborn rat hearts. Further downstream metabolic assessments included measurement of total and phosphorylated AKT2 and GSK3β, as well as quantification of glycolytic capacity by extracellular flux analysis and glycogen staining. Results: Transcriptional analysis identified significant fuel-mediated changes in offspring cardiac gene expression. Specifically, functional pathways analysis identified two key signaling cascades that were functionally prioritized in combination exposed offspring hearts: (1) downregulation of fibroblast growth factor (FGF) activated PI3K/AKT pathway and (2) upregulation of peroxisome proliferator-activated receptor gamma coactivator alpha (PGC1α) mitochondrial biogenesis signaling. Functional metabolic and histochemical assays supported these transcriptome changes, corroborating diabetes-and diet-induced cardiac transcriptome remodeling and cardiac metabolism in offspring. Conclusion: This study provides the first data accounting for the compounding effects of maternal hyperglycemia and hyperlipidemia on the developmental cardiac transcriptome, and elucidates nuanced and novel features of maternal diabetes and diet on regulation of heart health.

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Section: Animal Model Characteristicsmentioning

confidence: 86%

Section: Downregulated Fgfr2/pi3k/akt Activation Underlies Metabolic mentioning

confidence: 99%

Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways That Regulate Cardiac Metabolism and Cell Fate in Newborn Rat Hearts

et al. 2020

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“…Oil Red O staining was performed on placenta cryosections, as described previously (Louwagie et al . ). Placenta samples including the labyrinth zone were excised, fixed with paraformaldehyde and embedded in OCT (Thermo 6502; Thermo Fisher Scientific, Waltham, MA, USA).…”

Section: Methodsmentioning

confidence: 97%

Exercise prevents the adverse effects of maternal obesity on placental vascularization and fetal growth

Son

Liu

Tian

et al. 2019

The Journal of Physiology

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Key pointsr Maternal exercise improves the metabolic health of maternal mice challenged with a high-fat diet.r Exercise intervention of obese mothers prevents fetal overgrowth. r Exercise intervention reverses impaired placental vascularization in obese mice. r Maternal exercise activates placental AMP-activated protein kinase, which was inhibited as a result of maternal obesity.Abstract More than one-third of pregnant women in the USA are obese and maternal obesity (MO) negatively affects fetal development, which predisposes offspring to metabolic diseases. The placenta mediates nutrient delivery to fetuses and its function is impaired as a result of MO. Exercise ameliorates metabolic dysfunction resulting from obesity, although its effect on placental function of obese mothers has not been explored. In the present study, C57BL/6J female mice were randomly assigned into two groups fed either a control or a high-fat diet (HFD) and then the mice on each diet were further divided into two subgroups with/without exercise. In HFD-induced obese mice, daily treadmill exercise during pregnancy reduced body weight gain, lowered serum glucose and lipid concentration, and improved insulin sensitivity of maternal mice. Importantly, maternal exercise prevented fetal overgrowth (macrosomia) induced by MO. To further examine the preventive effects of exercise on fetal overgrowth, placental vascularization and nutrient transporters were analysed. Vascular density and the expression of vasculogenic factors were reduced as a result of MO but were recovered by maternal exercise. On the other hand, the contents of nutrient transporters were not substantially altered by MO or exercise, suggesting that the protective effects of exercise in MO-induced fetal overgrowth were primarily a result of the alteration of placental vascularization and improved maternal metabolism. Furthermore, exercise enhanced downstream insulin signalling and activated AMP-activated protein kinase in HFD placenta. In sum, maternal exercise prevented fetal overgrowth induced by MO, which was Jun Seok Son received MS Degree in Kinesiology from Seoul National University. Currently, Jun Seok is a PhD student in the . His research interests focus on the impacts of maternal obesity, exercise, nutrition and other physiological conditions on fetal development and offspring health, especially the epigenetic mechanisms linking nutrients/metabolites to progenitor cell differentiation into myocytes/adipocytes. Ultimately, he aims to translate his work into clinical practice with respect to improving health outcomes for mothers and children affected by obesity.

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“…Unfortunately, even when maternal hyperglycemia is well-controlled during pregnancy, the risk of heart disease in IDM persists [12,13,15,50]; this implicates additional targetable triggers including lipids. We previously used a rat model to show that a maternal HF diet compounded the effects of late-gestation diabetes by exposing the offspring not only to hyperglycemia, but also to hyperlipidemia which increased fetal insulin production, placental lipotoxicity, cardiac dysfunction, and perinatal mortality [26,51]. The present study used cardiac-speci c transcriptomic pro ling to identify potential underlying mechanisms.…”

Section: Discussionmentioning

confidence: 95%

“…We previously demonstrated that combination exposed offspring (P1) are exposed to high levels of circulating maternal glucose and lipids which incite insulin and C-peptide overproduction in the offspring [26][27][28][29]37]. This triad of maternal hyperglycemia and hyperlipidemia and fetal hyperinsulinemia causes insulin resistance with attendant downregulation of growth hormone receptors and less PI3K/AKT activation to drive a glycolysis-to-gluconeogenesis switch [29,[38][39][40].…”

Section: Downregulated Fgfr2/pi3k/akt Activation Underlies Metabolic mentioning

confidence: 99%

Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways that Regulate Cardiac Metabolism and Cell Fate in Newborn Rat Hearts

Preston

Larsen

Eclov

et al. 2020

Preprint

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Background Children born to diabetic or obese mothers have a higher risk of heart disease at birth and later in life. Our previous work using chromatin immunoprecipitation sequencing revealed that late-gestation diabetes in combination with maternal high fat (HF) diet cause a distinct fuel-mediated epigenetic reprogramming of rat cardiac tissue during fetal cardiogenesis. The objective of the present study was to investigate the overall transcriptional signature of newborn offspring exposed to the combination of maternal diabetes and maternal HF diet. Methods Gene expression profiling from hearts of diabetes exposed, HF diet exposed, combination exposed and control newborn rats was compared for differential transcriptome expression. Functional annotation, pathway and network analysis was performed on statistically significant differentially expressed genes from the combination exposed group compared with controls. Downstream metabolic assessments included measurement of total and phosphorylated AKT2 and GSK3β assays, as well as quantification of glycolytic capacity by extracellular flux analysis and glycogen staining. Results Transcriptome analysis of newborn rat hearts showed significant changes in cardiac gene expression following exposure to maternal diabetes or HF diet individually, as well as the combination of diabetes + HF compared with controls. Reactome analyses identified expression changes in two key signaling cascades functionally prioritized in male control and combination exposed offspring hearts. These pathways included downregulation of the fibroblast growth factor (FGF) pathway and concomitant downstream PI3K/AKT activation canonically recognized as a regulator of cell metabolism, growth, and development. In contrast, the second pathway exhibited significant upregulation of mitoribosomal signaling that regulates mitochondrial biogenesis, mitophagy and cell fate. Focused bioinformatic analysis on mitochondrial genes enriched in the combination exposed dataset revealed genes associated with diverse aspects of mitochondrial structure, function, and dynamism. Functional biochemical, metabolic, and histochemical assays supported these transcriptome changes, confirming the essential role of mitochondrial energetics in facilitating diabetes- and diet-induced cardiac transcriptome remodeling and phenotype in offspring. Conclusions This study provides the first data accounting for the compounding effects of maternal hyperglycemia and hyperlipidemia on the developmental cardiac transcriptome, and elucidates nuanced and novel features of maternal diabetes and diet on intergenerational regulation of heart health.

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Placental lipid processing in response to a maternal high-fat diet and diabetes in rats

Cited by 27 publications

References 39 publications

Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways That Regulate Cardiac Metabolism and Cell Fate in Newborn Rat Hearts

Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways That Regulate Cardiac Metabolism and Cell Fate in Newborn Rat Hearts

Exercise prevents the adverse effects of maternal obesity on placental vascularization and fetal growth

Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways that Regulate Cardiac Metabolism and Cell Fate in Newborn Rat Hearts

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