A Decrease in DKK1, a WNT Inhibitor, Contributes to Placental Lipid Accumulation in an Obesity-Prone Rat Model1

Strakovsky, Rita S.; Pan, Yuan Xiang

doi:10.1095/biolreprod.111.094482

Cited by 47 publications

(49 citation statements)

References 76 publications

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“…Here, we observed increased lipid content in the placentae from obese dams, consistent with findings in obese human placentae where it has been localized in the villi stroma and syncytium8. In our model as well as in obesity-prone rats, lipid was found to be localized predominantly in the decidua19. One study in Fatp2 and Fatp4 knockout mice20 observed an increased lipid deposition in the decidual/junctional zones of the placentae, suggesting these fatty acid transporters are essential for the trafficking of lipids across the placenta.…”

Section: Discussionsupporting

confidence: 90%

Exercise rescues obese mothers’ insulin sensitivity, placental hypoxia and male offspring insulin sensitivity

Fernandez‐Twinn

Gascoin

Musiał

et al. 2017

Sci Rep

109

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The prevalence of obesity during pregnancy continues to increase at alarming rates. This is concerning as in addition to immediate impacts on maternal wellbeing, obesity during pregnancy has detrimental effects on the long-term health of the offspring through non-genetic mechanisms. A major knowledge gap limiting our capacity to develop intervention strategies is the lack of understanding of the factors in the obese mother that mediate these epigenetic effects on the offspring. We used a mouse model of maternal-diet induced obesity to define predictive correlations between maternal factors and offspring insulin resistance. Maternal hyperinsulinemia (independent of maternal body weight and composition) strongly associated with offspring insulin resistance. To test causality, we implemented an exercise intervention that improved maternal insulin sensitivity without changing maternal body weight or composition. This maternal intervention prevented excess placental lipid deposition and hypoxia (independent of sex) and insulin resistance in male offspring. We conclude that hyperinsulinemia is a key programming factor and therefore an important interventional target during obese pregnancy, and propose moderate exercise as a promising strategy to improve metabolic outcome in both the obese mother and her offspring.

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Section: Discussionsupporting

confidence: 90%

Exercise rescues obese mothers’ insulin sensitivity, placental hypoxia and male offspring insulin sensitivity

Fernandez‐Twinn

Gascoin

Musiał

et al. 2017

Sci Rep

109

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“…Total RNA isolation, cDNA synthesis and real-time PCR were performed as previously described (Strakovsky and Pan, 2011). A serial dilution was used to create a standard curve for quantification and a dissociation curve was analyzed following each reaction.…”

Section: Methodsmentioning

confidence: 99%

Developmental bisphenol A (BPA) exposure leads to sex-specific modification of hepatic gene expression and epigenome at birth that may exacerbate high-fat diet-induced hepatic steatosis

Strakovsky

Wang

Engeseth

et al. 2015

Toxicology and Applied Pharmacology

Self Cite

141

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Developmental bisphenol A (BPA) exposure increases adulthood hepatic steatosis with reduced mitochondrial function. To investigate potential epigenetic mechanisms behind developmental BPA-induced hepatic steatosis, pregnant Sprague-Dawley rats were dosed with vehicle (oil) or BPA (100 μg/kg/day) from gestational day 6 until postnatal day (PND) 21. After weaning, offspring were either challenged with a high-fat (HF; 45% fat) or remained on a control (C) diet until PND110. From PND60 to 90, both BPA and HF diet increased the fat/lean ratio in males only, and the combination of BPA and HF diet appeared to cause the highest ratio. On PND110, Oil-HF, BPA-C, and BPA-HF males had higher hepatic lipid accumulation than Oil-C, with microvesicular steatosis being marked in the BPA-HF group. Furthermore, on PND1, BPA increased and modified hepatic triglycerides (TG) and free fatty acid (FFA) composition in males only. In PND1 males, BPA increased hepatic expression of FFA uptake gene Fat/Cd36, and decreased the expression of TG synthesis- and β-oxidation-related genes (Dgat, Agpat6, Cebpα, Cebpβ, Pck1, Acox1, Cpt1a, Cybb). BPA altered DNA methylation, histone marks (H3Ac, H4Ac, H3Me2K4, H3Me3K36), and decreased the binding of several transcription factors (Pol II, C/EBPβ, SREBP1) within the male Cpt1a gene, the key β-oxidation enzyme. In PND1 females, BPA only increased the expression of genes involved in FFA uptake and TG synthesis (Lpl, Fasn, and Dgat). These data suggest that developmental BPA exposure alters and reprograms hepatic β-oxidation capacity in males, potentially thorough the epigenetic regulation of genes, and further alters the response to a HF diet.

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“…In the same model, FATP4 mRNA expression was shown to be downregulated by chronic exposure to IL-6, but without corresponding alteration in protein expression [81]. It has been reported in animal models of maternal obesity that placental mRNA expression of FATP1 and FATP4 are increased [130, 131]. …”

Section: Fatty Acidsmentioning

confidence: 99%

Regulation of Nutrient Transport across the Placenta

Lager

Powell

2012

Journal of Pregnancy

335

278

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Abnormal fetal growth, both growth restriction and overgrowth, is associated with perinatal complications and an increased risk of metabolic and cardiovascular disease later in life. Fetal growth is dependent on nutrient availability, which in turn is related to the capacity of the placenta to transport these nutrients. The activity of a range of nutrient transporters has been reported to be decreased in placentas of growth restricted fetuses, whereas at least some studies indicate that placental nutrient transport is upregulated in fetal overgrowth. These findings suggest that changes in placental nutrient transport may directly contribute to the development of abnormal fetal growth. Detailed information on the mechanisms by which placental nutrient transporters are regulated will therefore help us to better understand how important pregnancy complications develop and may provide a foundation for designing novel intervention strategies. In this paper we will focus on recent studies of regulatory mechanisms that modulate placental transport of amino acids, fatty acids, and glucose.

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A Decrease in DKK1, a WNT Inhibitor, Contributes to Placental Lipid Accumulation in an Obesity-Prone Rat Model1

Cited by 47 publications

References 76 publications

Exercise rescues obese mothers’ insulin sensitivity, placental hypoxia and male offspring insulin sensitivity

Exercise rescues obese mothers’ insulin sensitivity, placental hypoxia and male offspring insulin sensitivity

Developmental bisphenol A (BPA) exposure leads to sex-specific modification of hepatic gene expression and epigenome at birth that may exacerbate high-fat diet-induced hepatic steatosis

Regulation of Nutrient Transport across the Placenta

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