Reduction of the PI3K/Akt related signaling activities in skeletal muscle tissues involves insulin resistance in intrauterine growth restriction rats with catch-up growth

Xing, Yan; Zhang, Jin; Wei, Hongling; Zhang, Hui; Guan, Yu; Wu, Xinli; Tong, Xiaomei

doi:10.1371/journal.pone.0216665

Cited by 28 publications

(22 citation statements)

References 45 publications

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“…We speculate that lower insulin levels in FGR fetus was due to fetal pancreatic dysplasia. Increased insulin levels in adulthood may be due to significant insulin resistance in tissues such as the liver and skeletal muscle, which has been confirmed by several reports [28,29].…”

Section: Discussionsupporting

confidence: 53%

Dysregulation in the Unfolded Protein Response in the FGR Rat Pancreas

Liu

Guo

Wang

et al. 2020

International Journal of Endocrinology

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Accumulating evidence suggests that fetal growth restriction (FGR) leads to the development of diabetes mellitus in adults. The aim of this study was to investigate the effect of protein malnutrition in utero on the pancreatic unfolded protein response (UPR) pathway in FGR offspring. An FGR model was developed by feeding a low-protein diet to pregnant rats throughout gestation. Eighty-four UPR pathway components in the pancreas were investigated by quantitative PCR arrays and confirmed by qPCR and western blotting. Activating transcription factor (Atf4 and Atf6), herpud1, protein kinase R-like endoplasmic reticulum kinase (Perk), X-box binding protein 1 (Xbp1), and the phosphorylation of eIF2α were upregulated, while cyclic AMP-responsive element-binding protein 3-like protein was markedly downregulated in FGR fetuses compared with controls. Investigation in adult offspring revealed temporal changes, for most UPR factors restored to normal, except that dysregulation of Atf6 and Creb3l3 maintained until adulthood. Moreover, autophagy was suppressed in FGR fetal pancreas and may be associated with decreased activation of AMP-activated protein kinase (Ampk). Apoptosis regulators Bax and cleaved-caspase 3 and 9 were upregulated in FGR fetal pancreas. Given that islet size and number were decreased in FGR fetus, we speculated that the aberrant intrauterine milieu impaired UPR signaling in fetal pancreas development. Whether these alterations early in life contribute to the predisposition of FGR fetuses to adult metabolic disorders invites further exploration.

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Section: Discussionsupporting

confidence: 53%

Dysregulation in the Unfolded Protein Response in the FGR Rat Pancreas

Liu

Guo

Wang

et al. 2020

International Journal of Endocrinology

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“…We also discovered thatgenes overexpressed by DNA hypomethylation in placentae were enriched in the pathways related to a set of metabolism pathways, such as the ChREBPactivation of metabolic gene expression and thePI3K-Akt signaling pathway( Figure 3 B). These metabolic pathways are known to have functional implications with FGR occurrence(Zinkhan et al 2018 ; Xing et al 2019 ). In the case of genes underexpressed by DNA hypermethylation in cord blood, pathways related to lipid metabolism, such as the glycerolipid biosynthetic process, glycerophospholipid metabolic process, phospholipid biosynthetic process, and the regulation of the lipid metabolic process, were found to be affected.…”

Section: Resultsmentioning

confidence: 99%

DNA Methylation and gene expression patterns are widely altered in fetal growth restriction and associated with FGR development

Lee

Kim

et al. 2021

Animal Cells and Systems

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Fetal growth restriction (FGR) is the failure of the fetus toachieve its genetically determined growth potential, which increasesrisks for a variety of genetic diseases, such as type 2 diabetes mellitus, coronary artery disease, and stroke, during the lifetime. The dysregulation of DNA methylationis known to interact with environmental fluctuations, affect gene expressions comprehensively, and be fatal to fetus development in specific cases. Therefore, we set out to find out epigenetic and transcriptomic alterations associated with FGR development. We found a set of differentially expressed genes associated with differentially methylated regions in placentae and cord blood samples. Using dimensional reduction analysis, the expression and methylation variables of the epigenetically altered genes classified the FGR samples from the controls. These genes were also enriched in the biological pathways such as metabolism and developmental processes related to FGR. Furthermore, three genes of INS, MEG3, and ZFP36L2 are implicated in epigenetic imprinting, which has been associated with FGR. These results strongly suggest that DNA methylation is highly dysregulated during FGR development, and abnormal DNA methylation patterns are likely to alter gene expression.

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“…The ELK3 protein is a transcriptional repressor whose knockdown induced the activation of the PI3k/Akt/mTOR pathway in breast cancer cell line 52 . In addition, intrauterine growth restriction in rats has been associated with reduced activity of this pathway 53 . We found FoxO6 significantly more connected in the RES group.…”

Section: Discussionmentioning

confidence: 99%

Cerebrum, liver, and muscle regulatory networks uncover maternal nutrition effects in developmental programming of beef cattle during early pregnancy

Diniz

Crouse

Cushman

et al. 2021

Sci Rep

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The molecular basis underlying fetal programming in response to maternal nutrition remains unclear. Herein, we investigated the regulatory relationships between genes in fetal cerebrum, liver, and muscle tissues to shed light on the putative mechanisms that underlie the effects of early maternal nutrient restriction on bovine developmental programming. To this end, cerebrum, liver, and muscle gene expression were measured with RNA-Seq in 14 fetuses collected on day 50 of gestation from dams fed a diet initiated at breeding to either achieve 60% (RES, n = 7) or 100% (CON, n = 7) of energy requirements. To build a tissue-to-tissue gene network, we prioritized tissue-specific genes, transcription factors, and differentially expressed genes. Furthermore, we built condition-specific networks to identify differentially co-expressed or connected genes. Nutrient restriction led to differential tissue regulation between the treatments. Myogenic factors differentially regulated by ZBTB33 and ZNF131 may negatively affect myogenesis. Additionally, nutrient-sensing pathways, such as mTOR and PI3K/Akt, were affected by gene expression changes in response to nutrient restriction. By unveiling the network properties, we identified major regulators driving gene expression. However, further research is still needed to determine the impact of early maternal nutrition and strategic supplementation on pre- and post-natal performance.

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Reduction of the PI3K/Akt related signaling activities in skeletal muscle tissues involves insulin resistance in intrauterine growth restriction rats with catch-up growth

Cited by 28 publications

References 45 publications

Dysregulation in the Unfolded Protein Response in the FGR Rat Pancreas

Dysregulation in the Unfolded Protein Response in the FGR Rat Pancreas

DNA Methylation and gene expression patterns are widely altered in fetal growth restriction and associated with FGR development

Cerebrum, liver, and muscle regulatory networks uncover maternal nutrition effects in developmental programming of beef cattle during early pregnancy

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