Role of placental insufficiency and intrauterine growth restriction on the activation of fetal hepatic glucose production

Wesolowski, Stephanie R.; Hay, William W.

doi:10.1016/j.mce.2015.12.016

Cited by 31 publications

(28 citation statements)

References 114 publications

(199 reference statements)

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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: 54%

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: 54%

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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“…Intestinal dysbiosis has been correlated with NAFLD in children and adults; however, whether early life microbial composition influences hepatic fat accumulation and immunity before the disease occurs in humans is unclear ( 61 , 64 , 65 ). Our human studies ( 66 ), and those of others ( 67 ), using MRI/MRS, have documented that maternal BMI predicts newborn intrahepatocellular lipid storage, suggesting risk factors for pediatric obesity/NAFLD begin in early life (even in utero ) and might permanently change the body’s structure, physiology, immune system, and metabolism, leading to an increased lifetime disease risk ( 68 ). A murine study showed that maternal HFD promoted increased liver adiposity, increased pro-fibrinogenic gene expression, and epigenetic changes in many genes in their offspring compared with offspring born from control diet-fed dams ( 69 ).…”

Section: Early Gut Dysbiosis Is Associated With Elevated Risk For Nafmentioning

confidence: 70%

Early Microbes Modify Immune System Development and Metabolic Homeostasis—The “Restaurant” Hypothesis Revisited

2017

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The developing infant gut microbiome affects metabolism, maturation of the gastrointestinal tract, immune system function, and brain development. Initial seeding of the neonatal microbiota occurs through maternal and environmental contact. Maternal diet, antibiotic use, and cesarean section alter the offspring microbiota composition, at least temporarily. Nutrients are thought to regulate initial perinatal microbial colonization, a paradigm known as the “Restaurant” hypothesis. This hypothesis proposes that early nutritional stresses alter both the initial colonizing bacteria and the development of signaling pathways controlled by microbial mediators. These stresses fine-tune the immune system and metabolic homeostasis in early life, potentially setting the stage for long-term metabolic and immune health. Dysbiosis, an imbalance or a maladaptation in the microbiota, can be caused by several factors including dietary alterations and antibiotics. Dysbiosis can alter biological processes in the gut and in tissues and organs throughout the body. Misregulated development and activity of both the innate and adaptive immune systems, driven by early dysbiosis, could have long-lasting pathologic consequences such as increased autoimmunity, increased adiposity, and non-alcoholic fatty liver disease (NAFLD). This review will focus on factors during pregnancy and the neonatal period that impact a neonate’s gut microbiome, as well as the mechanisms and possible links from early infancy that can drive increased risk for diseases including obesity and NAFLD. The complex pathways that connect diet, the microbiota, immune system development, and metabolism, particularly in early life, present exciting new frontiers for biomedical research.

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“…Maternal nutrition is critical for fetuses, as the nutrients and biologically active substances transferred through the placenta affect fetal development [ 7 , 33 , 34 ]. Gupta et al .…”

Section: Discussionmentioning

confidence: 99%

Intrauterine growth retardation promotes fetal intestinal autophagy in rats via the mechanistic target of rapamycin pathway

Wang

Zhang

Zhou

et al. 2017

Journal of Reproduction and Development

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Intrauterine growth retardation (IUGR) impairs fetal intestinal development, and is associated with high perinatal morbidity and mortality. However, the mechanism underlying this intestinal injury is largely unknown. We aimed to investigate this mechanism through analysis of intestinal autophagy and related signaling pathways in a rat model of IUGR. Normal weight (NW) and IUGR fetuses were obtained from primiparous rats via ad libitum food intake and 50% food restriction, respectively. Maternal serum parameters, fetal body weight, organ weights, and fetal blood glucose were determined. Intestinal apoptosis, autophagy, and the mechanistic target of rapamycin (mTOR) signaling pathway were analyzed. The results indicated that maternal 50% food restriction reduced maternal serum glucose, bilirubin, and total cholesterol and produced IUGR fetuses, which had decreased body weight; blood glucose; and weights of the small intestine, stomach, spleen, pancreas, and kidney. Decreased Bcl-2 and increased Casp9 mRNA expression was observed in IUGR fetal intestines. Analysis of intestinal autophagy showed that the mRNA expression of WIPI1, MAP1LC3B, Atg5, and Atg14 was also increased, while the protein levels of p62 were decreased in IUGR fetuses. Compared to NW fetuses, IUGR fetuses showed decreased mTOR protein levels and enhanced mRNA expression of ULK1 and Beclin1 in the small intestine. In summary, the results indicated that maternal 50% food restriction on gestational days 10–21 reduced maternal serum glucose, bilirubin, and total cholesterol contents, and produced IUGR fetuses that had low blood glucose and reduced small intestine weight. Intestinal injury of IUGR fetuses caused by maternal food restriction might be due to enhanced apoptosis and autophagy via the mTOR signaling pathway.

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Role of placental insufficiency and intrauterine growth restriction on the activation of fetal hepatic glucose production

Cited by 31 publications

References 114 publications

Dysregulation in the Unfolded Protein Response in the FGR Rat Pancreas

Dysregulation in the Unfolded Protein Response in the FGR Rat Pancreas

Early Microbes Modify Immune System Development and Metabolic Homeostasis—The “Restaurant” Hypothesis Revisited

Intrauterine growth retardation promotes fetal intestinal autophagy in rats via the mechanistic target of rapamycin pathway

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