Intrauterine Growth Restriction Increases Fetal Hepatic Gluconeogenic Capacity and Reduces Messenger Ribonucleic Acid Translation Initiation and Nutrient Sensing in Fetal Liver and Skeletal Muscle

Thorn, Stephanie R.; Regnault, Timothy R. H.; Brown, Laura D.; Rozance, Paul J.; Keng, Jane; Roper, Michael; Wilkening, Randall B.; Hay, William W.; Friedman, Jacob E.

doi:10.1210/en.2008-1789

Cited by 142 publications

(227 citation statements)

References 70 publications

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“…Fetuses affected by IUGR have alterations in mRNA levels of key regulatory genes, likely due to epigenetic modifications (1,13,21,23), which may alter their response to amino acid supplementation. Furthermore, substrate metabolic rates and hormone concentrations differ dramatically in the IUGR fetus compared with a normally grown fetus and may change differently following fetal nutrient supplementation (24,42,44). Investigation into the most optimal maternal or fetal amino acid supplementation protocols is needed to develop nutritional strategies to more positively affect growth in the IUGR fetus.…”

Section: Discussionmentioning

confidence: 99%

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Prolonged infusion of amino acids increases leucine oxidation in fetal sheep

Maliszewski

Gadhia

O'Meara

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Maliszewski AM, Gadhia MM, O'Meara MC, Thorn SR, Rozance PJ, Brown LD. Prolonged infusion of amino acids increases leucine oxidation in fetal sheep. Am J Physiol Endocrinol Metab 302: E1483-E1492, 2012. First published March 27, 2012 doi:10.1152/ajpendo.00026.2012.-Maternal high-protein supplements designed to increase birth weight have not been successful. We recently showed that maternal amino acid infusion into pregnant sheep resulted in competitive inhibition of amino acid transport across the placenta and did not increase fetal protein accretion rates. To bypass placental transport, singleton fetal sheep were intravenously infused with an amino acid mixture (AA, n ϭ 8) or saline [control (Con), n ϭ 10] for ϳ12 days during late gestation. Fetal leucine oxidation rate increased in the AA group (3.1 Ϯ 0.5 vs. 1.4 Ϯ 0.6 mol·min Ϫ1 ·kg Ϫ1 , P Ͻ 0.05). Fetal protein accretion (2.6 Ϯ 0.5 and 2.2 Ϯ 0.6 mol·min Ϫ1 ·kg Ϫ1 in AA and Con, respectively), synthesis (6.2 Ϯ 0.8 and 7.0 Ϯ 0.9 mol·min Ϫ1 ·kg Ϫ1 in AA and Con, respectively), and degradation (3.6 Ϯ 0.6 and 4.5 Ϯ 1.0 mol·min Ϫ1 ·kg Ϫ1in AA and Con, respectively) rates were similar between groups. Net fetal glucose uptake decreased in the AA group (2.8 Ϯ 0.4 vs. 3.9 Ϯ 0.1 mg·kg Ϫ1 ·min Ϫ1 , P Ͻ 0.05). The glucose-O2 quotient also decreased over time in the AA group (P Ͻ 0.05). Fetal insulin and IGF-I concentrations did not change. Fetal glucagon increased in the AA group (119 Ϯ 24 vs. 59 Ϯ 9 pg/ml, P Ͻ 0.05), and norepinephrine (NE) also tended to increase in the AA group (785 Ϯ 181 vs. 419 Ϯ 76 pg/ml, P ϭ 0.06). Net fetal glucose uptake rates were inversely proportional to fetal glucagon (r 2 ϭ 0.38, P Ͻ 0.05), cortisol (r 2 ϭ 0.31, P Ͻ 0.05), and NE (r 2 ϭ 0.59, P Ͻ 0.05) concentrations. Expressions of components in the mammalian target of rapamycin signaling pathway in fetal skeletal muscle were similar between groups. In summary, prolonged infusion of amino acids directly into normally growing fetal sheep increased leucine oxidation. Amino acid-stimulated increases in fetal glucagon, cortisol, and NE may contribute to a shift in substrate oxidation by the fetus from glucose to amino acids. pregnancy; insulin; fetal protein metabolism; fetal growth PREVIOUS ATTEMPTS TO IMPROVE fetal outcomes with use of maternal high-protein supplementation have actually increased the risk for small-for-gestational-age birth and infant mortality (26,36). Similarly, supplementation of pregnant sheep with intravenous amino acids for several days at the end of gestation demonstrated adverse fetal effects, including hypoxia and respiratory and metabolic acidosis (34). The mechanisms that explain poor fetal outcomes in response to maternal protein supplementation during pregnancy are unknown.Experiments using normal pregnant sheep have led to some testable explanations for how high-protein supplementation during pregnancy might adversely affect fetal outcomes (4). Short-and long-term maternal amino acid infusions using mixtures of amino acids with a higher essential-nonessential ...

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Section: Discussionmentioning

confidence: 99%

“…RNA isolation and real-time PCR. RNA from fetal liver was isolated, reverse-transcribed, and used for real-time PCR (42). Realtime PCR assays for phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), and 18S rRNA (18S) were performed as previously described (42).…”

Section: Methodsmentioning

confidence: 99%

Prolonged infusion of amino acids increases leucine oxidation in fetal sheep

Maliszewski

Gadhia

O'Meara

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…miRNAs regulate gene expression by binding to miRNA recognition elements (MERs) located in the 3'-untranslated region (3'-UTR) of target messenger RNAs (mRNAs), leading to their translational repression or degradation (3). It has been estimated that ~60% of all proteincoding genes in humans are regulated by miRNAs (4). Recently, the abnormal expression of miRNAs in several types of cancer has been confirmed, including colon cancer, hepatocellular carcinoma, lung cancer and breast cancer (5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

microRNA-214 enhances the invasion ability of breast cancer cells by targeting p53

Wang

et al. 2015

International Journal of Molecular Medicine

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Abstract. Breast cancer (BC) is the foremost cause of cancerrelated mortality in women worldwide. An increasing number of studies has confirmed that microRNAs (miRNAs or miRs) play an important role in the development and progression of BC. microRNA-214 (miR-214), a member of the miRNA family, has been demonstrated to function as both a tumor suppressor and oncogene in various types of human cancer. However, the biological function of miR-214 in BC remains unclear. The present study was designed to investigate the potential role of miR-214 in the development and progression of BC. Our results revealed that miR-214 expression was significantly increased in the BC tissues compared with the adjacent benign tissues, and that the upregulation of miR-214 was significantly associated with the invasion ability of the BC cells. Furthermore, p53, which has been reported to be downregulated in BC, was predicted to be the target gene of miR-214 using bioinformatics software programs. Moreover, luciferase reporter vectors were constructed and it was confirmed that p53 is a target of miR-214. Following the transfection of miR-214 into BC cells, we found that the overexpression of miR-214 markedly enhanced cell invasion through the downregulation of p53 expression. By contrast, the overexpression of p53 abrogated the effects of miR-214. In conclusion, this study demonstrates that miR-214 functions as an oncogene in BC, at least partly by promoting cell invasion through the downregulation of p53. Therefore, miR-214 may be a potential therapeutic target for the treatment of BC.

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“…One of these conditions is decreased fetal glucose supply and fetal plasma glucose concentrations produced during maternal fasting and maternal hypoglycemia (11,26,50). Other conditions that also increase these factors and fetal HGP include acute maternal hypoxia, bilateral uterine artery ligation, umbilical cord compression, and intrauterine growth restriction from placental insufficiency (PI-IUGR) (5,15,25,34,38,40,48). A characteristic that is common to these conditions is fetal hypoxemia or low fetal blood oxygen concentration.…”

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confidence: 99%

“…A characteristic that is common to these conditions is fetal hypoxemia or low fetal blood oxygen concentration. Studies specifically testing the impact of low blood oxygen concentration and/or low PO 2 on factors regulating fetal HGP are limited to acute hypoxemia, intermittent hypoxemia, or hypoxemia coupled with hypoglycemia such as PI-IUGR (5,15,40,44,48,50). The effect of chronic sustained fetal hypoxemia without hypoglycemia on the factors that regulate HGP has not been studied.…”

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confidence: 99%

Chronic anemic hypoxemia increases plasma glucagon and hepatic PCK1 mRNA in late-gestation fetal sheep

Culpepper

Wesolowski

Benjamin

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Wilkening RB, Hay WW Jr, Rozance PJ. Chronic anemic hypoxemia increases plasma glucagon and hepatic PCK1 mRNA in late-gestation fetal sheep. Am J Physiol Regul Integr Comp Physiol 311: R200 -R208, 2016. First published May 11, 2016; doi:10.1152/ajpregu.00037.2016.-Hepatic glucose production (HGP) normally begins just prior to birth. Prolonged fetal hypoglycemia, intrauterine growth restriction, and acute hypoxemia produce an early activation of fetal HGP. To test the hypothesis that prolonged hypoxemia increases factors which regulate HGP, studies were performed in fetuses that were bled to anemic conditions (anemic: n ϭ 11) for 8.9 Ϯ 0.4 days and compared with control fetuses (n ϭ 7). Fetal arterial hematocrit and oxygen content were 32% and 50% lower, respectively, in anemic vs. controls (P Ͻ 0.005). Arterial plasma glucose was 15% higher in the anemic group (P Ͻ 0.05). Hepatic mRNA expression of phosphonenolpyruvate carboxykinase (PCK1) was twofold higher in the anemic group (P Ͻ 0.05). Arterial plasma glucagon concentrations were 70% higher in anemic fetuses compared with controls (P Ͻ 0.05), and they were positively associated with hepatic PCK1 mRNA expression (P Ͻ 0.05). Arterial plasma cortisol concentrations increased 90% in the anemic fetuses (P Ͻ 0.05), but fetal cortisol concentrations were not correlated with hepatic PCK1 mRNA expression. Hepatic glycogen content was 30% lower in anemic vs. control fetuses (P Ͻ 0.05) and was inversely correlated with fetal arterial plasma glucagon concentrations. In isolated primary fetal sheep hepatocytes, incubation in low oxygen (3%) increased PCK1 mRNA threefold compared with incubation in normal oxygen (21%). Together, these results demonstrate that glucagon and PCK1 may potentiate fetal HGP during chronic fetal anemic hypoxemia.glucose; oxygen; PEPCK; glycogen; hepatocyte GLUCOSE IS THE PRINCIPAL ENERGY substrate for the fetus and is essential for normal fetal metabolism and growth. The transport of glucose from the mother to the fetus occurs by facilitated diffusion across the placenta. Therefore, the rate of fetal glucose uptake depends largely on the maternal arterial plasma glucose concentration (19). Normally, transported maternal arterial glucose is the sole source of fetal glucose, and there is no fetal hepatic glucose production (HGP) (20).As part of the transition to extrauterine life, fetal HGP is activated just prior to delivery (13). At birth, infants have a period of reduced glucose intake when they are removed from their placental glucose supply and their mother's milk is being established. Thus, to avoid hypoglycemia, the neonate must rely on endogenous HGP. Fetal sheep at 0.97 gestation have increased endogenous HGP, as well as higher hepatic levels of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK, encoded by PCK1) and glucose-6-phosphatase (G6Pase, encoded by G6PC) compared with 0.95 gestation (11, 13). PEPCK catalyzes the rate-limiting step, and G6Pase catalyzes the final step in gluconeogenesis. Increased perinatal trans...

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Intrauterine Growth Restriction Increases Fetal Hepatic Gluconeogenic Capacity and Reduces Messenger Ribonucleic Acid Translation Initiation and Nutrient Sensing in Fetal Liver and Skeletal Muscle

Cited by 142 publications

References 70 publications

Prolonged infusion of amino acids increases leucine oxidation in fetal sheep

Prolonged infusion of amino acids increases leucine oxidation in fetal sheep

microRNA-214 enhances the invasion ability of breast cancer cells by targeting p53

Chronic anemic hypoxemia increases plasma glucagon and hepatic PCK1 mRNA in late-gestation fetal sheep

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