scholarly journals Effects of cortisol and oestradiol on hepatic 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor proteins in late-gestation sheep fetus

2003 ◽  
Vol 176 (2) ◽  
pp. 175-184 ◽  
Author(s):  
S Gupta ◽  
N Alfaidy ◽  
AC Holloway ◽  
WL Whittle ◽  
SJ Lye ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Fetal Liver ◽  
Reductase Activity ◽  
Plasma Concentrations ◽  
Hydroxysteroid Dehydrogenase ◽  
Late Gestation ◽  
Concurrent Administration ◽  
Fetal Plasma ◽  
Fetal Organ

In the late-gestation sheep, increased fetal plasma cortisol concentration and placental oestradiol (E(2)) output contribute to fetal organ maturation, in addition to the onset of parturition. Both cortisol and E(2) are believed to regulate the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which interconverts bioactive 11-hydroxy glucocorticoids and their inactive 11-keto metabolites. 11beta-HSD1, abundantly expressed in fetal liver, operates primarily as a reductase enzyme to produce bioactive cortisol and thus regulates local hepatic glucocorticoid concentrations. Cortisol acts through the glucocorticoid receptor (GR) present in the liver. In this study, we examined the effects of cortisol and E(2) on hepatic 11beta-HSD1 and GR in the liver of chronically catheterized sheep fetuses treated with saline (n=5), cortisol (1.35 mg/h; n=5), saline+4-hydroxyandrostendione, a P450 aromatase inhibitor (4-OHA; 1.44 mg/h; n=5), or cortisol+4-OHA (n=5). Cortisol infusion resulted in increased plasma concentrations of fetal cortisol and E(2); concurrent administration of 4-OHA attenuated the increase in plasma E(2) concentrations. Using immunohistochemistry, we showed that fetal hepatocytes expressed both 11beta-HSD1 and GR proteins. Cortisol treatment increased GR in both cytosol and nuclei of hepatocytes; concurrent administration of 4-OHA was associated with distinct nuclear GR staining. Western blot revealed that cortisol, in the absence of increased E(2) concentrations, significantly increased concentrations of 11beta-HSD1 (34 kDa) and GR (95 kDa) proteins. 11beta-HSD1 enzyme activity was measured in the liver microsomal fraction in the presence of [(3)H]cortisone (10(-)(6) M) or [(3)H]cortisol (10(-)(6) M) and NADPH (reductase activity) or NADP(+) (dehydrogenase activity) respectively. 11beta-HSD1 reductase activity was significantly greater in the presence of cortisol. In summary, we found that, in sheep during late gestation, cortisol increased both 11beta-HSD1 and GR in the fetal liver, and these effects were accentuated in the absence of increased E(2).

scholarly journals Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia

2015 ◽  
Vol 308 (4) ◽  
pp. E306-E314 ◽  
Author(s):  
Satya S. Houin ◽  
Paul J. Rozance ◽  
Laura D. Brown ◽  
William W. Hay ◽  
Randall B. Wilkening ◽  
...  
Keyword(s):  
Fetal Liver ◽  
Hepatic Glucose Production ◽  
Plasma Concentrations ◽  
Glucose Production ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Hepatic Glucose ◽  
Molar Percent ◽  
Glucose Output

Reduced fetal glucose supply, induced experimentally or as a result of placental insufficiency, produces an early activation of fetal glucose production. The mechanisms and substrates used to fuel this increased glucose production rate remain unknown. We hypothesized that in response to hypoglycemia, induced experimentally with maternal insulin infusion, the fetal liver would increase uptake of lactate and amino acids (AA), which would combine with hormonal signals to support hepatic glucose production. To test this hypothesis, metabolic studies were done in six late gestation fetal sheep to measure hepatic glucose and substrate flux before (basal) and after [days (d)1 and 4] the start of hypoglycemia. Maternal and fetal glucose concentrations decreased by 50% on d1 and d4 ( P < 0.05). The liver transitioned from net glucose uptake (basal, 5.1 ± 1.5 μmol/min) to output by d4 (2.8 ± 1.4 μmol/min; P < 0.05 vs. basal). The [U-13C]glucose tracer molar percent excess ratio across the liver decreased over the same period (basal: 0.98 ± 0.01, vs. d4: 0.89 ± 0.01, P < 0.05). Total hepatic AA uptake, but not lactate or pyruvate uptake, increased by threefold on d1 ( P < 0.05) and remained elevated throughout the study. This AA uptake was driven largely by decreased glutamate output and increased glycine uptake. Fetal plasma concentrations of insulin were 50% lower, while cortisol and glucagon concentrations increased 56 and 86% during hypoglycemia ( P < 0.05 for basal vs. d4). Thus increased hepatic AA uptake, rather than pyruvate or lactate uptake, and decreased fetal plasma insulin and increased cortisol and glucagon concentrations occur simultaneously with increased fetal hepatic glucose output in response to fetal hypoglycemia.

Neuroendocrine regulation of pituitary–adrenal function during fetal life

1996 ◽  
Vol 135 (2) ◽  
pp. 153-165 ◽  
Author(s):  
AN Brooks ◽  
DM Hagan ◽  
DC Howe
Keyword(s):  
Plasma Concentrations ◽  
Adrenal Function ◽  
Late Gestation ◽  
Neuroendocrine Regulation ◽  
Fetal Life ◽  
Acth Secretion ◽  
Feedback Effects ◽  
Fetal Plasma ◽  
Fetal Organ ◽  
Organ Systems

Brooks AN, Hagan DM, Howe DC. Neuroendocrine regulation of pituitary–adrenal function during fetal life. Eur J Endocrinol 1996;135:153–65. ISSN 0804–4643 During late gestation there is a rise in the concentration of corticosteroids in the fetal circulation that is essential for the coordinated maturation of many fetal organ systems and is a key component in the endocrine pathway leading to the onset of birth. Fetal plasma concentrations of adrenocorticotrophin (ACTH) increase during late, gestation and this rise precedes the increase in plasma corticosteroids. Paradoxically, ACTH and cortisol concentrations increase concomitantly even though cortisol would normally be expected to exert negative feedback effects to inhibit pituitary ACTH secretion. Elucidating the neuroendocrine signals that cause the increase in fetal ACTH, despite the elevated concentrations of cortisol at this time, will therefore provide vital clues as to the trigger for fetal organ maturation and birth. This article describes the normal ontogeny of the hypothalamo–pituitary–adrenal axis, discusses the neuroendocrine signals that trigger the increase in fetal ACTH secretion and provides potential explanations for the concomitant rise in ACTH and cortisol. AN Brooks, MRC Reproductive Biology Unit, 37 Chalmers Street, Edinburgh, EH3 9EW, Scotland, UK

scholarly journals Role of glucocorticoid receptor and CCAAT/enhancer-binding protein α in the feed-forward induction of 11β-hydroxysteroid dehydrogenase type 1 expression by cortisol in human amnion fibroblasts

2007 ◽  
Vol 195 (2) ◽  
pp. 241-253 ◽  
Author(s):  
Zhen Yang ◽  
Chunming Guo ◽  
Ping Zhu ◽  
Wenjiao Li ◽  
Leslie Myatt ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Mrna Expression ◽  
Promoter Region ◽  
Molecular Mechanisms ◽  
Hydroxysteroid Dehydrogenase ◽  
Dominant Negative ◽  
Forward Induction ◽  
Human Amnion ◽  
Feed Forward

The amount of cortisol available to its receptors is increased by the pre-receptor enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which converts cortisone to cortisol. We examined the molecular mechanisms of the feedback effect of cortisol on 11β-HSD1 mRNA expression in human amnion fibroblasts. Our data showed that cortisol-induced 11β-HSD1 mRNA expression dose dependently in amnion fibroblasts, which could be completely blocked both by the mRNA transcription inhibitor 5,6-dichlorobenzimidazole riboside and by the glucocorticoid receptor (GR) antagonist RU486, and partially blocked by global inhibition of CCAAT/enhancer-binding proteins (C/EBPs) with transfection of C/EBP-specific dominant-negative expression CMV500 plasmid (AC/EBP) into the cells. Likewise, the induction of the promoter activity by cortisol could also be completely blocked by RU486 and partially by AC/EBP transfection. Progressive 5′ deletion of the 11β-HSD1promoter located the region responsible for cortisol’s induction within −204 bp upstream to the transcription start site. Specific nucleotide mutations of the putative glucocorticoid responsive element or CCAAT in this promoter region attenuated the induction by cortisol. Moreover, chromatin immunoprecipitation assay and electrophoretic mobility shift assay showed that GR and C/EBPα but not C/EBPβ could bind this promoter region upon cortisol stimulation of amnion fibroblasts. In conclusion, we demonstrated that GR and C/EBPα were involved in cortisol-induced 11β-HSD1 mRNA expression via binding to 11β-HSD1 promoter in amnion fibroblasts, which may cast a feed-forward production of cortisol in the fetal membranes at the end of gestation.

Effect of alteration of maternal plasma progesterone concentrations on fetal behavioural state during late gestation

1997 ◽  
Vol 152 (3) ◽  
pp. 379-386 ◽  
Author(s):  
M B Nicol ◽  
J J Hirst ◽  
D Walker ◽  
G D Thorburn
Keyword(s):  
Plasma Concentrations ◽  
Maternal Plasma ◽  
Late Gestation ◽  
Emg Activity ◽  
Fetal Sheep ◽  
Plasma Progesterone ◽  
Fetal Plasma ◽  
Progesterone Synthesis ◽  
Progesterone Metabolites ◽  
Vascular Catheters

Placental progesterone synthesis exposes the fetus to high levels of progesterone and progesterone metabolites during late gestation which may influence fetal behaviour. To determine the role of maternal progesterone synthesis in the control of fetal arousal state and fetal breathing movements (FBM), the effect of raising and lowering maternal progesterone concentrations was examined in chronically catheterised fetal sheep. Fetal and maternal vascular catheters, fetal tracheal and amniotic fluid catheters as well as electrodes for recording fetal electrocortical (ECoG), electro-ocular (EOG) and nuchal muscle electromyographic (EMG) activity were implanted between 118 and 122 days gestational age (GA). Progesterone, 100 mg, administered twice daily i.m. for 3 days (130–133 days GA) resulted in a marked elevation in maternal plasma progesterone concentrations (370 ± 121%, n=5, P<0·05), but had no effect on fetal plasma concentrations. Fetal EOG episodes and the duration of fetal behavioural arousal were significantly suppressed throughout the progesterone treatment period (74·4–81·1% and 58–65% respectively, P<0·05, n=5). Four ewes received Trilostane (25 mg i.v.), a 3β-hydroxysteroid dehydrogenase inhibitor, between 136 and 140 days GA. Maternal and fetal progesterone concentrations were significantly lowered by 60 min after treatment (19·8 ± 8·0% and 39·5 ± 24·3% respectively, P<0·05). The incidence of fetal EOG activity increased from a pretreatment level of 26·8 ± 1·5 min/h to 30·3 ± 2·8 min/h at 1–6 h and to 35·0 ± 1·7 min/h (P<0·05) during the 7–12 h after Trilostane treatment. The duration of FBM episodes was significantly higher at 1–6 h and 7–12 h after Trilostane treatment (19·5 ± 3·0 and 23·6 ± 5·5 min/h respectively, P<0·05) compared with pretreatment levels (11·2 ± 1·2 min/h). We conclude that increasing maternal progesterone levels suppresses fetal EOG activity and behavioural arousal, whereas reducing maternal progesterone synthesis leads to an elevation of EOG activity and FBM. Journal of Endocrinology (1997) 152, 379–386

scholarly journals Enhancement of Cortisol-Induced 11β-Hydroxysteroid dehydrogenase Type 1 Expression by Interleukin 1β in Cultured Human Chorionic Trophoblast Cells

Endocrinology ◽  
2006 ◽  
Vol 147 (5) ◽  
pp. 2490-2495 ◽  
Author(s):  
Wenjiao Li ◽  
Lu Gao ◽  
Yan Wang ◽  
Tao Duan ◽  
Leslie Myatt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Phospholipase A2 ◽  
Mrna Expression ◽  
Reporter Gene ◽  
Reductase Activity ◽  
Hydroxysteroid Dehydrogenase ◽  
Cytosolic Phospholipase A2 ◽  
Trophoblast Cells ◽  
Cytosolic Phospholipase

Chorion is the most abundant site of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) expression within intrauterine tissues. It is important to study the regulation of 11β-HSD1 expression in the chorion in terms of local cortisol production during pregnancy. Using real-time PCR and enzyme activity assay, we found that cortisol (1 μm) and IL-1β (10 ng/ml) for 24 h significantly increased 11β-HSD1 mRNA expression and reductase activity in cultured human chorionic trophoblasts. A further significant increase of 11β-HSD1 mRNA expression and reductase activity was observed with cotreatment of cortisol and IL-1β. To explore the mechanism of induction, 11β-HSD1 promoter was cloned into pGL3 plasmid expressing a luciferase reporter gene. By transfecting the constructed vector into WISH cells, an amnion-derived cell line, we found that cortisol (1 μm) or IL-1β (10 ng/ml) significantly increased reporter gene expression. Likewise, an additional increase in reporter gene expression was observed with cotreatment of cortisol and IL-β. To explore the physiological significance of 11β-HSD1 induction in the chorion, we studied the effect of cortisol on cytosolic phospholipase A2 and cyclooxygenase 2 expression. We found that treatment of chorionic trophoblast cells with cortisol (1 μm) induced both cytosolic phospholipase A2 and cyclooxygenase 2 mRNA expression. We conclude that cortisol up-regulates 11β-HSD1 expression through induction of promoter activity, and the effect was enhanced by IL-1β, suggesting that more biologically active glucocorticoids could be generated in the fetal membranes in the presence of infection, which may consequently feed forward in up-regulation of prostaglandin synthesis.

scholarly journals 7-Oxysterols Modulate Glucocorticoid Activity in Adipocytes through Competition for 11β-Hydroxysteroid Dehydrogenase Type

Endocrinology ◽  
2008 ◽  
Vol 149 (12) ◽  
pp. 5909-5918 ◽  
Author(s):  
Malgorzata Wamil ◽  
Ruth Andrew ◽  
Karen E. Chapman ◽  
Jonathan Street ◽  
Nicholas M. Morton ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Reductase Activity ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Diabetes Type 2 ◽  
Selective Inhibition ◽  
Hydroxysteroid Dehydrogenase ◽  
Intracellular Enzyme ◽  
Increased Risk ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Reaction Direction

Obesity is associated with an increased risk of diabetes type 2, dyslipidemia, and atherosclerosis. These cardiovascular and metabolic abnormalities are exacerbated by excessive dietary fat, particularly cholesterol and its metabolites. High adipose tissue glucocorticoid levels, generated by the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), are also implicated in the pathogenesis of obesity, metabolic syndrome, and atherosclerosis. 11β-HSD1 also interconverts the atherogenic oxysterols 7-ketocholesterol (7KC) and 7β-hydroxycholesterol (7β-HC). Here, we report that 11β-HSD1 catalyzes the reduction of 7KC to 7β-HC in mature 3T3-L1 and 3T3-F442A adipocytes, leading to cellular accumulation of 7β-HC. Approximately 73% of added 7KC was reduced to 7β-HC within 24 h; this conversion was prevented by selective inhibition of 11β-HSD1. Oxysterol and glucocorticoid conversion by 11β-HSD1 was competitive and occurred with a physiologically relevant IC50 range of 450 nm for 7KC inhibition of glucocorticoid metabolism. Working as an inhibitor of 11β-reductase activity, 7KC decreased the regeneration of active glucocorticoid and limited the process of differentiation of 3T3-L1 preadipocytes. 7KC and 7β-HC did not activate liver X receptor in a transactivation assay, nor did they display intrinsic activation of the glucocorticoid receptor. However, when coincubated with glucocorticoid (10 nm), 7KC repressed, and 7β-HC enhanced, glucocorticoid receptor transcriptional activity. The effect of 7-oxysterols resulted from the modulation of 11β-HSD1 reaction direction, and could be ameliorated by overexpression of hexose 6-phosphate dehydrogenase, which supplies reduced nicotinamide adenine dinucleotide phosphate to 11β-HSD1. Thus, the activity and reaction direction of adipose 11β-HSD1 is altered under conditions of oxysterol excess, and could impact upon the pathophysiology of obesity and its complications.

scholarly journals Retinoic Acid Reduces Glucocorticoid Sensitivity in C2C12 Myotubes by Decreasing 11β-Hydroxysteroid Dehydrogenase Type 1 and Glucocorticoid Receptor Activities

Endocrinology ◽  
2009 ◽  
Vol 150 (6) ◽  
pp. 2700-2708 ◽  
Author(s):  
Evelyne M. Aubry ◽  
Alex Odermatt
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Glucose Tolerance ◽  
Glucocorticoid Receptor ◽  
Hormonal Regulation ◽  
Skeletal Muscles ◽  
Metabolic Diseases ◽  
Hydroxysteroid Dehydrogenase ◽  
C2c12 Myotubes

Vitamin A is a nutrient with remarkable effects on adipose tissue and skeletal muscles, and plays a role in controlling energy balance. Retinoic acid (RA), the carboxylic form of vitamin A, has been associated with improved glucose tolerance and insulin sensitivity. In contrast, elevated glucocorticoids have been implicated in the development of insulin resistance and impaired glucose tolerance. Here, we investigated whether RA might counteract glucocorticoid effects in skeletal muscle cells by lowering 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)-dependent local glucocorticoid activation and/or activation of glucocorticoid receptor (GR). We found a dose-dependent down-regulation of 11β-HSD1 mRNA expression and activity upon incubation of fully differentiated mouse C2C12 myotubes with RA. In addition, RA inhibited GR transactivation by an 11β-HSD1-independent mechanism. The presence of RA during myogenesis did not prevent myotube formation but resulted in relatively glucocorticoid-resistant myotubes, exhibiting very low 11β-HSD1 expression and GR activity. The use of selective retinoic acid receptor (RAR) and retinoid X receptor ligands provided evidence that these effects were mediated through RARγ. Importantly, short hairpin RNA against RARγ abolished the effect of RA on 11β-HSD1 and GR. In conclusion, we provide evidence for an important role of RA in the control of glucocorticoid activity during myogenesis and in myotubes. Disturbances of the nutrient and hormonal regulation of glucocorticoid action in skeletal muscles might be relevant for metabolic diseases.

Dietary rumen-protected arginine and N-carbamylglutamate supplementation enhances fetal growth in underfed ewes

2018 ◽  
Vol 30 (8) ◽  
pp. 1116 ◽  
Author(s):  
Lingwei Sun ◽  
Hao Zhang ◽  
Ziyu Wang ◽  
Yixuan Fan ◽  
Yixuan Guo ◽  
...  
Keyword(s):  
Amino Acids ◽  
Fetal Growth ◽  
Fetal Liver ◽  
Plasma Concentrations ◽  
Longissimus Dorsi ◽  
Somatotropic Axis ◽  
Longissimus Dorsi Muscle ◽  
Fetal Plasma ◽  
Dorsi Muscle ◽  
Pregnant Sheep

The present study was conducted with an ovine intrauterine growth restriction (IUGR) model to test the hypothesis that dietary rumen-protected l-arginine (RP-Arg) or N-carbamylglutamate (NCG) supplementation in underfed ewes is effective in enhancing fetal growth. Between Days 35 and 110 of pregnancy, 32 multiparous ewes carrying two fetuses were randomly assigned to one of four groups: a control (CG) group (n = 8; 100% National Research Council (NRC) requirements for pregnant sheep), a nutrient-restricted (RG) group (n = 8; fed 50% NRC requirements, and two treatment (ARG and NCG) groups (n = 8 in each group; fed 50% NRC requirements supplemented with 20 g day−1 RP-Arg or 5 g day−1 NCG. All ewes were killed on Day 110 of pregnancy to determine fetal weight and fetal organ weights, and metabolites and hormones in fetal plasma, amino acid concentrations in the fetal liver and longissimus dorsi muscle, and expression of mRNAs in the somatotropic axis. Maternal and fetal bodyweight and the weight of most fetal organs expressed as a percentage of bodyweight increased in response to ARG and NCG compared with values for fetuses from RG ewes. Fetal plasma concentrations of insulin, insulin-like growth factor 1, total amino acids, lactate, thyroxine, and the thyroxine/tri-iodothyronine ratio were lower in fetuses from RG ewes compared with the other treatment groups, but concentrations of growth hormone, non-esterified fatty acids, and total cholesterol were greater in fetuses from RG ewes. Maternal RP-Arg or NCG supplementation increased concentrations of amino acids in fetal tissues and expression of mRNAs for somatotropic axis proteins in fetuses from RG ewes. These findings suggest that maternal RP-Arg and NCG supplementation of underfed ewes decreases fetal IUGR by improving metabolic homeostasis of fetal endocrinology, increasing the availability of amino acids in the fetal liver and longissimus dorsi muscle and affecting the expression of somatotropic axis genes.

scholarly journals Loss of the pregnancy-induced rise in cortisol concentrations in the ewe impairs the fetal insulin-like growth factor axis

2011 ◽  
Vol 23 (5) ◽  
pp. 665 ◽  
Author(s):  
Ellen C. Jensen ◽  
Laura Bennet ◽  
Charles Wood ◽  
Mark Vickers ◽  
Bernhard Breier ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fetal Growth ◽  
Fetal Liver ◽  
Plasma Concentrations ◽  
Late Gestation ◽  
Control Group ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Igf I ◽  
Low Cortisol

Maternal cortisol levels increase during pregnancy. Although this change is important for optimal fetal growth, the mechanisms of the changes in growth remain unclear. The hypothesis examined was that alterations in maternal plasma cortisol concentrations are associated with changes in the fetal insulin-like growth factor (IGF) axis. Pregnant ewes in late gestation (115 ± 0.4 days) were studied: six control animals, five ewes given 1 mg kg–1 day–1 cortisol (high cortisol) and five adrenalectomised ewes given 0.5–0.6 mg kg–1 day–1 cortisol (low cortisol). Blood samples were taken throughout the experiment and at necropsy (130 ± 0.2 days) and fetal liver was frozen for mRNA analysis. Fetal IGF-I and insulin plasma concentrations were lower and insulin-like growth factor-binding protein-1 (IGFBP-1) concentrations were higher in the low cortisol group compared with those in the control group (P < 0.05). Fetal liver IGF-II and IGFBP-3 mRNA were decreased in low cortisol animals compared with controls (P < 0.05). There were no significant changes in these parameters in the high cortisol group, and there were no changes in fetal liver IGF-I, growth hormone receptor, IGF-I receptor, IGF-II receptor, IGFBP-1 or IGFBP-2 mRNA levels between the groups. These data suggest that reduced fetal IGF availability contributes to reduced fetal growth when maternal cortisol secretion is impaired, but not during exposure to moderate increases in cortisol.

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