Effects of age on ACTH, corticosterone, glucose, insulin, and mRNA levels during intermittent hypoxia in the neonatal rat

2013 ◽  
Vol 304 (9) ◽  
pp. R782-R789 ◽  
Author(s):  
Kathan Chintamaneni ◽  
Eric D. Bruder ◽  
Hershel Raff
Keyword(s):  
Mrna Expression ◽  
Glucose Homeostasis ◽  
Intermittent Hypoxia ◽  
Neonatal Rat ◽  
Mrna Levels ◽  
Plasma Acth ◽  
Tissue Samples ◽  
Rat Pups ◽  
Developmental Age ◽  
Adrenal Response

Apnea, the temporary cessation of respiratory airflow, is a common cause of intermittent hypoxia (IH) in premature infants. We hypothesized that IH elicits a stress response and alters glucose homeostasis in the neonatal rat. Rat pups were studied on postnatal day (PD) 2, 8, 10, 12, and 14. Pups were exposed to normoxia (control) or six cycles consisting of 30-s exposures to hypoxia (FiO2 = 3%) over a 60-min period. Blood samples were obtained at baseline, after the third cycle (∼30 min), and after the sixth cycle (∼60 min). Tissue samples were collected following the sixth cycle. Plasma ACTH, corticosterone, glucose, and insulin were analyzed at all ages. Hypothalamic, pituitary, and adrenal mRNA expression was evaluated by quantitative PCR in PD2, PD8, and PD12 pups. Exposure to IH elicited significant increases in plasma ACTH and corticosterone at all ages studied. The largest increase in corticosterone occurred in PD2 pups, despite only a very small increase in plasma ACTH. This ACTH-independent increase in corticosterone in PD2 pups was associated with increases in adrenal Ldlr and Star mRNA expression. Additionally, IH caused hyperglycemia and hyperinsulinemia at all ages. We conclude that IH elicits a significant pituitary-adrenal response and significantly alters glucose homeostasis. Furthermore, the quantitative and qualitative characteristics of these responses depend on developmental age.

Pituitary-adrenal response to bacterial endotoxin in developing rats

1988 ◽  
Vol 255 (4) ◽  
pp. E525-E530 ◽  
Author(s):  
L. Witek-Janusek
Keyword(s):  
Plasma Corticosterone ◽  
Neonatal Rat ◽  
Bacterial Endotoxin ◽  
Plasma Acth ◽  
Adult Rats ◽  
Age Related ◽  
Corticosterone Response ◽  
Adrenal Response ◽  
Old Rats ◽  
Related Pattern

The neonatal rat is very sensitive to the lethal effects of bacterial endotoxin. Because of the adaptive importance of pituitary-adrenal secretions to stress, this study examined the ontogeny of the plasma corticosterone and adrenocorticotropic hormone (ACTH) responses to endotoxin. The lethal sensitivity of young rats to endotoxin ranged from 0.5 to 30 mg/kg (ip) in the 1- to 21-day-old rat. After endotoxin treatment, the 1- and 2-day-old rat showed marked elevations of corticosterone similar in magnitude to that seen in 21-day-old and adult rats; however, significantly depressed corticosterone increments were observed in the 5-, 10-, and 14-day-old rats. This age-related pattern of adrenocortical secretion was correlated with the developing rat's corticosterone response to exogenous ACTH. In contrast, endotoxin administered to 5-, 10-, and 14-day-old rats resulted in increments of plasma ACTH similar to those observed in the 21-day-old and adult rats. Although plasma ACTH levels increased by 84-127% in the 1- and 2-day-old rats, these increases were significantly less than those of rats at all other ages tested. Thus the newborn rat mounts an effective corticosterone response to endotoxin, loses this ability between ages 5-14 days, and regains this response at 21 days of age. Because the hyporesponsive ages exhibit a marked increase in ACTH secretion, the loss of the adrenocortical response to endotoxin appears to be a result of a depressed responsiveness of the adrenal cortex to ACTH.

scholarly journals Plasma leptin and ghrelin in the neonatal rat: interaction of dexamethasone and hypoxia

2005 ◽  
Vol 185 (3) ◽  
pp. 477-484 ◽  
Author(s):  
Eric D Bruder ◽  
Lauren Jacobson ◽  
Hershel Raff
Keyword(s):  
Mrna Expression ◽  
Energy Homeostasis ◽  
Metabolic Stress ◽  
Plasma Corticosterone ◽  
Neonatal Rat ◽  
Plasma Acth ◽  
Pomc Mrna ◽  
And Shifts ◽  
Plasma Leptin ◽  
Pituitary Adrenal Axis

Ghrelin, leptin, and endogenous glucocorticoids play a role in appetite regulation, energy balance, and growth. The present study assessed the effects of dexamethasone (DEX) on these hormones, and on ACTH and pituitary proopiomelanocortin (POMC) and corticotropin-releasing hormone receptor-1 (CRHR1) mRNA expression, during a common metabolic stress – neonatal hypoxia. Newborn rats were raised in room air (21% O2) or under normobaric hypoxia (12% O2) from birth to postnatal day (PD) 7. DEX was administered on PD3 (0.5 mg/kg), PD4 (0.25 mg/kg), PD5 (0.125 mg/kg), and PD6 (0.05 mg/kg). Pups were studied on PD7 (24 h after the last dose of DEX). DEX significantly increased plasma leptin and ghrelin in normoxic pups, but only increased ghrelin in hypoxic pups. Hypoxia alone resulted in a small increase in plasma leptin. Plasma corticosterone and pituitary POMC mRNA expression were decreased 24 h following the last dose of DEX, whereas plasma ACTH and pituitary CRHR1 mRNA expression had already increased (normoxia and hypoxia). Hypoxia alone increased corticosterone, but had no effect on ACTH or pituitary POMC and CRHR1 mRNA expression. Neonatal DEX treatment, hypoxia, and the combination of both affect hormones involved in energy homeostasis. Pituitary function in the neonate was quickly restored following DEX-induced suppression of the hypothalamic–pituitary–adrenal axis. The changes in ghrelin, leptin, and corticosterone may be beneficial to the hypoxic neonate through the maintenance of appetite and shifts in intermediary metabolism.

scholarly journals A high-carbohydrate diet in the immediate postnatal life of rats induces adaptations predisposing to adult-onset obesity

2008 ◽  
Vol 197 (3) ◽  
pp. 565-574 ◽  
Author(s):  
Malathi Srinivasan ◽  
Paul Mitrani ◽  
Gigani Sadhanandan ◽  
Catherine Dodds ◽  
Suhad Shbeir-ElDika ◽  
...  
Keyword(s):  
Body Weight ◽  
Insulin Receptor ◽  
Neonatal Rat ◽  
Melanocortin Receptor ◽  
Milk Formula ◽  
Postnatal Life ◽  
Mrna Levels ◽  
Adult Onset ◽  
High Carbohydrate ◽  
Rat Pups

Newborn rat pups artificially raised on a high-carbohydrate (HC) milk formula are chronically hyperinsulinemic and develop adult-onset obesity. As HC rats display aberrations in body weight regulation, hypothalamic adaptations predisposing to obesity have been investigated in this study. The artificial rearing of neonatal rat pups on the HC milk formula resulted in significant increases in the mRNA levels of neuropeptide Y, agouti-related polypeptide, and galanin in the hypothalamus of 12-day-old HC rats. Simultaneously, decreases in the mRNA levels of POMC, melanocortin receptor-4, cocaine- and amphetamine-regulated transcript, and corticotrophin-releasing factor were observed in the hypothalamus of these rats. These changes persisted in 100-day-old HC rats despite weaning onto a rodent diet on postnatal day 24. Marked hyperphagia and increased body weight gain were observed in the post-weaning period. The mRNA levels and protein content of insulin receptor β (IR-β) and leptin receptor (long form) showed significant decreases in the hypothalamus of both 12- and 100-day-old HC rats. Further investigation of insulin signaling in the hypothalamus of HC rats indicated significant decreases in the proximal signaling components (insulin receptor substrate proteins 1 and 2 and phosphotidylinositol 3-kinase) in 100-day-old HC rats. These results suggest that hypothalamic neuropeptides respond to the increased carbohydrate availability with associated hormonal alterations during the period of dietary modulation and that these adaptations by persisting in the post-weaning period predispose the HC rats for adult-onset obesity.

Adrenocorticotropic hormone and corticosterone responses to acute hypoxia in the neonatal rat: effects of body temperature maintenance

2011 ◽  
Vol 300 (3) ◽  
pp. R708-R715 ◽  
Author(s):  
Eric D. Bruder ◽  
Kimberli J. Kamer ◽  
Mitchell A. Guenther ◽  
Hershel Raff
Keyword(s):  
Stress Response ◽  
Body Temperature ◽  
Acute Hypoxia ◽  
Plasma Corticosterone ◽  
Neonatal Rat ◽  
Plasma Acth ◽  
Neonatal Hypoxia ◽  
Rat Pups ◽  
Expression Of Genes ◽  
Corticosterone Response

The corticosterone response to acute hypoxia in neonatal rats develops in the 1st wk of life, with a shift from ACTH independence to ACTH dependence. Acute hypoxia also leads to hypothermia, which may be protective. There is little information about the endocrine effects of body temperature maintenance during periods of neonatal hypoxia. We hypothesized that prevention of hypothermia during neonatal hypoxia would augment the adrenocortical stress response. Rat pups separated from their dams were studied at postnatal days 2 and 8 ( PD2 and PD8). In one group of pups, body temperature was allowed to spontaneously decrease during a 30-min prehypoxia period. Pups were then exposed to 8% O2 for 3 h and allowed to become spontaneously hypothermic or externally warmed (via servo-controlled heat) to maintain isothermia. In another group, external warming was used to maintain isothermia during the prehypoxia period, and then hypoxia with or without isothermia was applied. Plasma ACTH and corticosterone and mRNA expression of genes for upstream proteins involved in the steroidogenic pathway were measured. Maintenance of isothermia during the prehypoxia period increased baseline plasma ACTH at both ages. Hypothermic hypoxia caused an increase in plasma corticosterone; this response was augmented by isothermia at PD2, when the response was ACTH-independent, and at PD8, when the response was ACTH-dependent. In PD8 rats, isothermia also augmented the plasma ACTH response to hypoxia. We conclude that maintenance of isothermia augments the adrenocortical response to acute hypoxia in the neonate. Prevention of hypothermia may increase the stress response during neonatal hypoxia, becoming more pronounced with increased age.

scholarly journals Intermittent hypoxia training in prediabetes patients: Beneficial effects on glucose homeostasis, hypoxia tolerance and gene expression

2017 ◽  
Vol 242 (15) ◽  
pp. 1542-1552 ◽  
Author(s):  
Tetiana V Serebrovska ◽  
Alla G Portnychenko ◽  
Tetiana I Drevytska ◽  
Vladimir I Portnichenko ◽  
Lei Xi ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Mrna Expression ◽  
Glucose Homeostasis ◽  
Intermittent Hypoxia ◽  
Target Genes ◽  
Acute Hypoxia ◽  
Hypoxia Tolerance ◽  
Oral Glucose ◽  
Beneficial Effects ◽  
Positive Effects

The present study aimed at examining beneficial effects of intermittent hypoxia training (IHT) under prediabetic conditions. We investigate the effects of three-week IHT on blood glucose level, tolerance to acute hypoxia, and leukocyte mRNA expression of hypoxia inducible factor 1α (HIF-1α) and its target genes, i.e. insulin receptor, facilitated glucose transporter–solute carrier family-2, and potassium voltage-gated channel subfamily J. Seven healthy and 11 prediabetic men and women (44–70 years of age) were examined before, next day and one month after three-week IHT (3 sessions per week, each session consisting 4 cycles of 5-min 12% O2 and 5-min room air breathing). We found that IHT afforded beneficial effects on glucose homeostasis in patients with prediabetes reducing fasting glucose and during standard oral glucose tolerance test. The most pronounced positive effects were observed at one month after IHT termination. IHT also significantly increased the tolerance to acute hypoxia (i.e. SaO2 level at 20th min of breathing with 12% O2) and improved functional parameters of respiratory and cardiovascular systems. IHT stimulated HIF-1α mRNA expression in blood leukocytes in healthy and prediabetic subjects, but in prediabetes patients the maximum increase was lagged. The greatest changes in mRNA expression of HIF-1α target genes occurred a month after IHT and coincided with the largest decrease in blood glucose levels. The higher expression of HIF-1α was positively associated with higher tolerance to hypoxia and better glucose homeostasis. In conclusion, our results suggest that IHT may be useful for preventing the development of type 2 diabetes. Impact statement The present study investigated the beneficial effects of intermittent hypoxia training (IHT) in humans under prediabetic conditions. We found that three-week moderate IHT induced higher HIF-1α mRNA expressions as well as its target genes, which were positively correlated with higher tolerance to acute hypoxia and better glucose homeostasis in both middle-aged healthy and prediabetic subjects. This small clinical trial has provided new data suggesting a potential utility of IHT for management of prediabetes patients.

159 Effect of bisphenol A and bisphenol S on AMH and AMHR mRNA expression during in vitro bovine oocyte maturation and early embryo development

2019 ◽  
Vol 31 (1) ◽  
pp. 204 ◽  
Author(s):  
A. Saleh ◽  
L. Favetta
Keyword(s):  
Bisphenol A ◽  
Mrna Expression ◽  
Cumulus Cells ◽  
Early Embryo ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Bisphenol S ◽  
Tissue Samples ◽  
Receptor Mrna

Exposure to chemicals with known endocrine-disrupting effects, such as bisphenol A (BPA) and bisphenol S (BPS), leads to repercussions on oocyte development and, ultimately, on fertility. Bisphenol A is a plasticizer used worldwide that has been detected in blood, urine, tissue samples and follicular fluid. Due to its widely reported detrimental effects, BPA has been substituted with its analogue BPS. Previous experiments in our laboratory have shown that exposure of bovine oocytes to physiologically relevant doses of BPA resulted in spindle abnormalities, reduced meiosis progression, decreased blastocyst rate and gene expression changes. However, the effects of BPS have not yet been investigated. Anti-Müllerian hormone (AMH) has been reported to be a good marker of ovarian reserve and oocyte developmental capability and is commonly used in assisted reproduction for diagnostic measurements. There is evidence that women undergoing IVF with higher BPA levels have lower AMH levels and pregnancy success. The aim of this study was to assess the effect of BPA and BPS on AMH and its receptor as measures of oocyte developmental capability. Abattoir-derived bovine cumulus-oocyte complexes (COC) were matured in vitro in 4 groups: (1) control, (2) vehicle (0.1% ethanol), (3) BPA (0.05mg mL−1 in 0.1% ethanol), and (4) BPS (0.05mg mL−1 in 0.1% ethanol). Pools of 30 COC, 30 denuded oocytes, and cumulus cells corresponding to denuded oocytes were collected for each of the 4 experimental groups, and a minimum of 4 biological replicates were used for each analysis. Anti-Müllerian hormone and AMH receptor mRNA expression was measured in COC, denuded oocytes, and their corresponding cumulus cells using quantitative real-time PCR. Statistical analyses were performed using 1-way ANOVA. Results showed a decrease (P<0.05) in AMH mRNA expression in BPA-treated oocytes (without cumulus cells). In addition, there was an increase (P<0.05) in mRNA AMH receptor levels in COC when treated with BPS. Finally, analyses on cumulus cells alone showed an increase (P<0.05) in the AMH receptor mRNA levels in BPA-treated cells. These results suggest that BPA has an effect on AMH mRNA transcript levels in oocytes, while affecting the receptor expression in cumulus cells. Conversely, BPS affects AMH indirectly, increasing the mRNA levels of its receptor only. Further investigation of the effects of BPA and BPS on AMH expression in in vitro-produced blastocysts derived from treated oocytes will aid in understanding the potential consequences of exposure to BPA and its analogues on early embryonic development.

Abstract 13402: FHL-1 Contributes to and Colocalizes With Titin in Cardiac Hypertrophy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Nesrine El-Bizri ◽  
Jing Liu ◽  
Rachel Matt ◽  
Rugmani P Iyer ◽  
Girija Raman ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Diastolic Dysfunction ◽  
Neonatal Rat ◽  
In Vivo Studies ◽  
Myoblast Differentiation ◽  
Mrna Levels ◽  
Tissue Samples ◽  
Diastolic Compliance

Increased myocardial stiffness is a hallmark of impaired diastole in heart failure (HF). Hypo-phosphorylation of the N2B unique sequence (N2Bus) of titin (TTN), a giant myofilament protein, increases passive tension leading to diastolic dysfunction in HF. Enhancing the altered N2Bus phosphorylation improves cardiac stiffness and function. FHL-1, an interacting protein potentially modulating N2Bus phosphorylation is increased in HF. FHL-1 knockout mice display blunted cardiac hypertrophy and improved diastolic compliance in response to pressure-overload by transverse aortic constriction, TAC. FHL-1 also regulates skeletal muscle hypertrophy. We hypothesize that FHL-1 contributes to cardiac hypertrophy and colocalizes/interacts with TTN in heart failure. In house IHC data showed site-specific N2Bus hypo-phosphorylation at S4099, S4010 and S4185 in human HCM and/or DCM tissue samples. Longitudinal in-vivo studies showed that FHL-1 and cardiac hypertrophy markers genes were increased in left ventricles (LV) of TAC mice using RNA-seq. A persistently enhanced FHL-1 protein expression by immunoblotting and mass spectrometry strongly correlated with LV hypertrophy at 1, 4, and 6 weeks post-TAC. In addition, LV hypertrophy correlated negatively with function (fractional shortening). Increases in FHL-1 and hypertrophy markers mRNA levels were confirmed by RT-qPCR in neonatal rat ventricular myocytes (NRVM) under phenylephrine (PE) and endothelin-1 (ET-1) induced hypertrophy. Under similar conditions, FHL-1 protein levels were increased by immunofluorescence (IF) in cytoplasmic, perinuclear and nuclear regions of NRVM. Colocalization of phospho-TTN and FHL-1 was observed in NRVM and was enhanced under PE- and ET-1 induced hypertrophy. IF studies in human skeletal myotubes showed that FHL-1 expression was increased during myoblast differentiation and IGF1-E3R induced hypertrophy. Preliminary data using Microscale Thermophoresis showed binding affinity between N2Bus and FHL-1 proteins. Our studies show that FHL-1 contributes to hypertrophy in addition to N2B hypo-phosphorylation status contributing to diastolic dysfunction in HF. Targeting FHL-1 and TTN can be a potential strategy to improve diastolic compliance in HF.

scholarly journals Effect of a melanocortin type 2 receptor (MC2R) antagonist on the corticosterone response to hypoxia and ACTH stimulation in the neonatal rat

2018 ◽  
Vol 315 (1) ◽  
pp. R128-R133 ◽  
Author(s):  
Adam J. Goldenberg ◽  
Ashley L. Gehrand ◽  
Emily Waples ◽  
Mack Jablonski ◽  
Brian Hoeynck ◽  
...  
Keyword(s):  
Neonatal Rat ◽  
Acth Stimulation ◽  
Rat Pups ◽  
Baseline Corticosterone ◽  
Acth Concentration ◽  
Corticosterone Response ◽  
Adrenal Response ◽  
Insight Into

The adrenal stress response in the neonatal rat shifts from ACTH-independent to ACTH-dependent between postnatal days 2 (PD2) and 8 (PD8). This may be due to an increase in an endogenous, bioactive, nonimmunoreactive ligand to the melanocortin type 2 receptor (MC2R). GPS1574 is a newly described MC2R antagonist that we have shown to be effective in vitro. Further experimentation with GPS1574 would allow better insight into this seemingly ACTH-independent steroidogenic response in neonates. We evaluated the acute corticosterone response to hypoxia or ACTH injection following pretreatment with GPS1574 (32 mg/kg) or vehicle for GPS1574 in PD2, PD8, and PD15 rat pups. Pretreatment with GPS1574 decreased baseline corticosterone in PD2 pups but increased baseline corticosterone in PD8 and PD15 pups. GPS1574 did not attenuate the corticosterone response to hypoxia in PD2 pups and augmented the corticosterone response in PD8 and PD15 pups. GPS1574 augmented the corticosterone response to ACTH in PD2 and PD15 pups but had no significant impact on the response in PD8 pups. Baseline adrenal Mrap and Star mRNA increased from PD2 to PD15, whereas Mrap2 mRNA expression was low and did not change with age. The data suggest that GPS1574 is not a pure MC2R antagonist, but rather acts as a biasing agonist/antagonist. Its ability to attenuate or augment the adrenal response may depend on the ambient plasma ACTH concentration and/or developmental changes in early transduction steroidogenic pathway genes.

scholarly journals Effects of Zidovudine Treatment on Heart mRNA Expression and Mitochondrial DNA Copy Number Associated with Alterations in Deoxynucleoside Triphosphate Composition in a Neonatal Rat Model

2015 ◽  
Vol 59 (10) ◽  
pp. 6328-6336 ◽  
Author(s):  
Jacob W. Snowdin ◽  
Chia-Heng Hsiung ◽  
Daniel G. Kesterson ◽  
Vasudeva G. Kamath ◽  
Edward E. McKee
Keyword(s):  
Mitochondrial Dna ◽  
Mrna Expression ◽  
Rat Model ◽  
Neonatal Rat ◽  
Mrna Levels ◽  
Hypertrophic Growth ◽  
Hiv Therapy ◽  
Mitochondrial Dna Copy Number ◽  
Deoxynucleoside Triphosphate ◽  
Neonatal Rat Model

ABSTRACTThe prevention of mother-to-child transmission (MTCT) of HIV is a crucial component in HIV therapy. Nucleoside reverse transcriptase inhibitors (NRTIs), primarily 3′-azido-3′-thymidine (AZT [zidovudine]), have been used to treat both mothers and neonates. While AZT is being replaced with less toxic drugs in treating mothers in MTCT prevention, it is still commonly used to treat neonates. Problems related to mitochondrial toxicity and potential mutagenesis associated with AZT treatment have been reported in treated cohorts. Yet little is known concerning the metabolism and potential toxicity of AZT on embryonic and neonatal tissues, especially considering that the enzymes of nucleoside metabolism change dramatically as many tissues convert from hyperplastic to hypertrophic growth during this period. AZT is known to inhibit thymidine phosphorylation and potentially alter deoxynucleoside triphosphate (dNTP) pools in adults. This study examines the effects of AZT on dNTP pools, mRNA expression of deoxynucleoside/deoxynucleotide metabolic enzymes, and mitochondrial DNA levels in a neonatal rat model. Results show that AZT treatment dramatically altered dNTP pools in the first 7 days of life after birth, which normalized to age-matched controls in the second and third weeks. Additionally, AZT treatment dramatically increased the mRNA levels of many enzymes involved in deoxynucleotide synthesis and mitochondrial biogenesis during the first week of life, which normalized to age-matched controls by the third week. These results were correlated with depletion of mitochondrial DNA noted in the second week. Taken together, results demonstrated that AZT treatment has a powerful effect on the deoxynucleotide synthesis pathways that may be associated with toxicity and mutagenesis.

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