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MON-LB039 Developmental Programming: Prenatal Testosterone Excess Induces Endoplasmic Reticulum (ER) Stress in the Metabolic Tissues of the Female Sheep

Prenatal exposure to excess testosterone (T) programs peripheral insulin resistance (IR) and dyslipidemia along with tissue-specific changes in ectopic lipid accumulation, oxidative stress and IR in liver and muscle, and inflammation, oxidative stress, and reduced adipogenesis, differentiation, and...

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Autores principales: Puttabyatappa, Muraly, Padmanabhan, Vasantha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Endocrine Society 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550894/
http://dx.doi.org/10.1210/js.2019-MON-LB039
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author Puttabyatappa, Muraly
Padmanabhan, Vasantha
author_facet Puttabyatappa, Muraly
Padmanabhan, Vasantha
author_sort Puttabyatappa, Muraly
collection PubMed
description Prenatal exposure to excess testosterone (T) programs peripheral insulin resistance (IR) and dyslipidemia along with tissue-specific changes in ectopic lipid accumulation, oxidative stress and IR in liver and muscle, and inflammation, oxidative stress, and reduced adipogenesis, differentiation, and adipocyte size but not IR in the visceral adipose tissue (VAT) of the female sheep. The reduced Insulin sensitivity in liver and muscle is likely the result of oxidative stress and lipotoxicity. Recently, homeostatic disturbance in endoplasmic reticulum (ER), a crucial site for protein and lipid metabolism, called ER stress has emerged as a key player in the development and maintenance of IR and adipocyte defects. Abnormal lipid metabolism and cellular protein damage due to oxidative stress or inflammation can elicit ER stress through double-stranded RNA-dependent protein kinase-like ER kinase (PERK), inositol-requiring protein 1 (IRE1), and activating transcription factor 6 (ATF6) and transcription factors C/EBP homologous protein (CHOP) and X box-binding protein 1 (XBP1). We therefore hypothesized that the tissue-specific ER stress may underlie the prenatal T programmed IR state and adipocyte defects in the female sheep. To test this premise and determine if ER stress are programmed by androgen or insulin (as T excess induces maternal hyperinsulinemia), liver, muscle and visceral adipose (VAT) tissues from control, prenatal T- (100mg T propionate twice a week from days 30-90 of gestation), prenatal T plus androgen antagonist, flutamide (15 mg/kg/day)-, and prenatal T plus insulin sensitizer, Rosiglitazone (0.11 mg/kg/day)-treated female sheep were studied at 24 months of age. The changes in expression of ER stress markers were assessed by real time RTPCR and data analyzed by ANOVA and Cohen’s effect size analysis. By effect size analysis, Prenatal T-treatment induced a large magnitude increase in only CHOP10 mRNA expression in the liver and muscle, a large magnitude decrease in XBP1 in the muscle and large magnitude increase in IRE1, PERK and CHOP10 In the VAT. Intervention with androgen antagonist and insulin sensitizer reversed prenatal T- induced decrease in XBP1 in the muscle but did not reverse the changes in other markers of ER stress. These preliminary findings support the hypothesis that prenatal T-treatment induces ER stress in the liver, muscle and VAT and appear to be programmed independent of androgen or insulin dependent pathways. Based on these data ER stress may potentially underlie the development or maintenance of IR status of liver and muscle and adipocyte defects of VAT in the prenatal T-treated sheep. These findings are of translational relevance to female offspring of hyperandrogenic pregnancies. Support: NIH P01 HD44232 Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.
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spelling pubmed-65508942019-06-13 MON-LB039 Developmental Programming: Prenatal Testosterone Excess Induces Endoplasmic Reticulum (ER) Stress in the Metabolic Tissues of the Female Sheep Puttabyatappa, Muraly Padmanabhan, Vasantha J Endocr Soc Reproductive Endocrinology Prenatal exposure to excess testosterone (T) programs peripheral insulin resistance (IR) and dyslipidemia along with tissue-specific changes in ectopic lipid accumulation, oxidative stress and IR in liver and muscle, and inflammation, oxidative stress, and reduced adipogenesis, differentiation, and adipocyte size but not IR in the visceral adipose tissue (VAT) of the female sheep. The reduced Insulin sensitivity in liver and muscle is likely the result of oxidative stress and lipotoxicity. Recently, homeostatic disturbance in endoplasmic reticulum (ER), a crucial site for protein and lipid metabolism, called ER stress has emerged as a key player in the development and maintenance of IR and adipocyte defects. Abnormal lipid metabolism and cellular protein damage due to oxidative stress or inflammation can elicit ER stress through double-stranded RNA-dependent protein kinase-like ER kinase (PERK), inositol-requiring protein 1 (IRE1), and activating transcription factor 6 (ATF6) and transcription factors C/EBP homologous protein (CHOP) and X box-binding protein 1 (XBP1). We therefore hypothesized that the tissue-specific ER stress may underlie the prenatal T programmed IR state and adipocyte defects in the female sheep. To test this premise and determine if ER stress are programmed by androgen or insulin (as T excess induces maternal hyperinsulinemia), liver, muscle and visceral adipose (VAT) tissues from control, prenatal T- (100mg T propionate twice a week from days 30-90 of gestation), prenatal T plus androgen antagonist, flutamide (15 mg/kg/day)-, and prenatal T plus insulin sensitizer, Rosiglitazone (0.11 mg/kg/day)-treated female sheep were studied at 24 months of age. The changes in expression of ER stress markers were assessed by real time RTPCR and data analyzed by ANOVA and Cohen’s effect size analysis. By effect size analysis, Prenatal T-treatment induced a large magnitude increase in only CHOP10 mRNA expression in the liver and muscle, a large magnitude decrease in XBP1 in the muscle and large magnitude increase in IRE1, PERK and CHOP10 In the VAT. Intervention with androgen antagonist and insulin sensitizer reversed prenatal T- induced decrease in XBP1 in the muscle but did not reverse the changes in other markers of ER stress. These preliminary findings support the hypothesis that prenatal T-treatment induces ER stress in the liver, muscle and VAT and appear to be programmed independent of androgen or insulin dependent pathways. Based on these data ER stress may potentially underlie the development or maintenance of IR status of liver and muscle and adipocyte defects of VAT in the prenatal T-treated sheep. These findings are of translational relevance to female offspring of hyperandrogenic pregnancies. Support: NIH P01 HD44232 Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO. Endocrine Society 2019-04-30 /pmc/articles/PMC6550894/ http://dx.doi.org/10.1210/js.2019-MON-LB039 Text en Copyright © 2019 Endocrine Society https://creativecommons.org/licenses/by-nc-nd/4.0/ This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Reproductive Endocrinology
Puttabyatappa, Muraly
Padmanabhan, Vasantha
MON-LB039 Developmental Programming: Prenatal Testosterone Excess Induces Endoplasmic Reticulum (ER) Stress in the Metabolic Tissues of the Female Sheep
title MON-LB039 Developmental Programming: Prenatal Testosterone Excess Induces Endoplasmic Reticulum (ER) Stress in the Metabolic Tissues of the Female Sheep
title_full MON-LB039 Developmental Programming: Prenatal Testosterone Excess Induces Endoplasmic Reticulum (ER) Stress in the Metabolic Tissues of the Female Sheep
title_fullStr MON-LB039 Developmental Programming: Prenatal Testosterone Excess Induces Endoplasmic Reticulum (ER) Stress in the Metabolic Tissues of the Female Sheep
title_full_unstemmed MON-LB039 Developmental Programming: Prenatal Testosterone Excess Induces Endoplasmic Reticulum (ER) Stress in the Metabolic Tissues of the Female Sheep
title_short MON-LB039 Developmental Programming: Prenatal Testosterone Excess Induces Endoplasmic Reticulum (ER) Stress in the Metabolic Tissues of the Female Sheep
title_sort mon-lb039 developmental programming: prenatal testosterone excess induces endoplasmic reticulum (er) stress in the metabolic tissues of the female sheep
topic Reproductive Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550894/
http://dx.doi.org/10.1210/js.2019-MON-LB039
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