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Perturbed ovarian and uterine glucocorticoid receptor signaling accompanies the balanced regulation of mitochondrial function and NFκB-mediated inflammation under conditions of hyperandrogenism and insulin resistance.

Journal article
Authors Min Hu
Yuehui Zhang
Xiaozhu Guo
Wenyan Jia
Guoqi Liu
Jiao Zhang
Peng Cui
Juan Li
Wei Li
Xiaoke Wu
Hongxia Ma
Mats Brännström
Linus Ruijin Shao
Håkan Billig
Published in Life sciences
Volume 232
ISSN 1879-0631
Publication year 2019
Published at Institute of Neuroscience and Physiology, Department of Physiology
Institute of Clinical Sciences, Department of Obstetrics and Gynecology
Language en
Links dx.doi.org/10.1016/j.lfs.2019.11668...
www.ncbi.nlm.nih.gov/entrez/query.f...
Keywords 11HSD; Glucocorticoid receptor; Inflammation; Mitochondrial malfunction; NFκB; Ovary; Polycystic ovary syndrome; Uterus
Subject categories Physiology, Cell and Molecular Biology, Endocrinology and Diabetes, Obstetrics, Gynecology and Reproductive Medicine

Abstract

This study aimed to determine whether glucocorticoid receptor (GR) signaling, mitochondrial function, and local inflammation in the ovary and uterus are intrinsically different in rats with hyperandrogenism and insulin resistance compared to controls.Female Sprague Dawley rats were exposed to daily injections of human chorionic gonadotropin and/or insulin.In both the ovary and the uterus, decreased expression of the two GR isoforms was concurrent with increased expression of Fkbp51 but not Fkbp52 mRNA in hCG + insulin-treated rats. However, these rats exhibited contrasting regulation of Hsd11b1 and Hsd11b2 mRNAs in the two tissues. Further, the expression of several oxidative phosphorylation-related proteins decreased in the ovary and uterus following hCG and insulin stimulation, in contrast to increased expression of many genes involved in mitochondrial function and homeostasis. Additionally, hCG + insulin-treated rats showed increased expression of ovarian and uterine NFκB signaling proteins and Tnfaip3 mRNA. The mRNA expression of Il1b, Il6, and Mmp2 was decreased in both tissues, while the mRNA expression of Tnfa, Ccl2, Ccl5, and Mmp3 was increased in the uterus. Ovaries and uteri from animals co-treated with hCG and insulin showed increased collagen deposition compared to controls.Our observations suggest that hyperandrogenism and insulin resistance disrupt ovarian and uterine GR activation and trigger compensatory or adaptive effects for mitochondrial homeostasis, allowing tissue-level maintenance of mitochondrial function in order to limit ovarian and uterine dysfunction. Our study also suggests that hyperandrogenism and insulin resistance activate NFκB signaling resulting in aberrant regulation of inflammation-related gene expression.

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