Molecular characterization of insulin resistance and glycolytic metabolism in the rat uterus

Zhang, Yuehui; Sun, Xue; Sun, Xiaoyan; Meng, Fanci; Hu, Min; Li, Xin; Li, Wei; Wu, Xiaoke; Brännström, Mats; Shao, Ruijin; Billig, Håkan

doi:10.1038/srep30679

Cited by 45 publications

(72 citation statements)

References 61 publications

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“…Experiment 1: Rats were randomly divided into control (saline treatment, n = 20) and experimental (PCOS-like, n = 20) groups. The experimental group was treated with insulin plus hCG to induce a PCOS-like metabolic and reproductive phenotype, and the control rats were treated with an equal volume of saline 29 . In brief, insulin was started at 0.5 IU/day and gradually increased to 6.0 IU/day between day 1 and the day 22 to induce hyperinsulinemia and insulin resistance, and 3.0 IU/day hCG was given on all 22 days to induce hyperandrogenism.…”

Section: Experimental Animals and Tissue Preparationsmentioning

confidence: 99%

“…Rats with repeated insulin injections have not shown any hypoglycemic episodes [35][36][37] . Detailed analysis of endocrine and metabolic parameters as well as the uterine morphology in these animals has been reported previously 29 . On day 23, each group of rats was divided into two subgroups of 10 rats each (Supplemental Fig.…”

Section: Experimental Animals and Tissue Preparationsmentioning

confidence: 99%

“…Uterine tissues were fixed in 10% formalin, embedded in paraffin, and sectioned for hematoxylin and eosin staining according to standard procedures. Immunohistochemistry and immunofluorescence were performed according to previously described methods 28,29 . The endogenous peroxidase and nonspecific binding were removed by incubation with 3% H 2 O 2 for 10 min and with 10% normal goat serum for 1 h at room temperature.…”

Section: Morphological Assessment and Immunostainingmentioning

confidence: 99%

“…A detailed explanation of the Western blot analysis protocol has been published 28,29 . Total protein was isolated from whole uterine tissue by homogenization in RIPA buffer (Sigma-Aldrich) supplemented with cOmplete Mini protease inhibitor cocktail tablets (Roche Diagnostics, Mannheim, Germany) and PhosSTOP phosphatase inhibitor cocktail tablets (Roche Diagnostics).…”

Section: Protein Isolation and Western Blot Analysismentioning

confidence: 99%

“…To address this hypothesis, we analyzed PCOS-associated PGR isoform expression and the MAPK signaling network in human and rat uterine tissues. By combining a PCOS-like rat model 29 and in vitro tissue culture approach 30 , we aimed to determine whether metformin directly reverses aberrant PGR-targeted and implantation-related gene expression in the PCOS-like rat uterus.…”

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confidence: 99%

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Uterine progesterone signaling is a target for metformin therapy in PCOS-like rats

Zhang

Feng

et al. 2017

Preprint

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Impaired progesterone (P4) signaling is linked to endometrial dysfunction and infertility in women with polycystic ovary syndrome (PCOS). Here we report for the first time that elevated expression of progesterone receptor (PGR) isoforms A and B parallels increased estrogen receptor (ER) expression in PCOS-like rat uteri. The aberrant PGR-targeted gene expression in PCOS-like rats before and after implantation overlaps with dysregulated expression of Fkbp52 and Ncoa2, two genes that contribute to the development of uterine P4 resistance. In vivo and in vitro studies of the effects of metformin on the regulation of the uterine P4 signaling pathway under PCOS conditions showed that metformin directly inhibits the expression of PGR and ER along with the regulation of several genes that are targeted dependently or independently of PGR-mediated uterine implantation. Functionally, metformin treatment corrected the abnormal expression of cell-specific PGR and ER and some PGR-target genes in PCOS-like rats with implantation. Additionally, we documented how metformin contributes to the regulation of the PGR-associated MAPK/ERK/p38 signaling pathway in the PCOS-like rat uterus. Our data provide novel insights into how metformin therapy regulates uterine P4 signaling molecules under PCOS conditions.

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Section: Experimental Animals and Tissue Preparationsmentioning

confidence: 99%

Section: Experimental Animals and Tissue Preparationsmentioning

confidence: 99%

Section: Morphological Assessment and Immunostainingmentioning

confidence: 99%

Section: Protein Isolation and Western Blot Analysismentioning

confidence: 99%

mentioning

confidence: 99%

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Uterine progesterone signaling is a target for metformin therapy in PCOS-like rats

Zhang

Feng

et al. 2017

Preprint

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Overactivation of the androgen receptor exacerbates gravid uterine ferroptosis via interaction with and suppression of the NRF2 defense signaling pathway

Zhang

et al. 2022

FEBS Letters

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The mechanisms through which the androgen-dependent activation of the androgen receptor (AR) regulates gravid uterine ferroptosis remain unknown. We show that while co-exposure of pregnant rats to the androgen 5adihydrotestosterone (DHT) and insulin (INS) triggered uterine ferroptotic signaling cascades, additional treatment with the anti-androgen flutamide increased expression of the key ferroptosis-inhibitory proteins SLC7A11, GSH, and GPX4; reduced iron content; normalized levels of ferroptosisassociated Tfrc, Fpn1, and Ho1 mRNAs; reduced levels of proteins modified by 4-HNE (a marker of ferroptosis); and restored protein levels of NRF2, a key transcription factor regulating antioxidant defense signaling, in the gravid uterus. Furthermore, exposure to DHT alone increased uterine ferroptosis, and NRF2 abundance was negatively correlated with AR status. Coimmunoprecipitation and Western blot assays revealed that the AR physically interacted with endogenous NRF2, and this interaction was increased by DHT exposure in vivo. Our results suggest that AR overactivation and NRF2 suppression cooperate in the regulation of NRF2-targets in uterine ferroptosis.

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Divergent Metabolic Effects of Acute Versus Chronic Repeated Forced Swim Stress in the Rat

Rabasa

Askevik

Schéle

et al. 2019

Obesity

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Objective This study sought to examine divergence regarding the impact of acute versus chronic repeated stress on energy balance. Methods Rats were exposed to either chronic repeated forced swim (FS) stress for 7 days or an acute stress (a single FS). Body weight and food intake were measured daily. Metabolic parameters explored included brown adipose tissue (BAT) weight and activity. Results Chronic repeated FS stress decreased body weight and caloric efficiency. It also increased the relative weight of BAT. The same stressor delivered only once did not alter adrenal or BAT weight, but it did increase the metabolic activity of BAT. In stress‐naive rats, acute FS stress induced an anorexigenic response during the first day after the stressor that caused a reduction in body weight (that persisted for 4 days). By contrast, the chronic FS rats did not show an anorexigenic response after the final stressor, and there was no change in body weight during the following 4 days. Conclusions Rats exposed to chronic repeated FS stress adapt to the stressor over time; they become less sensitive to its anorexigenic effects and its metabolic effects in BAT, adaptations that ultimately reduce sensitivity to the weight‐lowering effects of an acute stressor.

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Molecular characterization of insulin resistance and glycolytic metabolism in the rat uterus

Cited by 45 publications

References 61 publications

Uterine progesterone signaling is a target for metformin therapy in PCOS-like rats

Uterine progesterone signaling is a target for metformin therapy in PCOS-like rats

Overactivation of the androgen receptor exacerbates gravid uterine ferroptosis via interaction with and suppression of the NRF2 defense signaling pathway

Divergent Metabolic Effects of Acute Versus Chronic Repeated Forced Swim Stress in the Rat

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