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

Hu, Min; Zhang, Yuehui; Feng, Jiaxing; Xue, Xiang; Zhang, Jiao; Zhao, Wei; Guo, Xiaozhu; Li, Juan; Vestin, Edvin; Cui, Peng; Li, Xin; Wu, Xiaoke; Brännström, Mats; Shao, Ruijin; Billig, Håkan

doi:10.1530/joe-18-0086

Cited by 33 publications

(25 citation statements)

References 52 publications

(89 reference statements)

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“…Moreover, elevated ERα protein expression (Fig. 2B) was associated with high levels of cell proliferative factors (vimentin and Ki-67) in PCOS patients with endometrium hyperplasia 39, 47. This indicates that activation of estrogen-ERα signaling is related to sustained endometrial proliferation in PCOS patients with endometrium hyperplasia.…”

Section: Resultsmentioning

confidence: 76%

“…Because in vivo and in vitro pre-clinical and clinical studies have shown that metformin reverses PCOS-induced inhibition of glucose transporter (Glut) isoforms 17, 42 and reverses PCOS-induced enhancement of ERα mRNA expression in the uterus 42, 47, it is possible that metformin can directly regulate endometrial glycolysis and mitochondrial function in PCOS patients with hyperplasia. To address this question, we cultured endometrial hyperplasia tissues in the presence of 20 mM metformin.…”

Section: Resultsmentioning

confidence: 99%

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Differential Expression Patterns of Glycolytic Enzymes and Mitochondria-Dependent Apoptosis in PCOS Patients with Endometrial Hyperplasia, an Early Hallmark of Endometrial Cancer, In Vivo and the Impact of Metformin In Vitro

Wang¹,

Zhang²,

Hu³

et al. 2019

Int. J. Biol. Sci.

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Section: Resultsmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Differential Expression Patterns of Glycolytic Enzymes and Mitochondria-Dependent Apoptosis in PCOS Patients with Endometrial Hyperplasia, an Early Hallmark of Endometrial Cancer, In Vivo and the Impact of Metformin In Vitro

Wang¹,

Zhang²,

Hu³

et al. 2019

Int. J. Biol. Sci.

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“…Histological processing and immunohistochemistry were performed according to previously described methods (32, 42). Fresh tissues were dissected and immediately fixed in 4% formaldehyde in neutral buffered solution at 4°C for 24 h and then embedded in paraffin.…”

Section: Methodsmentioning

confidence: 99%

Induction of hyperandrogenism and insulin resistance differentially modulates ferroptosis in uterine and placental tissues of pregnant rats

Zhang

Jia

et al. 2020

Preprint

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Ferroptosis, a form of regulated necrotic cell death, plays roles in diverse physiological processes and diseases. Women with polycystic ovary syndrome (PCOS) have hyperandrogenism and insulin resistance (HAIR) and an increased risk of miscarriage and placental dysfunction during pregnancy. However, whether maternal HAIR alters mechanisms leading to ferroptosis in the gravid uterus and placenta remains unknown. Previous studies in rats showed that maternal exposure to 5α-dihydrotestosterone (DHT) and insulin (INS) from gestational day 7.5 to 13.5 induces HAIR and subsequently leads to placental insufficiency and fetal loss. We therefore hypothesized that maternal HAIR triggers ferroptosis in the uterus and placenta in association with fetal loss in pregnant rats. Compared with controls, we found that co-exposure to DHT and INS led to decreased levels of Gpx4 and glutathione (GSH), increased GSH+glutathione disulfide (GSSG) and malondialdehyde (MDA), aberrant expression of ferroptosis-associated genes (Acsl4, Tfrc, Slc7a11, and Gclc), increased iron deposition, and activated ERK/p38/JNK phosphorylation in the gravid uterus. However, in the placenta, DHT and INS exposure only partially altered the expression of ferroptosis-related markers (e.g., region-dependent Gpx4, GSH+GSSG, MDA, Gls2 and Slc7a11 mRNAs, and phosphorylated p38 levels). In the uteri co-exposed to DHT and INS, we also observed shrunken mitochondria with electron-dense cristae, which are key features of ferroptosis-related mitochondrial morphology, as well as increased expression of Dpp4, a mitochondria-encoded gene responsible for ferroptosis induction. In contrast, in placentas co-exposed to DHT and INS we found decreased expression of Dpp4 mRNA and increased expression of Cisd1 mRNA (a mitochondria-encoded iron-export factor). Further, DHT+INS-exposed pregnant rats exhibited decreased apoptosis in the uterus and increased necroptosis in the placenta. Our findings suggest that maternal HAIR causes the activation of ferroptosis in the gravid uterus and placenta, although this is mediated via different mechanisms operating at the molecular and cellular levels. Furthermore, our data suggest other cell death pathways may play a role in coordinating or compensating for HAIR-induced ferroptosis when the gravid uterus and placenta are dysfunctional.

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“…The protein band densities were normalized to the total‐protein loading control. The analysis was performed as described previously .…”

Section: Methodsmentioning

confidence: 99%

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

Cited by 33 publications

References 52 publications

Differential Expression Patterns of Glycolytic Enzymes and Mitochondria-Dependent Apoptosis in PCOS Patients with Endometrial Hyperplasia, an Early Hallmark of Endometrial Cancer, In Vivo and the Impact of Metformin In Vitro

Differential Expression Patterns of Glycolytic Enzymes and Mitochondria-Dependent Apoptosis in PCOS Patients with Endometrial Hyperplasia, an Early Hallmark of Endometrial Cancer, In Vivo and the Impact of Metformin In Vitro

Induction of hyperandrogenism and insulin resistance differentially modulates ferroptosis in uterine and placental tissues of pregnant rats

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

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