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Dehydroepiandrosterone-induced activation of mTORC1 and inhibition of autophagy contribute to skeletal muscle insulin resistance in a mouse model of polycystic ovary syndrome.

ABSTRACT: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age and also an important metabolic disorder associated with insulin resistance (IR). Hyperandrogenism is a key feature of PCOS. However, whether hyperandrogenism can cause IR in PCOS remains largely unknown. The mammalian target of rapamycin complex 1 (mTORC1) and its regulated autophagy are closely associated with IR. In the present study, we investigated the role of mTORC1-autophagy pathway in skeletal muscle IR in a dehydroepiandrosterone (DHEA)-induced PCOS mouse model. DHEA-treated mice exhibited whole-body and skeletal muscle IR, along with the activated mTORC1, repressed autophagy, impaired mitochondria, and reduced plasma membrane glucose transporter 4 (GLUT4) expression in skeletal muscle of the mice. In cultured C2C12 myotubes, treatment with high dose testosterone activated mTORC1, reduced autophagy, impaired mitochondria, decreased insulin-stimulated glucose uptake, and induced IR. Inhibition of mTORC1 or induction of autophagy restored mitochondrial function, up-regulated insulin-stimulated glucose uptake, and increased insulin sensitivity. On the contrary, inhibition of autophagy exacerbated testosterone-induced impairment. Our findings suggest that the mTORC1-autophagy pathway might contribute to androgen excess-induced skeletal muscle IR in prepubertal female mice by impairing mitochondrial function and reducing insulin-stimulated glucose uptake. These data would help understanding the role of hyperandrogenism and the underlying mechanism in the pathogenesis of skeletal muscle IR in PCOS.

SUBMITTER: Song X

PROVIDER: S-EPMC5844717 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Dehydroepiandrosterone-induced activation of mTORC1 and inhibition of autophagy contribute to skeletal muscle insulin resistance in a mouse model of polycystic ovary syndrome.

Song Xi X Shen Qiyang Q Fan Liting L Yu Qiuxiao Q Jia Xiao X Sun Yu Y Bai Wenpei W Kang Jihong J

Oncotarget 20180112 15

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age and also an important metabolic disorder associated with insulin resistance (IR). Hyperandrogenism is a key feature of PCOS. However, whether hyperandrogenism can cause IR in PCOS remains largely unknown. The mammalian target of rapamycin complex 1 (mTORC1) and its regulated autophagy are closely associated with IR. In the present study, we investigated the role of mTORC1-autophagy pathway in skeletal ...[more]

PMID: 29552281

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Project description:Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder affecting up to 15% of women at reproductive age. The main features of PCOS are hyperandrogenism and irregular menstrual cycles together with metabolic dysfunctions including hyperinsulinemia and insulin resistance and a 4-fold increased risk of developing type 2 diabetes. Despite the high prevalence the pathophysiology of the syndrome is unclear. Insulin resistance in women with PCOS likely affect the skeletal muscle and recently it was demonstrated that changes in DNA methylation affects the gene expression in skeletal muscle that in part can explain their metabolic abnormalities. The objective of this work was to combine gene expression array data from different datasets to improve statistical power and thereby identify novel biomarkers that can be further explored. In this narrative review, we performed a meta-analysis of skeletal muscle arrays available from Gene Expression Omnibus and from publications. The eligibility criteria were published articles in English, and baseline (no treatment) skeletal muscle samples from women with PCOS and controls. The R package Metafor was used for integration of the datasets. One hundred and fourteen unique transcripts were differentially expressed in skeletal muscle from women with PCOS vs. controls (q < 0.05), 87% of these transcripts have not been previously identified as altered in PCOS muscle. ING2, CDKAL1, and AKTIP had the largest differential increase in expression, and TSHZ2, FKBP2, and OCEL1 had the largest decrease in expression. Two genes, IRX3 and CDKAL1 were consistently upregulated (q < 0.05) in the individual analyses and meta-analysis. Based on the meta-analysis, we identified several dysregulated immunometabolic pathways as a part of the molecular mechanisms of insulin resistance in the skeletal muscle of women with PCOS. The transcriptomic data need to be verified by functional analyses as well as proteomics to advance our understanding of PCOS specific insulin resistance in skeletal muscle.

Project description:BACKGROUND:Previous studies have shown that chronic inflammation and oxidative stress may play an important role in the pathophysiology of polycystic ovary syndrome (PCOS), and glutamine (Gln) have showed the anti-inflammatory and antioxidant properties. So the aim of this study is to investigate the effect of glutamine supplementation on PCOS rats. METHODS:Female Sprague-Dawley rats were randomly assigned into four groups (n =?10 /group), control group, PCOS group, PCOS+?0.5?g/kg Gln group and PCOS+?1.0?g/kg Gln group. All the PCOS rats were administrated with 6?mg/100?g dehydroepiandrosterone (DHEA) for 20 consecutive days, all the PCOS+Gln groups were intraperitoneal injected glutamine twice in the next morning after the last DHEA injection. All the samples were collected 12?h after the last administration. Ovarian histological examinations were analyzed and the concentration of serum hormone, inflammatory and oxidative stress factors were measured. RESULTS:There was no obvious ovarian histological change among the PCOS group and PCOS+Gln groups. All the detected inflammation factors [C-reactive protein, interleukin (IL)-6, IL-18, tumor necrosis factor] showed significantly higher in all the PCOS groups compared to the control group (P <?0.01), and were significantly decreased with the supplementation of 0.5?g/kg glutamine (P <?0.01). Concentrations of superoxide dismutase were significantly lower in all the PCOS groups (P <?0.01) compared to the control group, and increased significantly with the supplementation of 0.5?g/kg glutamine (P <?0.01). Serum concentrations of malondialdehyde, nitric oxide synthase and nitric oxide were significantly higher in PCOS group (P <?0.01) compared with the control group, and significantly decreased to the comparative levels of control group with supplementation of 0.5?g/kg glutamine (P <?0.01). CONCLUSION:There is low-grade inflammation and oxidative stress in DHEA-induced PCOS rats. The supplementation of 0.5?g/kg glutamine could effectively ameliorate the inflammation and oxidative stress conditions of PCOS.

Project description:BackgroundPolycystic ovary syndrome (PCOS) is the most common endocrinopathy associated with infertility and metabolic disorder in women of reproductive age. Animal models have been developed and used as tools to unravel the pathogenesis of PCOS, among which most postnatal models employ continuing experimental manipulations. However, the persistence and stability of these animals after modeling is unknown. Dehydroepiandrosterone (DHEA)-induced PCOS mouse model is commonly used in PCOS studies. Thus the aim of the present study was to investigate the reproductive features of DHEA-induced PCOS mice fed a normal chow or an high-fat diet (HFD) with treatment withdrawal or consecutive treatments after PCOS mouse models were established.MethodsPrepubertal C57BL/6 J mice (age 25 days) were injected (s.c.) daily with DHEA on a normal chow or a 60% HFD for 20 consecutive days to induce PCOS mouse models. Mice injected with the vehicle sesame oil were used as controls. After 20 days, mice were divided into 2 groups, namely "Continue dosing group" and "Stop dosing group". The animals were consecutively treated with DHEA or DHEA + HFD, or housed without any treatment for 2 or 4 weeks. Estrous cycles were evaluated during this period. At the end of the experiment, serum testosterone (T) levels were measured and the morphology of ovaries was evaluated.ResultsThe mice in Continue dosing groups maintained reproductive phenotypes of PCOS mouse models. In contrast, 2 or 4 weeks after PCOS models were established, the mice with treatment withdrawal in Stop dosing groups exhibited normal serum testosterone levels, regular estrous cycle, and relatively normal ovarian morphology. In addition, even with consecutive treatments, there was no marked difference in body weight between DHEA mice on the normal chow or an HFD in Continue dosing groups and the control animals 3 weeks after modeling.ConclusionsAfter PCOS mice were induced with DHEA or DHEA + HFD, the mice still need consecutive treatments to maintain reproductive phenotypes to be regarded as PCOS mice that meet the diagnostic criteria of PCOS defined by the 2003 Rotterdam criteria.

Dataset Information

Dehydroepiandrosterone-induced activation of mTORC1 and inhibition of autophagy contribute to skeletal muscle insulin resistance in a mouse model of polycystic ovary syndrome.

Publications

Dehydroepiandrosterone-induced activation of mTORC1 and inhibition of autophagy contribute to skeletal muscle insulin resistance in a mouse model of polycystic ovary syndrome.

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