High insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process

Su, Yan; Wu, Juan; He, Junlin; Liu, Xueqing; Ding, Yubin; Zhang, Chen; Chen, Wenqi; Wang, Yingxiong; Gao, Rufei

doi:10.1507/endocrj.ej16-0494

Cited by 22 publications

(16 citation statements)

References 42 publications

(42 reference statements)

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“…Meanwhile, elevated insulin levels and/or insulin resistance are commonly seen in women with PCOS, and this is one of the most important mechanisms in PCOS pathogenesis [31,32]. It was found to be able to impair ovarian autophagy and function in mice [33]. Recently, insulin-sensitizers such as inositol have been used to improve the insulin resistance in PCOS by regulating autophagy [34].…”

Section: Discussionmentioning

confidence: 99%

Protein–Protein Interaction Network Analysis Reveals Several Diseases Highly Associated with Polycystic Ovarian Syndrome

Ramly

Afiqah‐Aleng

Mohamed‐Hussein

2019

IJMS

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Based on clinical observations, women with polycystic ovarian syndrome (PCOS) are prone to developing several other diseases, such as metabolic and cardiovascular diseases. However, the molecular association between PCOS and these diseases remains poorly understood. Recent studies showed that the information from protein–protein interaction (PPI) network analysis are useful in understanding the disease association in detail. This study utilized this approach to deepen the knowledge on the association between PCOS and other diseases. A PPI network for PCOS was constructed using PCOS-related proteins (PCOSrp) obtained from PCOSBase. MCODE was used to identify highly connected regions in the PCOS network, known as subnetworks. These subnetworks represent protein families, where their molecular information is used to explain the association between PCOS and other diseases. Fisher’s exact test and comorbidity data were used to identify PCOS–disease subnetworks. Pathway enrichment analysis was performed on the PCOS–disease subnetworks to identify significant pathways that are highly involved in the PCOS–disease associations. Migraine, schizophrenia, depressive disorder, obesity, and hypertension, along with twelve other diseases, were identified to be highly associated with PCOS. The identification of significant pathways, such as ribosome biogenesis, antigen processing and presentation, and mitophagy, suggest their involvement in the association between PCOS and migraine, schizophrenia, and hypertension.

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Section: Discussionmentioning

confidence: 99%

Protein–Protein Interaction Network Analysis Reveals Several Diseases Highly Associated with Polycystic Ovarian Syndrome

Ramly

Afiqah‐Aleng

Mohamed‐Hussein

2019

IJMS

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“…As shown in Figure 5C, an undetectable level of autophagy-related protein LC3B (microtubule-associated protein 1 light chain 3) (Jiang et al, 2017) was observed in the oocytes of TGFA SFs, whereas the oocytes of WT and TGF normal follicles displayed a normal level of LC3B. This result demonstrates that autophagy activity of the oocytes of TGFA follicles, which is fundamental to the cellular processes of the oocytes, was largely weakened (Su et al, 2017).…”

Section: Resultsmentioning

confidence: 82%

Bone Morphogenetic Protein 15 Knockdown Inhibits Porcine Ovarian Follicular Development and Ovulation

Qin

Tang

et al. 2019

Front. Cell Dev. Biol.

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Bone morphogenetic protein 15 (BMP15) is strongly associated with animal reproduction and woman reproductive disease. As a multifunctional oocyte-specific secret factor, BMP15 controls female fertility and follicular development in both species-specific and dosage-sensitive manners. Previous studies found that BMP15 played a critical role in follicular development and ovulation rate in mono-ovulatory mammalian species, especially in sheep and human, but study on knockout mouse model implied that BMP15 possibly has minimal impact on female fertility of poly-ovulatory species. However, this needs to be validated in other poly-ovulatory species. To investigate the regulatory role of BMP15 on porcine female fertility, we generated a BMP15-knockdown pig model through somatic nuclear transfer technology. The BMP15-knockdown gilts showed markedly reduced fertility accompanied by phenotype of dysplastic ovaries containing significantly declined number of follicles, increased number of abnormal follicles, and abnormally enlarged antral follicles resulting in disordered ovulation, which is remarkably different from the unchanged fertility observed in BMP15 knockout mice. Molecular and transcriptome analysis revealed that the knockdown of BMP15 significantly affected both granulosa cells (GCs) and oocytes development, including suppression of cell proliferation, differentiation, and follicle stimulating hormone receptor (Fshr) expression, leading to premature luteinization and reduced estradiol (E2) production in GCs, and simultaneously decreased quality and meiotic maturation of oocyte. Our results provide in vivo evidence of the essential role of BMP15 in porcine ovarian and follicular development, and new insight into the complicated regulatory function of BMP15 in female fertility of poly-ovulatory species.

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“…5C, an undetectable level of autophagy-related protein LC3B (microtubule-associated protein 1 light chain 3)(Jiang et al, 2017) was shown in oocytes of TGFA SFs, while oocytes of WT and TGF normal follicles displayed a normal level of LC3B. This result demonstrated that autophagy activity of the oocytes of TGFA follicles was largely weakened, which was fundamental to many oocyte cellular processes(Su et al, 2017).…”

Section: Resultsmentioning

confidence: 98%

Essential role of Bone morphogenetic protein 15 in porcine ovarian and follicular development and ovulation

Qin

Tang

et al. 2019

Preprint

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13Bone morphogenetic protein 15 (BMP15) is a multifunctional oocyte-specific secreted factor. It controls 14 female fertility and follicular development in both species-specific and dosage-sensitive manners. Previous 15 studies found that BMP15 played a critical role on follicular development and ovulation rate of 16 mono-ovulatory mammalian species, but has minimal impact on poly-ovulatory mice. However, whether this 17 is true in non-rodent poly-ovulatory species need to be validated. To investigate this question, we generated a 18 BMP15 knockdown pig model. We found that BMP15 knockdown gilts showed markedly reduced fertility 19 accompanied with phenotype of dysplastic ovaries containing significantly declined number of follicles, 20 increased number of abnormal follicles, and abnormally enlarged antral follicles resulting in disordered 21 ovulation. Molecular and transcriptome analysis revealed that knockdown of BMP15 significantly suppressed 22 cell proliferation, differentiation, Fshr expression, leading to premature luteinization and reduced estradiol 23 production in GCs, and simultaneously decreased the quality and meiotic maturation of oocyte. Our results 24 provide in vivo evidences for the essential role of BMP15 in porcine ovarian and follicular development, and 25 new insight into the complicated regulatory function of BMP15 in female fertility of poly-ovulatory species. 26 KEY WORDS: BMP15; transgenic pig; follicular development; ovarian development 27 28 96cells (PEFs) derived from a male Yorkshire pig. Transfected PEFs then were subjected to G418 selection to 97 screen the cells with stable expression of EGFP as donor cells for somatic cell nuclear transfer (SCNT). Clone 98 embryos then were transferred into Large White sow recipients to generate F0 TG pigs as described in our 99 previous report (Liu et al., 2019) (Fig. S1A). We obtained two healthy F0 TG males at last. After sexual 100 maturity, one F0 TG boar was mated with wild-type sows to generate F1 TG gilts for subsequent experiments. 101Both F0 and F1 TG pigs showed visible intense GFP fluorescence on toes and muscle while subjected to 102 sunlight (Fig. 1C, Fig. S1B), directly suggesting that the pEGFP-BMP15 shRNA plasmid was successfully 103 integrated into the genome of F0 TG boar, and can be transmitted to the next generation through the germline. 104This was confirmed by PCR analysis of fragment of integrated plasmid in muscle tissue of F1 TG gilts ( Fig. 105 S2A). The copy number of integrated plasmid was estimated to be approximate seven in F1 TG pigs through 106 the combination of both qPCR that using a transferrin receptor gene to normalize the genomic DNA (data 107 not shown), and Southern blot analysis ( Fig. S2B). More importantly, evidently decrease level of BMP15 108 mRNA ( Fig. 1E) in 365 days old TG ovaries and BMP15 protein level in 30 days old TG ovaries ( Fig. 1F, G) 109 strongly demonstrated the successful generation of the BMP15 knockdown model, and implied an in vivo 110 BMP15 knockdown efficiency of about 50%...

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High insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process

Cited by 22 publications

References 42 publications

Protein–Protein Interaction Network Analysis Reveals Several Diseases Highly Associated with Polycystic Ovarian Syndrome

Protein–Protein Interaction Network Analysis Reveals Several Diseases Highly Associated with Polycystic Ovarian Syndrome

Bone Morphogenetic Protein 15 Knockdown Inhibits Porcine Ovarian Follicular Development and Ovulation

Essential role of Bone morphogenetic protein 15 in porcine ovarian and follicular development and ovulation

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