Decreased Oocyte-Granulosa Cell Gap Junction Communication and Connexin Expression in a Type 1 Diabetic Mouse Model

Ratchford, Ann M.; Esguerra, Cybill; Moley, Kelle H.

doi:10.1210/me.2007-0495

Cited by 66 publications

(60 citation statements)

References 70 publications

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“…In a mouse model of type 1 diabetes, a reduction in GLUT-mediated pyruvate production may account for the observed apoptosis of ovarian follicle cumulus cells via the extrinsic pathway (5). In addition, follicles from type 1 diabetic mice exhibit lower connexin 37 and 43 with reduced gap junction communication between granulosa cells and oocytes compared with controls (1,29).…”

Section: Importance Of Glycolysis To Oocyte Metabolism: a Focus On Glmentioning

confidence: 93%

Hypoxia-mediated carbohydrate metabolism and transport promote early-stage murine follicle growth and survival

Makanji¹,

Tagler

Pahnke³

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Makanji Y, Tagler D, Pahnke J, Shea LD, Woodruff TK. Hypoxia-mediated carbohydrate metabolism and transport promote early-stage murine follicle growth and survival. Am J Physiol Endocrinol Metab 306: E893-E903, 2014. First published February 25, 2014 doi:10.1152/ajpendo.00484.2013.-Oxygen tension is critical for follicle growth and metabolism, especially for early-stage follicles, where vascularity is limited. Its role and underlying mechanism in the in vitro activation and maturation of immature to ovulatory follicles is largely unknown. In this study, early secondary (110 m) murine follicles were isolated and encapsulated in alginate hydrogels to replicate the in vivo environment of the growing/maturing follicle. Encapsulated follicles were cultured for 8 days at either 2.5 or 20% O2. Survival (2.6-fold) and growth (1.2-fold) were significantly higher for follicles cultured at 2.5% compared with 20% O2. Using a mouse hypoxia-signaling pathway qRT-PCR array and GeneGo Metacore analysis, we found that direct target genes of the hypoxia-activated HIF1-complex were significantly upregulated in follicles cultured for 8 days at 2.5% compared with 20% O2, including the carbohydrate transport and metabolism genes Slc2a3, Vegfa, Slc2a1, Edn1, Pgk1, Ldha, and Hmox1. Other upregulated genes included carbohydrate transporters (Slc2a1, Slc2a3, and Slc16a3) and enzymes essential for glycolysis (Pgk1, Hmox1, Hk2, Gpi1, Pfkl, Pfkp, Aldoa, Gapdh, Pgam1, Eno1, Pkm2, and Ldha). For follicles cultured at 2.5% O2, a 7.2-fold upregulation of Vegfa correlated to an 18-fold increase in VEGFA levels, and a 3.2-fold upregulation of Ldha correlated to a 4.8-fold increase in lactate levels. Both VEGFA and lactate levels were significantly higher in follicles cultured at 2.5% compared with 20% O2. Therefore, enhanced hypoxia-mediated glycolysis is essential for growth and survival of early secondary follicles and provides vital insights into improving in vitro culture conditions. hypoxia; ovarian; follicle metabolism; glycolysis; oxygen GROWTH AND MATURATION OF OVARIAN FOLLICLES requires coordinated activity of various growth factors and hormones that interact with the physical environment of the follicle, including pH, temperature, and oxygen (O 2 ) tension. O 2 is critical for aerobic ATP production, in which pyruvate is converted to energy; however, excess O 2 generates free radicals and reactive oxygen species, which can damage the oocyte and its precious DNA cargo within the follicle (44). By design, ovarian follicles operate in a moderate hypoxic environment rather than an anoxic one (16). Granulosa cells use relatively less O 2 and convert glucose to pyruvate and lactate via the glycolytic pathway; the pyruvate is shunted to oocyte, which uses it and O 2 to create ATP via the TCA cycle (8, 13).The ability to culture follicles in vitro to produce mature, fertilizable oocytes has potential clinical applications in fertility preservation, and yet recapitulating the complexity of follicle growth and metabolism in vitro has been chall...

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Section: Importance Of Glycolysis To Oocyte Metabolism: a Focus On Glmentioning

confidence: 93%

Hypoxia-mediated carbohydrate metabolism and transport promote early-stage murine follicle growth and survival

Makanji¹,

Tagler

Pahnke³

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Poor oocyte growth, meiotic competence and glucose metabolism within COCs derived from diabetic mice may also be attributed to decreased gene and protein expression of connexins, the structural units making up gap junction channels, resulting in 60% less gap-junction communication between the oocyte and cumulus vestment (Ratchford et al 2008). This is significant considering the reliance of the oocyte on cumulus cell communication for developmental competence.…”

Section: Maternal Environment and Oocyte Developmental Competencementioning

confidence: 99%

The pivotal role of glucose metabolism in determining oocyte developmental competence

Sutton‐McDowall

Gilchrist²,

Thompson³

2010

Reproduction

433

325

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The environment that the cumulus oocyte complex (COC) is exposed to during either in vivo or in vitro maturation (IVM) can have profound effects on the success of fertilisation and subsequent embryo development. Glucose is a pivotal metabolite for the COC and is metabolised by glycolysis, the pentose phosphate pathway (PPP), the hexosamine biosynthesis pathway (HBP) and the polyol pathway. Over the course of oocyte maturation, a large proportion of total glucose is metabolised via the glycolytic pathway to provide substrates such as pyruvate for energy production. Glucose is also the substrate for many cellular functions during oocyte maturation, including regulation of nuclear maturation and redox state via the PPP and for the synthesis of substrates of extracellular matrices (cumulus expansion) and O-linked glycosylation (cell signalling) via the HBP. However, the oocyte is susceptible to glucose concentration-dependent perturbations in nuclear and cytoplasmic maturation, leading to poor embryonic development post-fertilisation. For example, glucose concentrations either too high or too low result in precocious resumption of nuclear maturation. This review will discuss the relevant pathways of glucose metabolism by COCs during in vivo maturation and IVM, including the relative contribution of the somatic and gamete compartments of the COC to glucose metabolism. The consequences of exposing COCs to abnormal glucose concentrations will also be examined, either during IVM or by altered maternal environments, such as during hyperglycaemia induced by diabetes and obesity.Reproduction (2010) 139 685-695

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“…Maternal type I diabetes also causes increased granulosa cell apoptosis [37]. The above-mentioned gap junction communication that is important in mediating signals from the cumulus cells to the oocyte is also impaired due to maternal diabetes [39]. Mice fed a high fat diet for 16 weeks led to an increase in weight and elevated glucose, but not to the point of being considered diabetic.…”

Section: Oocyte Maturation and Fertilizationmentioning

confidence: 99%

The impact of obesity on egg quality

Purcell

Moley

2011

J Assist Reprod Genet

Self Cite

136

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Obesity in women is a concern in many countries. This causes numerous health issues; however, this review focuses on the impact of obesity on women's reproduction, and in particular the oocyte. Data from infertility clinics and experimental animal models that address the effects of obesity are presented. Bidirectional communication and metabolic support from the surrounding cumulus cells are critical for oocyte development, and the impact of obesity on these cells is also addressed. Both oocyte maturation and metabolism are impaired due to obesity, negatively impacting further development. In addition to reproductive hormones, obesity induced elevations in insulin, glucose, or free fatty acids, and changes in adipokines appear to impact the developmental competence of the oocyte. The data indicate that any one of these hormones or metabolites can impair oocyte developmental competence in vivo, and the combination of all of these factors and their interactions are the subject of ongoing investigations.

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Decreased Oocyte-Granulosa Cell Gap Junction Communication and Connexin Expression in a Type 1 Diabetic Mouse Model

Cited by 66 publications

References 70 publications

Hypoxia-mediated carbohydrate metabolism and transport promote early-stage murine follicle growth and survival

Hypoxia-mediated carbohydrate metabolism and transport promote early-stage murine follicle growth and survival

The pivotal role of glucose metabolism in determining oocyte developmental competence

The impact of obesity on egg quality

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