Deciphering the Roles of Endometrial Glycogen Reserves and the Impact of Obesity on Fertility

解读子宫内膜糖原储备的作用以及肥胖对生育力的影响

• 批准号: 10638028
• 负责人: Matthew J Dean
• 金额: $ 37.29万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-08 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638028
• 关键词: AMHR2 gene; Address; Affect; Area; C-Peptide; C57BL/6 Mouse; Circadian Rhythms; Data; Decidua; Decidual Cell Reactions; Defect; Diestrus; Diet; Embryo; Embryonic Development; Endometrial; Endometrial Stromal Cell; Endometrium; Ensure; Enzymes; Epithelium; Estradiol; Fat-Restricted Diet; Fatty acid glycerol esters; Fertility; Fertilization; GYS1 gene; Global Change; Glucose; Glucose Transporter; Glycogen; Glycogen Phosphorylase; Glycolysis; Growth Factor; High Fat Diet; Hormonal; Human; Hyperglycemia; Hyperinsulinism; Hypoxia; Immunohistochemistry; Impairment; In Vitro; Infertility; Insulin; Invaded; Knock-out; Lactoferrin; Length; Link; Litter Size; LoxP-flanked allele; Metabolism; Modeling; Morula; Mus; National Institute of Child Health and Human Development; Nutrient; Obesity; Pathogenesis; Placentation; Pre-implantation Embryo Development; Pregnancy; Pregnancy Outcome; Pregnancy loss; Process; Proestrus; Progesterone; Regulation; Reproduction; Research; Role; Serum; Site; Spain; Time; Tissues; Uterus; Woman; blastocyst; diet-induced obesity; early pregnancy; early pregnancy loss; endometrial stroma; fasting glucose; glucose metabolism; glucose uptake; glucose-6-phosphatase; glycogen metabolism; human data; implantation; macromolecule; maternal obesity; metabolomics; mouse model; natural Blastocyst Implantation; novel; nutrition; pregnancy failure; preimplantation; reproductive; response; spatiotemporal; treatment group

Project Summary Over 40% of pregnancies fail in women, most before or during embryo implantation. During this time, embryos are dependent on secretions into the uterine lumen that contains all of the growth factors and nutrients necessary for embryo development. In particular, embryos need glucose. From fertilization until the morula stage, glucose uptake is low, but without glucose, the embryo degenerates. As embryos approach the blastocyst stage, glucose uptake increases dramatically, providing ATP to the embryo within the hypoxic uterine lumen. The endometrial stroma also uses a large amount of glucose to decidualize. After decidualization, the stroma relies on Warburg metabolism to produce ATP and supplies glucose to the invading embryo. Thus, it is clear that glucose availability must be regulated in a spatiotemporal manner to ensure a successful pregnancy. Finally, obesity leads to reduced fertility in women through, in part, effects on the uterus and its ability to support pregnancy. Most research on endometrial glucose has focused on the role of glucose transporters. However, the endometrium can also transiently store glucose as the macromolecule glycogen. In women, endometrial glycogen concentrations are correlated with fertility, but a direct link between uterine glycogen and fertility has never been established. To investigate this in mice, we collected uteri on proestrus and days post coitum (DPC) 1.5, 3.5, and 5.5. Our preliminary data show that the mouse endometrium stores two distinct glycogen pools: in the uterine epithelium and the uterine decidua. Epithelial glycogen peaked at proestrus and significantly reduced during the preimplantation period. The epithelial expressed glycogen phosphorylase and glucose-6-phosphatase, suggesting the epithelium can catabolize glycogen and secrete the resulting glucose. In contrast, the endometrial stroma stored little glycogen until decidualization, when glycogen content increased 7-fold. Similarly, artificially induced decidualization in hormonally primed mice resulted in a 5-fold increase in glycogen levels. In order to establish a definitive relationship between these distinct pools of glycogen and fertility, we obtained glycogen synthase 1 (GYS1) floxed mice so that we can knockout GYS1 in a tissue-specific manner. Aim 1 will generate an LTFiCre/+ GYS1flox/flox mouse to study the role of epithelial glycogen in glucose secretion and preimplantation embryo survival. Aim 2 will use AMHR2Cre/+ GYS1flox/flox mice to study the role of glycogen in the decidua. Collectively these aims will establish a causative link between the ability of the uterus to store glycogen in the epithelium and decidua and fertility. Aim 3 will use a diet-induced obesity model to study how maternal obesity affects glycogen metabolism in the mouse uterus. We will determine how a 45% and 60% fat diet affects uterine metabolism and fertility in a C57BL/6 mouse model. In vitro, we will determine the effects of hyperglycemia and hyperinsulinemia on decidual glycogen. In summary, this research will evaluate the role of endometrial glycogen stores in support of early pregnancy and assess the potential for maternal obesity to result in dysfunctional endometrial glycogen metabolism.

项目摘要 女性的怀孕中有40％以上，大多数在胚胎植入之前或期间。在此期间，胚胎 取决于包含所有生长因子和营养的子宫内腔的分泌物 胚胎开发所必需的。特别是，胚胎需要葡萄糖。从受精到毛拉 阶段，葡萄糖摄取量很低，但没有葡萄糖，胚胎会退化。当胚胎接近 胚泡阶段，葡萄糖摄取大大增加，为低氧内的胚胎提供ATP 子宫腔。子宫内膜基质还使用大量的葡萄糖来确定化。后 结论性，基质依赖于沃堡的代谢产生ATP并为入侵提供葡萄糖 胚胎。因此，很明显，必须以时空的方式调节葡萄糖可用性，以确保 成功怀孕。最后，肥胖会导致女性的生育能力降低，部分原因是对子宫的影响 及其支持怀孕的能力。关于子宫内膜葡萄糖的大多数研究都集中在葡萄糖的作用上 运输商。但是，子宫内膜还可以将葡萄糖瞬时储存为大分子糖原。在 女性，子宫内膜糖原浓度与生育率相关，但子宫之间的直接联系 糖原和生育率从未建立。为了在小鼠中调查这一点 和涂色后（DPC）1.5、3.5和5.5的天数。我们的初步数据表明，小鼠子宫内膜存储 两个不同的糖原池：在子宫上皮和子宫decip。上皮糖原在 在植入前的期间，预反系症显着降低。上皮表达的糖原 磷酸化酶和葡萄糖-6-磷酸酶，表明上皮可以分解糖原并分泌 产生的葡萄糖。相比之下，子宫内膜基质几乎没有糖原，直到切成骨化，直到脱生作用 糖原含量增加了7倍。同样，荷尔蒙引发的小鼠人为地诱导的cydialization 导致糖原水平增加了5倍。为了在这些之间建立确定的关系 不同的糖原和生育能力池，我们获得了糖原合酶1（Gys1）floxed小鼠，以便我们可以 以组织特异性方式敲除gys1。 AIM 1将产生LTFICRE/+ GYS1FLOX/FLOX小鼠研究角色 葡萄糖分泌和植入前胚胎存活中上皮糖原的生存。 AIM 2将使用AMHR2CRE/+ Gys1flox/Flox小鼠研究糖原在Decidua中的作用。这些目标共同建立了一种因果关系 子宫将糖原储存在上皮和生育能力的能力之间。 AIM 3将使用 饮食引起的肥胖模型，以研究孕产妇肥胖如何影响小鼠子宫中的糖原代谢。 我们将确定45％和60％的脂肪饮食如何影响子宫代谢和C57BL/6小鼠的生育 模型。在体外，我们将确定高血糖和高胰岛素血症对决定型糖原的影响。在 总而言之，这项研究将评估子宫内膜糖原存储在支持早期怀孕和 评估孕产妇肥胖的潜力导致功能失调的子宫内膜糖原代谢。