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.

项目总结