Exposure to maternal obesity during development leads to increased risk of obesity in adult-life. Recent evidence suggests that this susceptibility is initiated during the peri-conception period. This work focused on characterizing the effects of obesity on ovarian and oocyte gene expression. We hypothesized that obesity will up-regulate ovarian and oocyte inflammation leading to significant changes in oocyte development. We further hypothesized that obesity would be associated with an upregulation of ovarian early growth response protein 1 (EGR-1) signaling pathway and with changes in follicular fluid content. We used a translational approach to test our hypotheses. An experimental model of total enteral nutrition (TEN) induced obesity in rats by overconsumption of kilocalories. Ovarian gene and protein expression were evaluated and immunohistochemistry was used to determine the cell-specific localization of Egr-1. Superovulation protocols were used to collect oocytes and granulosa cells. In a translational approach normal weight (N=13) and obese women (N=11) who were undergoing fertility treatments requiring oocyte retrieval were recruited. Oocytes of various maturation stages (germinal vesicle (GV); metaphase I (MI); metaphase II (MII)) and follicular (FF) were collected for gene expression and content analyses. Obese (OB) dams showed an up-regulation of inflammatory genes expression and Egr-1 nuclear content in ovarian tissue, and a concurrent down-regulation of glucose transporters (GLUTs) and Protein kinase B (AKT) and phosphatidylinositol 3-kinase (PI3K) protein levels. Using DSeq analyses, we observed that 918 genes were differentially expressed in oocytes from OB compared to lean dams. Using single cell transcriptomic analysis, we observed that 192 genes in GV, 624 genes in MI, and 411 genes in MII oocytes were differentially expressed between OW and NW women. Leptin, triglyceride (TG), total cholesterol (TC) and C-reactive protein (CRP) were increased in FF from OW compared to NW (p<0.05). In conclusion, obesity was associated with a pro-inflammatory ovarian response, altered follicular environment and differential oocyte gene expression. These results demonstrate that obesity impacts germ cells prior to fertilization, which suggest that intervention to prevent obesity in offspring may need to begin before conception.
|Commitee:||Badger, Thomas, Cleves, Mario, Gaddy, Dana, Moutos, Dean, Shankar, Kartik|
|School:||University of Arkansas for Medical Sciences|
|Department:||Interdisciplinary Biomedical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 78/02(E), Dissertation Abstracts International|
|Keywords:||Adiposity, Clinical study, Oocyte, Ovary, Rat, Rna sequencing|
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