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Title: Maternal obesity is associated with ovarian inflammation and up-regulation of early growth response factor 1

Author
item RUEBEL, MEGHAN - Arkansas Children'S Nutrition Research Center (ACNC)
item SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC)
item GADDY, DANA - Texas A&M University
item LINDSEY, FORREST - Arkansas Children'S Nutrition Research Center (ACNC)
item Badger, Thomas
item ANDRES, ALINE - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/1/2016
Publication Date: 6/7/2016
Citation: Ruebel, M., Shankar, K., Gaddy, D., Lindsey, F., Badger, T.M., Andres, A. 2016. Maternal obesity is associated with ovarian inflammation and up-regulation of early growth response factor 1. American Journal of Physiology - Endocrinology and Metabolism. 311(1):E269-E277. doi: 10.1152/ajpendo.00524.2015.

Interpretive Summary: Along with the rising obesity epidemic in adults and children, we have a concurrent increase of women entering pregnancy while being obese. Research has suggested that obesity of the mother may be affecting the ovarian functions and environment, where the embryo develops, prior to conception. In this present study we examined the effect of obesity on different hormones and metabolites in the serum and gene expression of ovaries from female rats. We found changes in body composition and elevated concentrations of different hormones and metabolites in the blood. Furthermore, ovarian genes that were involved in inflammation and ovarian function were changed. In addition, we found a transcription factor, Egr-1, to be increased, specifically within cummulus cells of the ovary with obesity. In conclusion, this suggests that obesity leads to alterations of the ovarian environment and can possibly impact the development of oocytes and embryos prior to birth.

Technical Abstract: Obesity impairs reproductive functions through multiple mechanisms, possibly through disruption of ovarian function. We hypothesized that increased adiposity will lead to a pro-inflammatory gene signature and up-regulation of Egr-1 protein in ovaries from obese (OB, n=7) compared to lean (LN, n=10) female Sprague Dawley rats during the peri-implantation period at 4.5 days post-coitus (dpc). Obesity was induced by overfeeding (40% excess calories for 28 d) via total enteral nutrition prior to mating. OB dams had higher body weight (p<0.001), greater fat mass (p<0.001), reduced lean mass (p<0.05), and developed metabolic dysfunction with elevated serum lipids, insulin, leptin, and CCL2 (p<0.05) compared to LN dams. Microarray analyses identified 284 differentially-expressed genes between ovaries from LN vs. OB dams (+/-1.3 fold, p<0.05). RT-qPCR confirmed a decrease in expression of glucose transporters GLUT4 and GLUT9 and elevation of pro-inflammatory genes including CCL2, CXCL10, CXCL11, CCR2, CXCR1, and TNF-a in ovaries from OB compared to LN (p<0.05). Protein levels of PI3K and phosphorylated AKT were significantly decreased (p<0.05) while nuclear levels of Egr-1 (p<0.05) were increased in OB compared to LN ovaries. Moreover, Egr-1 was localized to granulosa cells, with highest expression in cumulus cells of pre-ovulatory follicles. mRNA expression of VCAN, AURKB and PLAT (p<0.05) correlated with %visceral fat weight (r=0.51, -0.77, and -0.57, p<=0.05, respectively), suggesting alterations in ovarian function with obesity. In summary, maternal obesity led to an up-regulation of inflammatory genes and Egr-1 expression in peri-implantation ovarian tissue, and a concurrent down-regulation of GLUTs and AKT and PI3K protein levels.