In the United States, 36.5% of women between the ages of 20 and 39 years are obese. This obesity results in not only metabolic disorders including type II diabetes and cardiovascular disease, but also impaired female fertility. Systemic and tissue-specific chronic inflammation and oxidative stress are common characteristics of obesity. This is also true in the ovary. Several studies have demonstrated that pro-inflammatory cytokines and reactive oxygen species alter estrous cyclicity, steroidogenesis and ovulation. Inflammation and oxidative stress also impair meiotic and cytoplasmic maturation of the oocyte which reduces its developmental competence for fertilization and pre-implantation embryo development. Interestingly, there is recent evidence that obesity- and/or polycystic ovary syndrome (PCOS)-dependent changes to the gut microbiome contributes to ovarian inflammation, steroidogenesis and the expression of mRNAs in the oocyte. However, several gaps remain necessitating future studies to identify inflammation, oxidative stress and gut microbiome mechanisms that reduce ovarian function and oocyte quality.
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Alexandria P Snider and Jennifer R Wood
Elizabeth M Mack, Jacqueline E Smith, Scott G Kurz, and Jennifer R Wood
Granulosa cells play a crucial role as mediator of the LH-dependent ovulatory response. The intraovarian factor IGF1 is produced by ovarian somatic cells of healthy follicles during the ovulatory response. The objective of this study was to identify mechanisms by which IGF1, alone or in combination with LH, regulates the expression of genes in granulosa cells, which are crucial for ovulation. To achieve this objective, short-term, primary murine granulosa cell cultures were treated for 2–8 h with 1 mM 8-bromoadenosine 3′,5′-cAMP to mimic the LH surge and/or 100 ng/ml IGF1. While cAMP induced significant increases in the expression of important ovulatory response genes including amphiregulin (Areg), epiregulin (Ereg), betacellulin (Btc), or interleukin 6 (Il6), IGF1 alone had no effect. However, co-treatment of cells with IGF1 and cAMP had a synergistic effect on Areg, Ereg, Btc, and Il6 mRNA abundance. Pretreatment of granulosa cells with the MEK1/2 inhibitor U0126 demonstrated that cAMP-dependent increases in Areg, Ereg, Btc, and Il6 were mediated by extracellular regulated kinase 1/2 phosphorylation. However, western blot analyses coupled with pretreatment of cells with the PI3K inhibitor LY294002 indicated that the synergistic effect of cAMP and IGF1 on transcript levels was due in part to cooperative increases in Akt phosphorylation. Western blot analyses also demonstrated that IGF1 and the combined treatment of cAMP and IGF1 decreased NF-κB p65 phosphorylation and increased NF-κB p52 levels. Together, these data indicate that IGF1 may amplify cAMP-dependent regulation of ovulatory response gene expression above an important threshold level and therefore represents a novel role for IGF1 during ovulation.