SAT-134 - Loss of oocyte proteostasis induces endocrine changes to alter ovarian and brain metabolism in mouse

The ovarian microenvironment is responsible for producing a vast secretome of endocrine molecules required for normal functioning of not only reproductive structures, but also distal organ systems. During normal operation, the oocyte directly communicates with adjacent granulosa cells (GCs) to coordinate maturation of the follicle and secretion of sex steroids, estradiol and progesterone. These hormones feed back on gonadotropins secreted from the pituitary to regulate ovulation and help maintain body-wide insulin sensitivity. During various ovarian dysfunctions such as menopause and polycystic ovary syndrome, GC-derived disruptions in the ovarian secretome can alter hormonal feedback mechanisms to trigger a wide variety of distal symptoms. For example, in perimenopausal females, loss of circulating sex steroids promote rises in gonadotropin concentrations, insulin resistance, and likely contributes to increased risks of chronic illnesses such as Alzheimer’s Disease (AD). However, it is unknown to what extent poor oocyte quality, a trait shared between females with both aging and infertility conditions, could potentially impact organ function and systemic aging through endocrine means. Our lab has developed a novel model to study the systemic importance of oocyte quality by conditionally deleting a master regulator of proteostasis, Ubiquitin C-terminal Hydrolase L1 (Uchl1), from the oocytes of female mice (“cKO”). Our results garnered via quantitative proteomics have shown that in a reproductively young timepoint, just loss of oocyte quality is sufficient to induce compensatory fatty acid metabolism (p= .04) in GCs reminiscent of insulin resistance, and significantly alter circulating levels of gonadotropins (p=.02, .05). In the brains of reproductively mature cKO mice, the hypothalamus displays significant shifts to fatty acid metabolism (p=.004) while the hippocampus, a significantly altered region in AD, shows a metabolically-induced shift to pentose phosphate pathway activity (p= .01). This research is the first of its kind to show that a loss of oocyte quality is sufficient to induce endocrine dyscrasias sufficient to stress sensitive brain regions, and highlights the need for further research into the functionality of the ovarian secretome as a regulator of whole-body health. Females with poor oocyte quality due to menopause or infertility conditions could potentially improve their systemic health by targeting hormone alterations, insulin sensitizers or therapies aimed at protecting ovarian tissues.

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