SAT485 Knockout Of TLR4 Alters Reproductive And Metabolic Outcomes In Mouse Model Of Polycystic Ovary Syndrome

Abstract

Abstract Disclosure: K.D. Wiggins: None. G. De Robles: None. J. De La Torre: None. D. Nicholas: None. Title: Knockout of TLR4 Alters Reproductive and Metabolic Outcomes in Mouse Model of Polycystic Ovary Syndrome. Polycystic Ovarian Syndrome (PCOS) is a heterogeneous endocrine disorder often characterized by reproductive and metabolic dysfunction. Prior literature has found a correlation between PCOS and chronic low-grade inflammation. However, it remains unknown if inflammation plays a causal role in the pathology of PCOS. In women with PCOS, serum levels of Lipopolysaccharides (LPS), a ligand for Toll-like receptor 4 (TLR4), are elevated. The binding of LPS to TLR4 leads to the production of pro-inflammatory cytokines, which can result in low-grade inflammation and metabolic syndrome, a prominent feature of PCOS. Given the role of TLR4, we hypothesize that the induced inflammatory environment mediates the development and pathogenesis of PCOS. To test this hypothesis, we subcutaneously implanted a nonsteroidal aromatase inhibitor, Letrozole, in TLR4 knockout mice (TLR4KO) and C57BL/6J (wild type) mice. Following five weeks of letrozole treatment, wild type mice failed to cycle, whereas TLR4KO mice were able to enter each estrous cycle phase. Furthermore, in contrast to wild type mice, TLR4KO mice display normalized Luteinizing Hormone (LH) levels with increased levels of Follicle Stimulating Hormone (FSH). We also characterized how inflammation influences the metabolic phenotypes of PCOS. Our results reveal that the deletion of TLR4 reduces weight gain and improves glucose intolerance. Moreover, we show that the development of insulin resistance in letrozole-treated TLR4KO mice was independent of other metabolic outcomes. Our study demonstrates that disruption of this pro-inflammatory pathway mediates the development of reproductive and metabolic phenotypes. Thus, research on the modulation of chronic low-grade inflammation may lead to the development of new therapeutics for PCOS patients. Keywords: Reproduction, Inflammation, Polycystic Ovary Syndrome, Presentation Date: Saturday, June 17, 2023