THU644 Gene-by-PCOS Interactions In Cardio-metabolic Traits On A Panel Of Genetically Diverse Strains Of Mice

Abstract

Abstract Disclosure: L.M. Velez: None. C. Johnson: None. I. Yoon: None. K. Aberra: None. R. Feng: None. I. Tamburini: None. N. Ujagar: None. M. Nelson: None. A. Senior: None. D. Ashbrook: None. R. Williams: None. D. Nicholas: None. M. Seldin: None. Polycystic ovary syndrome (PCOS) is one of the most common female endocrinopathies, and is frequently associated with major metabolic abnormalities such as insulin resistance, cardiovascular disease, and obesity. Despite the prevalence of PCOS, the genetic architecture and subsequent interactions with metabolic and reproductive variables remain relatively unexplored. Here, our aim was to define genetic interactions which mediate susceptibility to PCOS using a panel of genetically diverse strains of female mice. Leveraging accessibility in mice and defined environmental variables, we aimed to interrogate major metabolic traits, to gain mechanistic insights into the pathophysiologic outcomes associated with PCOS. Specifically, our PCOS model involved a subcutaneous (sc) implantation of an aromatase inhibitor (Letrozole)-containing pellet (or matched controls) for 6 weeks, thus promoting increased levels of circulating androgen levels. In sum, 23 strains of female mice under normal or PCOS conditions (n = 180) were subjected to in vivo echocardiographic analysis of heart function, glucose tolerance tests (GTT), body weight and composition, estrous cycle determination, and terminal assessment of testosterone (T) levels in serum. Globally, T levels, ejection fraction (EF), fat mass (FM), and AUC from GTT were increased in PCOS vs CTRLs; however, genetics remained a strong determinant: we observed substantial variation in physiologic responses to PCOS depending on the genetic background. For example, comparing PCOS vs CTRLs, some strains showed high vs low T levels and consequent insulin resistance (i.e. strains BXD124, BXD60, 129X1/SvJ, A/J, DBA/2J), increased FM (i.e.,BXD124, 129X1/SvJ, BXD48a, C3H/Hej) or increased EF (i.e., DBA/2J, NOD, BXD79), while other genetic backgrounds showed changes in insulin resistance (AUC) (i.e.,BXD75, BXD73, AKR/J), FM (i.e.,BXD73, BXD77, BXD125) or EF (i.e.,BXD77, BXD73b) without changes in T, or high vs low T with no change in insulin resistance (i.e.,BXD125, C57BL/6J), FM (i.e., A/J, BALBc/j, DBA/2J) or EF (i.e.,129, BXD124, BXD60). As part of this ongoing project we intend to categorize degrees of metabolic and reproductive abnormalities of the PCOS models and relate to human PCOS phenotypes, and, along with integration with –omics analysis of diverse key tissues, survey the genetics of inter-tissue signaling as a result of PCOS.In summary, we present a framework to study genetic differences in the context of PCOS and here we showed that the effect of a PCOS-model on key reproductive and metabolic traits is heavily modulated by the genetic background, thus highlighting future directions for the assessment of gene by PCOS interactions. Presentation: Thursday, June 15, 2023