SUN-564 Cd1a Mediated Inflammation Overrides Sex-based Protection To Promote Metabolic Dysfunction In Female Mice

Abstract Disclosure: K.D. Wiggins: None. J.A. Ayala Angulo: None. Z. Del Mundo: None. N. Ujagar: None. D. Nicholas: None. Type 2 Diabetes (T2D) is a global health crisis affecting hundreds of millions of people worldwide, with women accounting for a significant portion. Despite substantial contributions from mouse models, particularly the diet-induced obese (DIO) model using high-fat diets, a complete cure for T2D remains elusive. Current models fail to fully recapitulate human disease pathogenesis, especially in terms of inflammation and gender differences, limiting the translational potential. While human T2D is associated with Th17 inflammation, mouse models predominantly develop Th1 inflammation. Our study introduces a novel female mouse model expressing CD1a, a lipid antigen presenting molecule involved in human Th17 responses. Female CD1a expressing mice fed a high fat diet for 24 weeks gained 5 grams more weight and showed a one-fold increase in fat to lean mass ratio compared to C57BL/6J controls. By week 16, CD1a mice exhibited elevated fasting blood glucose that continued to rise, while glucose levels in controls remained stable. Glucose tolerance tests revealed significantly higher area of the curve values in CD1a mice, indicating profound glucose intolerance. Although differences in insulin sensitivity were not statistically significant, CD1a mice trended toward higher, suggesting worsening metabolic dysfunction. Histological analysis showed heightened immune infiltration in gonadal fat tissue, while flow cytometry revealed an exclusive and dominant IL-17A+CD4+ T helper cell phenotype, completely absent in DIO C57BL/6J controls. By capturing human Th17 inflammation utilizing CD1a presentation, we show evidence of overcoming the female resistance barrier in DIO mouse models, offering a transformative platform for studying sex specific mechanisms of T2D. This model not only fills a critical gap in diabetes research but also highlights the urgency of developing gender responsive therapies to address this prevalent and pervasive global health crisis. Presentation: Sunday, July 13, 2025