MON-586 Cd1a-mediated Inflammation Contributes To T2d Pathology And Metabolic Homeostasis In Dio Mouse Model

Abstract Disclosure: J.A. Ayala Angulo: None. M.L. Lopez: None. K.D. Wiggins: None. C. Nguyen: None. Z. Del Mundo: None. N. Ujagar: None. G. De Robles: None. G. Pacheco Sanchez: None. J. Arriola: None. H. Aichlmayr: None. H. Choi: None. J. Ross: None. M. Seldin: None. C. Jang: None. D. Nicholas: None. Type 2 Diabetes (T2D) remains a global health crisis that is poorly modeled in mice, hindering a mechanistic understanding of the disease. The diet induced obese (DIO) mouse model does not replicate human T2D hyperglycemia, pancreatic dysfunction, and related adipose inflammation. While literature supports evidence of antigen-specific Th17 T cell function in human T2D, no specific protein antigen has been identified. CD1a, a lipid antigen presentation receptor linked to Th17 responses in humans, may drive T2D inflammation due to hyperlipidemia, and contribute to T2D progression through increased inflammatory burden. Using hCD1a expressing mice on a High Fat Diet (HFD), we show disrupted adipose tissue homeostasis including elevated immune cell infiltration as well as proportional fat mass relative to WT HFD controls. Further, CD1a expression with a HFD impairs the pancreatic functions characterized by a reduction in fasting insulin and c-peptide secretion. Additionally, CD1a mice on a HFD showed higher fasting blood glucose than WT controls after 25 weeks on diet, suggesting impaired glucose regulation. Additionally, CD1a HFD mice also display lowered fasting levels of GIP-1 relative to WT HFD mice. Metabolic chamber data show CD1a mice have a drastic shift from glucose to lipid oxidation when placed on a HFD relative to LFD baseline implying a major role for CD1a-mediated immunity in metabolic homeostasis. Together these data not only suggest lipid induced inflammation as contributors to T2D phenotypes but also a contributing driver of key T2D pathologies. These data present a novel mechanism of obesity induced inflammation through lipids as antigens as well as a novel T2D mouse model. Presentation: Monday, July 14, 2025