46-OR: Palmitic Acid Coordinates Impaired Adipose Tissue ICOShigh Treg Immunosuppression and Systemic Metabolic Disturbance during Obesity

Treg cells serve essential roles in immunological tolerance and tissue homeostasis remodeling. However, the precise mechanism by which Treg cells specifically regulate the immune response in adipose tissue during obesity remains largely unexplored. Here we show that Foxp3, the master transcription factor of Treg cells, is negatively regulated by CREBZF, which mediates the immunosuppression of Treg cells in visceral adipose Treg cells. We found that CREBZF was dramatically induced in Treg cells from visceral adipose tissue (VAT) of obese subjects and epididymal adipose tissue (eWAT) of mice. Interestingly, palmitic acid (PA), but not insulin or lactate, promotes the expression of CREBZF in Treg cells. Treg cell-specific CREBZF deficiency significantly attenuated high-fat high sucrose (HFHS) diet-induced obesity, hyperglycemia and insulin resistance. Moreover, CREBZF deletion exhibited ameliorated inflammation and hypertrophic morphology in eWAT and enhanced systemic energy expenditure. Furthermore, obesity induced Treg cells loss, impaired Foxp3 expression and IL-10 production were reversed by CREBZF deletion in Treg cells from eWAT of mice, suggesting a key role of CREBZF in regulating the stability and immunosuppression of Treg cells. Mechanistically, single-cell transcriptomic analysis has identified a ICOShigh Treg cell subset, which is distinct from previously characterized adipose Treg cell populations and exhibited enhanced immunosuppressive function and more accumulation in CREBZF-deficient mice. Importantly, expression levels of CREBZF are negatively correlated with Foxp3 in VAT of obese human and eWAT of mice. Collectively, these studies uncover a specific adipose ICOShigh Treg subpopulation, which plays crucial roles in palmitic acid-induced immunosuppression restriction and systemic metabolic disorders.