1487-P: Obesity Induces Metabolic Dysfunction in Adipose Tissue T-Cells

Individuals with obesity or diabetes often have impaired immune responses to infection despite elevated systemic inflammation. T cells are essential for controlling adaptive immune responses, and during chronic obesity, adipose tissue T (ATT) cells display features of exhaustion, which are characterized by impaired activation and cytokine production. How ATT cell exhaustion is generated is not well understood. We hypothesized that mitochondrial dysfunction leads to the loss of effector function in obese ATT cells. Flow cytometry-based assays were used to evaluate the effect of long-term diet-induced obesity in mouse adipose tissue. Mitochondrial dyes in conjunction with cell surface markers revealed dramatic decreases in mitochondrial mass and membrane potential by both CD8+ and CD4+ T cell populations in white adipose tissue, but not in the spleen, as early as 2 weeks of high-fat diet feeding. In addition, we performed SCENITH, an assay that determines the bioenergetic profiles of cells based on the high energetic cost of protein translation. Results from this assay showed that obese ATT cells have reduced glycolytic and mitochondrial metabolism, suggesting they have diminished metabolic activity overall. We have previously discovered that macrophages in adipose tissue of diabetic humans have induced genes associated with glucocorticoid (GC) exposure, which is in line with literature demonstrating elevated GC levels in obese adipose tissue. Our preliminary data suggest that GC receptor signaling may contribute to mitochondrial impairment, as treatment of the white adipose stromal vascular fraction with synthetic GC reduces mitochondrial mass and membrane potential in ATT cells. Overall, we have observed ATT cells experience loss of mitochondria and metabolic activity with diet-induced obesity and GC treatment. These findings will help expand understanding of the role of ATT cells in metabolic health and immunity. Disclosure H. Guak: None. C.N. Lumeng: None. Funding American Diabetes Association (4-24-PDF-81); National Institutes of Health (R01DK090262); National Institutes of Health (T32DK101357)