Fatty Acid Metabolites Combine with Reduced β Oxidation to Activate Th17 Inflammation in Human Type 2 Diabetes

Mechanisms that regulate metabolites and downstream energy generation are key determinants of T cell cytokine production, but the processes underlying the Th17 profile that predicts the metabolic status of people with obesity are untested. Th17 function requires fatty acid uptake, and our new data show that blockade of CPT1A inhibits Th17-associated cytokine production by cells from people with type 2 diabetes (T2D). A low CACT:CPT1A ratio in immune cells from T2D subjects indicates altered mitochondria! function and coincides with the preference of these cells to generate ATP through glycolysis rather than fatty acid oxidation. However, glycolysis was not critical for Th17 cytokines. Instead, beta oxidation blockade or CACT knockdown in T cells from lean subjects to mimic characteristics of T2D causes cells to utilize C-16-fatty acylcarnitine to support Th17 cytokines. These data show long-chain acylcarnitine combines with compromised beta oxidation to promote disease-predictive inflammation in human T2D.