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

• Published in: Cell metabolism Vol. 30; no. 3; pp. 447 - 461.e5
• Main Authors: Nicholas, Dequina A., Proctor, Elizabeth A., Agrawal, Madhur, Belkina, Anna C., Van Nostrand, Stephen C., Panneerseelan-Bharath, Leena, Jones, Albert R., Raval, Forum, Ip, Blanche C., Zhu, Min, Cacicedo, Jose M., Habib, Chloe, Sainz-Rueda, Nestor, Persky, Leah, Sullivan, Patrick G., Corkey, Barbara E., Apovian, Caroline M., Kern, Philip A., Lauffenburger, Douglas A., Nikolajczyk, Barbara S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03-09-2019
• Subjects: Adult; Aged; Carnitine - analogs & derivatives; Carnitine - metabolism; Carnitine O-Palmitoyltransferase - genetics; Cells, Cultured; Cross-Sectional Studies; Cytokines - metabolism; Diabetes Mellitus, Type 2 - metabolism; fatty acid oxidation; Fatty Acids - metabolism; Female; Gene Knockdown Techniques; glycolysis; Glycolysis - genetics; Humans; immunometabolism; Inflammation - metabolism; Lymphocyte Activation - immunology; Male; Membrane Transport Proteins - genetics; metaflammation; Middle Aged; Obesity - metabolism; Oxidation-Reduction; Th17 Cells - immunology; Transfection; Young Adult; metaflammation; fatty acid oxidation; immunometabolism; glycolysis
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2019.07.004

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 mitochondrial 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, β oxidation blockade or CACT knockdown in T cells from lean subjects to mimic characteristics of T2D causes cells to utilize 16C-fatty acylcarnitine to support Th17 cytokines. These data show long-chain acylcarnitine combines with compromised β oxidation to promote disease-predictive inflammation in human T2D.
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•Glycolysis in T cells/PBMCs from T2D subjects fails to stimulate T2D inflammation•T cells from T2D subjects have altered mitochondria•Altered import or oxidation of fatty acids activates inflammation in healthy cells•Mitochondrial changes combine with fatty acid metabolites to activate inflammation
Although glycolysis generally fuels inflammation, Nicholas, Proctor, and Agrawal et al. report that PBMCs from subjects with type 2 diabetes use a different mechanism to support chronic inflammation largely independent of fuel utilization. Loss- and gain-of-function experiments in cells from healthy subjects show mitochondrial alterations combine with increases in fatty acid metabolites to drive chronic T2D-like inflammation.