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

Dequina A. Nicholas, Elizabeth A. Proctor, Madhur Agrawal, Anna C. Belkina, Stephen C. Van Nostrand, Leena Panneerseelan-Bharath, Albert R. Jones, Forum Raval, Blanche C. Ip, Min Zhu, Jose M. Cacicedo, Chloe Habib, Nestor Sainz-Rueda, Leah Persky, Patrick G. Sullivan, Barbara E. Corkey, Caroline M. Apovian, Philip A. Kern, Douglas A. Lauffenburger, Barbara S. Nikolajczyk

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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. 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.

Original languageEnglish (US)
Pages (from-to)447-461.e5
JournalCell Metabolism
Volume30
Issue number3
DOIs
StatePublished - Sep 3 2019

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Nicholas, D. A., Proctor, E. A., Agrawal, M., Belkina, A. C., Van Nostrand, S. C., Panneerseelan-Bharath, L., Jones, A. R., Raval, F., Ip, B. C., Zhu, M., Cacicedo, J. M., Habib, C., Sainz-Rueda, N., Persky, L., Sullivan, P. G., Corkey, B. E., Apovian, C. M., Kern, P. A., Lauffenburger, D. A., & Nikolajczyk, B. S. (2019). Fatty Acid Metabolites Combine with Reduced β Oxidation to Activate Th17 Inflammation in Human Type 2 Diabetes. Cell Metabolism, 30(3), 447-461.e5. https://doi.org/10.1016/j.cmet.2019.07.004