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Cell Metab. 2019 Sep 3;30(3):447-461.e5. doi: 10.1016/j.cmet.2019.07.004. Epub 2019 Aug 1.

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

Author information

1
Department of Microbiology, Boston University School of Medicine, Boston, MA 02118 USA.
2
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
3
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA.
4
Department of Microbiology, Boston University School of Medicine, Boston, MA 02118 USA; Department of Pathology, Boston University School of Medicine, Boston, MA 02118, USA.
5
Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
6
Department of Neuroscience, Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, USA.
7
Department of Medicine, University of Kentucky, Lexington, KY 40536, USA; Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY 40536, USA.
8
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: lauffen@mit.edu.
9
Department of Microbiology, Boston University School of Medicine, Boston, MA 02118 USA; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA; Department of Pathology, Boston University School of Medicine, Boston, MA 02118, USA; Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY 40536, USA. Electronic address: barb.nik@uky.edu.

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.

KEYWORDS:

fatty acid oxidation; glycolysis; immunometabolism; metaflammation

PMID:
31378464
DOI:
10.1016/j.cmet.2019.07.004

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