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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Carnitine / analogs & derivatives
  • Carnitine / metabolism
  • Carnitine O-Palmitoyltransferase / genetics
  • Cells, Cultured
  • Cross-Sectional Studies
  • Cytokines / metabolism
  • Diabetes Mellitus, Type 2 / metabolism*
  • Fatty Acids / metabolism*
  • Female
  • Gene Knockdown Techniques
  • Glycolysis / genetics
  • Humans
  • Inflammation / metabolism
  • Lymphocyte Activation / immunology*
  • Male
  • Membrane Transport Proteins / genetics
  • Middle Aged
  • Obesity / metabolism
  • Oxidation-Reduction
  • Th17 Cells / immunology*
  • Transfection
  • Young Adult

Substances

  • Cytokines
  • Fatty Acids
  • Membrane Transport Proteins
  • acylcarnitine
  • SLC25A20 protein, human
  • CPT1A protein, human
  • Carnitine O-Palmitoyltransferase
  • Carnitine