Goliath induces inflammation in obese mice by linking fatty acid β‐oxidation to glycolysis

  • Hao S
  • Zhang S
  • Ye J
  • et al.
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Abstract

Obesity is associated with metabolic disorders and chronic inflammation. However, the obesity‐associated metabolic contribution to inflammatory induction remains elusive. Here, we show that, compared with lean mice, CD4 + T cells from obese mice exhibit elevated basal levels of fatty acid β‐oxidation (FAO), which promote T cell glycolysis and thus hyperactivation, leading to enhanced induction of inflammation. Mechanistically, the FAO rate‐limiting enzyme carnitine palmitoyltransferase 1a (Cpt1a) stabilizes the mitochondrial E3 ubiquitin ligase Goliath, which mediates deubiquitination of calcineurin and thus enhances activation of NF‐AT signaling, thereby promoting glycolysis and hyperactivation of CD4 + T cells in obesity. We also report the specific GOLIATH inhibitor DC‐Gonib32, which blocks this FAO‐glycolysis metabolic axis in CD4 + T cells of obese mice and reduces the induction of inflammation. Overall, these findings establish a role of a Goliath‐bridged FAO‐glycolysis axis in mediating CD4 + T cell hyperactivation and thus inflammation in obese mice. image The mitochondrial E3 ubiquitin ligase Goliath links fatty acid β‐oxidation (FAO) to glycolysis and mediates CD4 + T cell hyperactivation and inflammation in obese mice. A FAO‐glycolysis metabolic axis in CD4 + T cells promotes inflammation in obese mice. The FAO rate‐limiting enzyme Cpt1a stabilizes Goliath in mitochondria. Obesity‐upregulated Goliath links levels of FAO to the glycolytic rate in CD4 + T cells. A GOLIATH inhibitor curtails obesity‐related inflammation by blocking the FAO‐glycolysis axis.

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APA

Hao, S., Zhang, S., Ye, J., Chen, L., Wang, Y., Pei, S., … Xiao, Y. (2023). Goliath induces inflammation in obese mice by linking fatty acid β‐oxidation to glycolysis. EMBO Reports, 24(4). https://doi.org/10.15252/embr.202356932

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