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

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 beta-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.

Automated summary

Obesity is associated with elevated fatty acid beta-oxidation (FAO) and CD4(+) T cell hyperactivation, leading to enhanced induction of inflammation. The FAO rate-limiting enzyme Cpt1a stabilizes mitochondrial E3 ubiquitin ligase Goliath, promoting glycolysis and hyperactivation of CD4(+) T cells in obesity. Inhibiting the FAO-glycolysis metabolic axis with the Goliath inhibitor DC-Gonib32 reduces inflammation in obese mice.