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

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 b-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.

Chemoradiotherapy-induced ACKR2+ tumor cells drive CD8+ T cell senescence and cervical cancer recurrence

“…IF staining were performed as previously described. 49 Briefly, tissue samples were fixed in 4% paraformaldehyde and embedded in paraffin. Tissue sections on slides were incubated with primary antibody (4 °C, overnight), relevant secondary antibody (20 °C, 2 h) and DAPI (20 °C, 5 min) after antigen recovery.…”