OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance

Enhanced inflammation is believed to contribute to overnutrition-induced metabolic disturbance. Nutrient flux has also been shown to be essential for immune cell activation. Here, we report an un-expected role of nutrient-sensing O-linked beta-N-acetylglucosamine (O-GlcNAc) signaling in suppressing macrophage proinflammatory ac-tivation and preventing diet-induced metabolic dysfunction. Overnu-trition stimulates an increase in O-GlcNAc signaling in macrophages. O-GlcNAc signaling is down-regulated during macrophage proinflam-matory activation. Suppressing O-GlcNAc signaling by O-GlcNAc transferase (OGT) knockout enhances macrophage proinflammatory polarization, promotes adipose tissue inflammation and lipolysis, in-creases lipid accumulation in peripheral tissues, and exacerbates tissue-specific and whole-body insulin resistance in high-fat-diet -in-duced obese mice. OGT inhibits macrophage proinflammatory activa-tion by catalyzing ribosomal protein S6 kinase beta-1 (S6K1) O-GlcNAcylation and suppressing S6K1 phosphorylation and mTORC1 signaling. These findings thus identify macrophage O-GlcNAc signal-ing as a homeostatic mechanism maintaining whole-body metabolism under overnutrition.