OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance.

Abstract

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 unexpected role of nutrient-sensing <i>O</i>-linked β-<i>N</i>-acetylglucosamine (<i>O</i>-GlcNAc) signaling in suppressing macrophage proinflammatory activation and preventing diet-induced metabolic dysfunction. Overnutrition stimulates an increase in <i>O</i>-GlcNAc signaling in macrophages. <i>O</i>-GlcNAc signaling is down-regulated during macrophage proinflammatory activation. Suppressing <i>O</i>-GlcNAc signaling by <i>O</i>-GlcNAc transferase (OGT) knockout enhances macrophage proinflammatory polarization, promotes adipose tissue inflammation and lipolysis, increases lipid accumulation in peripheral tissues, and exacerbates tissue-specific and whole-body insulin resistance in high-fat-diet-induced obese mice. OGT inhibits macrophage proinflammatory activation by catalyzing ribosomal protein S6 kinase beta-1 (S6K1) <i>O</i>-GlcNAcylation and suppressing S6K1 phosphorylation and mTORC1 signaling. These findings thus identify macrophage <i>O</i>-GlcNAc signaling as a homeostatic mechanism maintaining whole-body metabolism under overnutrition.