期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：28
页码：16616-16625
DOI：10.1073/pnas.1916121117
出版社：The National Academy of Sciences of the United States of America
摘要：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 O -linked β- N -acetylglucosamine ( O -GlcNAc) signaling in suppressing macrophage proinflammatory activation and preventing diet-induced metabolic dysfunction. Overnutrition stimulates an increase in O -GlcNAc signaling in macrophages. O -GlcNAc signaling is down-regulated during macrophage proinflammatory activation. Suppressing O -GlcNAc signaling by O -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) O -GlcNAcylation and suppressing S6K1 phosphorylation and mTORC1 signaling. These findings thus identify macrophage O -GlcNAc signaling as a homeostatic mechanism maintaining whole-body metabolism under overnutrition.
