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.

增强的炎症被认为是导致营养过剩引起的代谢紊乱的原因。营养通量也已被证明是免疫细胞激活所必需的。在这里，我们报告了营养感应O-连接的 β- N-乙酰氨基葡萄糖( O- GlcNAc) 信号在抑制巨噬细胞促炎激活和预防饮食引起的代谢功能障碍中的意外作用。营养过剩会刺激巨噬细胞中O- GlcNAc 信号的增加。O -GlcNAc 信号在巨噬细胞促炎激活过程中被下调。通过O抑制O -GlcNAc 信号传导-GlcNAc 转移酶 (OGT) 敲除增强巨噬细胞促炎极化，促进脂肪组织炎症和脂肪分解，增加外周组织中的脂质积累，并加剧高脂肪饮食诱导的肥胖小鼠的组织特异性和全身胰岛素抵抗。OGT 通过催化核糖体蛋白 S6 激酶 beta-1 (S6K1) O -GlcNAcylation 并抑制 S6K1 磷酸化和 mTORC1 信号传导来抑制巨噬细胞促炎激活。因此，这些发现将巨噬细胞O- GlcNAc 信号确定为一种在营养过剩下维持全身代谢的稳态机制。