OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance
Yang Y, Li X, Luan HH, Zhang B, Zhang K, Nam JH, Li Z, Fu M, Munk A, Zhang D, Wang S, Liu Y, Albuquerque JP, Ong Q, Li R, Wang Q, Robert ME, Perry RJ, Chung D, Shulman GI, Yang X (2020) PNAS first published June 29, 2020 doi.org/10.1073/pnas.1916121117
Abstract:
SignificanceOvernutrition leads to metabolic disorders including obesity and diabetes. Studies have shown that enhanced inflammation is an essential player in the progression of metabolic diseases. However, how immune cells sense nutritional status and contribute to whole-body metabolism are largely unknown.
Protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification is thought to be a metabolic sensor that modulates cell signaling. Here, we show that overnutrition stimulates O-GlcNAc signaling in macrophages. O-GlcNAc signaling suppresses macrophage proinflammatory activation and protects against diet-induced obesity and metabolic dysfunction.
This study uncovers O-GlcNAc signaling as a homeostatic regulator at the interface of inflammation and metabolism and suggests that O-GlcNAc signaling may serve as a therapeutic target for obesity, diabetes, and other immune-related diseases.
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 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.
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