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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-sensingO-linked β-N-acetylglucosamine (O-GlcNAc) signaling in suppressing macrophage proinflammatory activation and preventing diet-induced metabolic dysfunction. Overnutrition stimulates an increase inO-GlcNAc signaling in macrophages.O-GlcNAc signaling is down-regulated during macrophage proinflammatory activation. SuppressingO-GlcNAc signaling byO-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 macrophageO-GlcNAc signaling as a homeostatic mechanism maintaining whole-body metabolism under overnutrition.

ObjectivesAsthma exacerbation, associated with many risks factors, can reflect management failure. However, little is known about how risk factors are associated with exacerbation, according to asthma severity. We aimed to investigate differences in risk factors in patients with different asthma severity and evaluate whether risk factors differed between frequent exacerbators and patients with single exacerbation.DesignNationwide population-based observational study.SettingKorean National Sample Cohort database.ParticipantsWe included 22 130 adults with asthma diagnoses more than twice (ICD-10 (International Classification of Diseases, Tenth revision) codes J45 and J46) and one prescription for asthma medication from 2010 to 2011.Outcome measuresAsthma exacerbation was defined as having a corticosteroid (CS) burst characterised by a prescription of high-dose oral CS for ≥3 days or one systemic CS injection, hospitalisation or emergency department visit.ResultsAmong severities, history of CS bursts was significantly associated with exacerbation. In mild and moderate asthma, exacerbation was significantly associated with age ≥45 years, being female, gastro-oesophageal reflux disease and chronic rhinitis. High medication possession ratio (MPR≥50%), compared with low MPR (<20%) showed adjusted ORs of 0.828 (95% CI 0.707 to 0.971) and 0.362 (0.185 to 0.708) in moderate and severe asthma, respectively. In severe asthma, compared with mild asthma, only allergic rhinitis and history of hospitalisation were strongly associated with exacerbation. When comparing frequent exacerbators to patients with single exacerbation, age ≥45 years, atopic dermatitis, anxiety and history of CS burst were significant risk factors in mild and moderate asthma, whereas no risk factors were significant in severe asthma.ConclusionsDifferent associations between risk factors and asthma exacerbations based on asthma severity suggest that patients with mild asthma require greater attention to their age and comorbidities, whereas those with severe asthma require greater attention to hospitalisation history and drug adherence.