[Metabolic dysregulation in adipose tissue macrophages and its link to obesity and obesity with type 2 diabetes based...

Objective: To identify the association between metabolic and functional dysregulation of adipose macrophages in obesity and type 2 diabetes. Methods: Major cell types of adipose tissue were dissected with canonical markers from the single-cell sequencing dataset HRA002549, which profiled the stromal vascular fraction from 2 healthy controls (2 females), 3 obese patients (1 female), and 3 obese patients with type 2 diabetes (1 female). Subtypes of macrophages were then discerned by unsupervised clustering and functional annotation. Single-cell level metabolic activities were profiled with a flux-balance algorithm. The alternation of metabolic activity in obesity was identified with metabolic differential and enrichment analysis. The associations between metabolic and functional alternation were identified with Spearman's correlation tests. Results: A total of four subpopulations of adipose tissue macrophages with different functional characteristics were identified. The distribution of each macrophage subpopulation in adipose tissue differed between the healthy control group, the obese group, and the obese group with type 2 diabetes (all P0.05). Differential analysis identified the activation of pro-inflammatory and metabolic-sensing pathways including phosphatidylinositol 3-kinase/protein kinase B (PI3K-Akt), Janus kinase/signal transducer and activator of transcription (JAK-STAT) and AMP-activated protein kinase (AMPK) pathways under both obese and type 2 diabetic conditions. Differential analysis of metabolic activities revealed significant alternations in metabolism profiles of adipose macrophages in obese and obese with type 2 diabetes groups, including decreased fatty acid synthesis, increased fatty acid oxidation, arachidonic acid synthesis, and elevated lysine metabolism activity. Correlation analysis identified significant correlations between macrophage functional dysregulation and disruption in fatty acid oxidation and branched-chain amino acid metabolism (all P0.05). Conclusion: In obesity and obesity with type 2 diabetes, adipose macrophages exhibit systematic metabolic dysregulation, with abnormal activation of reactions in branched-chain amino acid metabolism and fatty acid oxidation.