A Transcriptional and Cellular Exploration of Obesity and Type-II Diabetes in Human Adipose Tissues [scRNA-seq]

Obesity is tightly linked to metabolic disorders such as type-II diabetes (T2D), though a sub-population of individuals with obesity do not present with such morbidities. The biological factors conferring T2D vulnerability remain incompletely understood. We recruited 58 individuals with obesity with or without a clinical diagnosis of T2D (Ob+T2D and Ob). We profiled paired samples of omental and subcutaneous adipose by scRNA-seq (n=10), flow cytometry under basal and stimulated conditions (n=42), and histology (n=17). Flow cytometry and chemokine quantification were also performed in paired whole blood. We identified depot-specific reprogramming of the omental non-haematopoietic compartment in Ob+T2D, centred on mesothelial, endothelial, innate T cells, and macrophages. Mesothelial and IGFBP2+ cells exhibited a fibrotic, EMT-like phenotype, while omental endothelial cells exhibited a lipid-overload, inflammatory, antigen presentation profile in T2D. Omental and subcutaneous adipose innate T cells exhibited an inflammatory profile akin to that identified in mice to temper macrophage inflammation during obesity. These findings reveal new insights into the pathophysiology of T2D in adipose tissue and identify compensatory networks within the tissues that could be exploited by targeted therapeutics.