Adipose Tissue-Derived Small Extracellular Vesicles in Plasma Reveal Molecular Circuitries Underlying Glucose Intolerance.

Abstract

Glucose tolerance (GT) is a major effector for adipose tissue (AT) remodeling in obesity, yet its molecular mechanisms remain incompletely defined. We hypothesized that the biophysical and molecular profiles of AT-derived small extracellular vesicles (sEV^AT) change in response to glucose availability and differ by GT status. sEV^AT were isolated from plasma of individuals with normal GT (NGT) and impaired GT (IGT) (n = 5/group) at fasting (0 h) and 1 h post glucose challenge during oral glucose tolerance test (OGTT). sEV^AT were characterized for size, concentration, surface expression of insulin receptor-α (INSRα), proteome, and insulin signaling-related miRNAs. C2C12 myotubes were treated with sEV^AT for 48 h, followed by quantification of 84 insulin signaling-related genes. The size and concentration of sEV^AT did not differ between groups. At fasting, INSRα expression on sEV^AT was comparable; however, groups exhibited opposite directional changes at 1-h OGTT. LC-MS/MS identified significant proteomic differences between NGT and IGT sEV^AT. miR-27a-5p and miR-145a-5p levels in sEV^AT also differed significantly by GT status. Notably, treatment with sEV^AT (IGT-0 h) significantly downregulated insulin signaling-related genes in myotubes. Distinct molecular signatures in sEV^AT offer a unique insight into AT dysfunction during IGT and offer novel diagnostic and therapeutic targets.