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

OBJECTIVE

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 (sEVAT) change in response to glucose availability and differ by GT status.

METHODS

sEVAT 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). sEVAT were characterized for size, concentration, surface expression of insulin receptor-α (INSRα), proteome, and insulin signaling-related miRNAs. C2C12 myotubes were treated with sEVAT for 48 h, followed by quantification of 84 insulin signaling-related genes.

RESULT: The size and concentration of sEVAT did not differ between groups. At fasting, INSRα expression on sEVAT was comparable; however, groups exhibited opposite directional changes at 1-h OGTT. LC-MS/MS identified significant proteomic differences between NGT and IGT sEVAT. miR-27a-5p and miR-145a-5p levels in sEVAT also differed significantly by GT status. Notably, treatment with sEVAT (IGT-0 h) significantly downregulated insulin signaling-related genes in myotubes.

CONCLUSIONS

Distinct molecular signatures in sEVAT offer a unique insight into AT dysfunction during IGT and offer novel diagnostic and therapeutic targets.