Abstract
OBJECTIVE: Weight loss improves insulin sensitivity in people with obesity and type 2 diabetes. However, the mechanisms responsible for this effect are unclear. We hypothesized that alterations in adipose tissue biology and adipose tissue-related factors in plasma are involved in mediating the systemic metabolic benefits of weight loss. RESEARCH DESIGN AND METHODS: We evaluated blood and adipose tissue samples obtained from 10 adults with obesity and type 2 diabetes before and after marked (16-20%) weight loss and >50% increase in whole-body insulin sensitivity, assessed by using the hyperinsulinemic-euglycemic clamp procedure. RESULTS: Weight loss 1) decreased adipose tissue expression of genes related to extracellular matrix remodeling; 2) decreased adipose tissue expression of SERPINE 1, which encodes plasminogen activator inhibitor 1 (PAI-1); 3) did not decrease adipose tissue immune cell content or expression of genes involved in inflammation; 4) decreased adipose tissue ceramide content; 5) decreased plasma PAI-1 and leptin concentrations and increased plasma high-molecular weight (HMW) adiponectin; and 6) decreased plasma small extracellular vesicle (sEV) concentration and the sEV content of microRNAs proposed to inhibit insulin action, and completely reversed the inhibitory effect of plasma sEVs on insulin signaling in myotubes. CONCLUSIONS: These findings suggest that weight loss increases insulin sensitivity in people with obesity and type 2 diabetes by modifying adipose tissue biology, with concomitant alterations in circulating PAI-1, leptin, HMW adiponectin, and sEV microRNAs.