Circulating Adipocyte-Derived Exosomal MicroRNAs Associated with Decreased Insulin Resistance After Gastric Bypass

Objective: Exosomes from obese adipose contain dysregulated microRNAs linked to insulin signaling, as compared with lean controls, providing a direct connection between adiposity and insulin resistance. This study tested the hypotheses that gastric bypass surgery and its subsequent weight loss would normalize adipocyte-derived exosomal microRNAs associated with insulin signaling and the associated metabolome related to glucose homeostasis. Methods: African American female subjects with obesity (N = 6; age: 38.5 +/- 6.8 years; BMI: 51.26 +/- 8.8 kg/m(2)) were tested before and 1 year after surgery. Insulin resistance (HOMA), serum metabolomics, and global microRNA profiles of circulating adipocyte-derived exosomes were evaluated via ANCOVA and correlational analyses. Results: One year postsurgery, patients showed decreased BMI (-18.6 +/- 5.1 kg/m(2); P < 0.001), ameliorated insulin resistance (HOMA: 1.94 +/- 0.6 presurgery, 0.49 +/- 0.1 postsurgery; P < 0.001), and altered metabolites including branched chain amino acids (BCAA). Biological pathway analysis of predicted mRNA targets of 168 surgery-responsive microRNAs (P < 0.05) identified the insulin signaling pathway (P = 1.27E2-0; 52/138 elements), among others, in the data set. The insulin signaling pathway was also a target of 10 microRNAs correlated to changes in HOMA (P < 0.05; r > 0.4), and 48 microRNAs correlated to changes in BCAA levels. Conclusions: These data indicate that circulating adipocyte-derived exosomes are modified following gastric bypass surgery and correlate to improved postsurgery insulin resistance.