Exploring Organ-Specific Extracellular Vesicles in Metabolic Improvements Following Bariatric Surgery in Adolescents with Obesity

Aims/hypothesis Vertical sleeve gastrectomy (VSG) leads to significant metabolic improvements, though the underlying molecular mechanisms are not yet fully understood. Emerging evidence suggests that small extracellular vesicles (sEVs) contribute to metabolic improvements post-VSG; however, it is still unclear which organ-specific sEV correlate with various metabolic parameters and how they exert these effects. The study aimed to establish the role of organ-specific sEVs in the metabolic improvements associated with VSG. Methods Demographic, anthropometric, and blood samples were collected pre-VSG and 3- and 6-month post-VSG in adolescents with obesity. Blood samples were utilized to measure metabolic parameters and to isolate sEVs. sEV RNAs were analyzed via small RNA sequencing then bioinformatics analyses. Results A significant reduction in mRNA cargo from liver-specific genes was observed post- VSG, whereas adipose tissue- or skeletal muscle-specific genes showed no such reduction. Liver-derived RNA correlated with BMI, leptin, and resistin, while adipose-derived RNA correlated with leptin. Analysis of delta values (post-minus pre-surgery) revealed that adipose-derived RNA cargo correlated with markers of liver damage and HOMA-IR, whereas liver-derived RNA cargo correlated with BCAAs. Conclusions VSG modulates the EV system in the liver and adipose tissue. Liver-derived sEVs appear to regulate adipose metabolism, while adipose-derived sEVs are associated with liver function, suggesting a dynamic crosstalk between these tissues through sEVs that shapes systemic metabolic outcomes. Research in Context What is already known about this subject? - Vertical sleeve gastrectomy (VSG) is the most performed bariatric surgery, leading to significant metabolic improvements. - Small extracellular vesicles (sEVs) and their RNA cargo play a crucial role in metabolic regulation. - Levels of branched-chain amino acids (BCAAs), which are known metabolic regulators, decrease following bariatric surgery. What is the key question? - How do sEVs, BCAA and other metabolic molecules interact to drive the significant metabolic improvements observed after VSG? What are the new findings? - The levels of liver-specific RNA cargo in sEVs decrease after VSG and are correlated with BMI and leptin levels at 6 months post-surgery, suggesting a potential role for liver-specific RNA cargo in the metabolic benefits associated with VSG. - Changes in BCAA levels from baseline to 6 months post-surgery correlate with changes in liver-specific RNA cargo in sEVs, indicating liver-specific RNA cargo in sEVs may influence metabolic parameters through BCAA modulation. - Changes in the level of adipose-specific RNA cargo in sEVs from baseline to 6 month post-surgery correlate with changes HOMA-IR and ALT levels. How might this impact on clinical practice in the foreseeable future? The study identifies liver- and adipose-derived sEV RNA cargo as potential targets for non-invasive therapies that could replicate the metabolic benefits of VSG. While further investigation is needed, these findings suggest a tentative alternative for adolescents facing obesity who may be ineligible or reluctant to undergo bariatric surgery.