Investigating EV as a Mechanism Mediating the Cellular Effects of Adiponectin

Abstract

Adiponectin provides systemic protection in cardiometabolic health, yet the mechanisms underlying its tissue-specific effects remain poorly understood due to its functional complexity. Therapeutic development is further hindered by difficulties in generating stable, bioactive forms with sustained and targeted activity. Emerging evidence highlights extracellular vesicles (EV) as mediators of inter-organ communication and promising vehicles for the development of new therapeutics. This thesis investigates the cardioprotective role of plasma or adipocyte-derived EV isolated from mice that were treated with or without the adiponectin-mimetic peptide ALY688. EV isolated from adipocytes after mice were treated with ALY688, versus control, enhanced autophagic flux plus reduced reactive oxygen species, caspase-3/7 activation, and cell death in H9c2 cardiomyoblasts under hypoxia ± reoxygenation. EV were also isolated from HEK cells genetically modified to overexpress adiponectin and compared to wild-type cells. These EV improved insulin sensitivity in L6 skeletal muscle cells. This study identifies a previously uncharacterized role of adiponectin in modulating EV biogenesis and cargo to elicit cardioprotective and beneficial metabolic effects. This demonstrates the potential of EV-based adiponectin therapeutics as a new strategy for treating cardiometabolic diseases.