Platycodon grandiflorus-derived exosome-like nanovesicles drive AMPK-dependent glycolytic beige remodeling to ameliorate obesity

Abstract

Obesity is a pandemic with limited therapeutic options. Recent pharmacotherapies are constrained by tolerability, durability, accessibility, and incomplete resolution of adipose tissue dysfunction. Plant-derived exosome-like nanovesicles (ELNs) provide a natural nanoscale therapeutic platform. However, their anti-obesity effects and underlying mechanisms remain unexplored. In the present study, we investigated whether ELNs from Platycodon grandiflorus roots (P-ELNs) can mitigate obesity. P-ELNs were isolated, characterized and evaluated in high-fat diet-induced and genetic (db/db) obesity models. Analyses integrating transcriptomic profiling and metabolic flux assessment were performed to define the P-ELN-induced adipose remodeling program. Treatment with P-ELNs significantly attenuated body weight gain and reduced white adipose tissue (WAT) mass in obese mice without inducing systemic, hepatic or renal toxicity. Mechanistically, P-ELNs enhanced non-shivering thermogenesis in inguinal WAT through AMP-activated protein kinase (AMPK)-dependent remodeling toward a glycolytic beige fat state characterized by the coordinated activation of myogenic and glycolytic gene programs. Collectively, P-ELNs represent a safe and effective nanotherapeutic strategy to combat obesity through AMPK-dependent glycolytic beige fat remodeling. Therefore, P-ELNs are a first-in-class nanotherapeutic that induce this unique beige fat subtype, providing a novel strategy to treat obesity and related metabolic disorders.