Lipidomic Analysis of Plasma Extracellular Vesicles from Adiponectin Deficient Mice or Metabolic Syndrome Patients Reveals Pro‐Oxidative and Pro‐Inflammatory Lipid Signatures Correlating with Metabolic Dysfunction

Extracellular vesicles (EV) are emerging regulators of metabolic homeostasis through their bioactive cargo. This study first investigated the lipidomic profile and functional effects of plasma EV derived from adiponectin-knockout (KO) mice to identify EV-associated lipid signatures linked to metabolic dysfunction. Lipidomic profiling revealed that KO EV were enriched in sphingolipids and polyunsaturated phospholipids compared to wild-type (WT) EV. To evaluate functional consequences, recipient cell assays were conducted using macrophages, skeletal muscle cells, and pancreatic beta cells. KO EV showed an increased uptake in RAW 264.7 macrophages and induced elevated reactive oxygen species (ROS) and activation of NF-κB and IRF inflammatory pathways. In L6 skeletal muscle cells, WT EV increased ATP production, while KO EV failed to elicit this effect. Furthermore, KO EV impaired glucose-stimulated insulin secretion in INS-1 pancreatic beta cells. These findings suggested that altered lipid composition in EV from KO mice contributes to oxidative stress, inflammation, and impaired metabolic regulation in recipient cells. Next, translational relevance was established by documenting that plasma EV from patients with metabolic syndrome exhibited lipidomic remodeling features in parallel to the murine KO phenotype, in particular enriched PUFA-containing lipids. Together, these findings identify a conserved adiponectin-EV lipid composition axis regulating oxidative stress, inflammation, and impaired metabolic regulation. The new knowledge presented in this study has implications for biomarker discovery and therapeutic targeting in metabolic disease.