This project investigates proteomic remodeling of adipose tissue-derived extracellular vesicles (AT-EVs) under metabolic dysregulation. AT-EVs isolated from inguinal white adipose tissue of normal diet (ND)-fed and high-fat diet (HFD)-fed mice were subjected to DIA-based LC–MS/MS proteomic profiling. The analysis identified extensive differences in EV protein cargo between HFD-EVs and ND-EVs and revealed enrichment of proteins associated with metabolic, inflammatory, extracellular matrix, and secretory processes.