Adipocyte-derived extracellular vesicles differentially regulate MASLD-associated metabolic responses in hepatocytes depending on glucose conditions

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most prevalent chronic liver disorders and is closely linked to obesity, insulin resistance, and type 2 diabetes mellitus. Recent studies have reported that extracellular vesicles (EVs) secreted from adipose tissue play a pivotal role in the onset and progression of MASLD. In this study, we aimed to establish an adipocyte-derived EV-based in vitro model to investigate adipose tissue–liver metabolic communication associated with MASLD. EVs were isolated from adipocytes differentiated under normoglycemic and diabetic-like hyperglycemic conditions and subsequently applied to hepatocytes. EVs derived under normoglycemic conditions contained higher levels of adiponectin and were associated with gene expression patterns indicative of reduced lipid accumulation. In contrast, EVs derived under hyperglycemic conditions exhibited higher FABP4 levels and were associated with increased lipid accumulation in hepatocytes. These findings indicate that the metabolic state of adipocytes reshapes the biomolecular composition of EVs, which is associated with differential metabolic responses in hepatocytes. Collectively, our results support the potential utility of adipocyte-derived EVs as an in vitro platform for studying adipose tissue–liver metabolic communication associated with MASLD and highlight the importance of EV-mediated communication between adipose tissue and the liver.