Adipocyte‐Derived Exosomal miR‐5099 Mitigates M1 Macrophage Polarization and Adipose Inflammation via c‐Met/NF‐κB Axis to Improve Metabolic Health

ABSTRACT Obesity underlies metabolic dysfunction and contributes to the pathogenesis of various diseases. Obesity associated adipose tissue (AT) inflammation contributes to whole body inflammation vulnerability and metabolic disease development. Celastrol (CEL) exhibits significant therapeutic potential against obesity; however, its clinical application is limited by toxicity. Here, CEL treatment fundamentally reprograms the microRNA (miRNA) profile of adipocyte‐derived exosomes. Among the altered miRNAs, we identified miR‐5099 as being dramatically upregulated and enriched specifically within adipocyte‐derived exosomes. We found that CEL‐conditioned adipocyte culture medium exhibited the beneficial effects, including the suppression of M1 macrophage polarization, improvement of metabolic function, and reduction of inflammation in obese animals. Importantly, these beneficial effects are largely dependent on the presence of exosomal miR‐5099. Furthermore, direct administration of miR‐5099 in obese mice significantly ameliorated metabolic disorders, including adipose tissue inflammation and hepatic steatosis. Mechanistically, miR‐5099 attenuates AT inflammation by directly targeting the c‐Met/NF‐κB axis in infiltrated macrophages. Concomitantly, miR‐5099 enhances systemic insulin sensitivity and glucose homeostasis across metabolic tissues. Collectively, our study identifies miR‐5099 as the key downstream effector of CEL. This finding suggests that direct miR‐5099 administration offers a strategy to harness the therapeutic benefits of CEL while circumventing its toxicity, positioning it as a promising treatment for obesity and associated comorbidities.