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Objective: Studies have found that high expression of human Kallistatin (HKS) in adipose tissue can improve obesity and its associated comorbidities, but the underlying mechanism of specific regulation is unclear. Methods: An obesity model was built by injecting 8-week-old C57BL/6 mice ( n  = 6 mice per group) with (Ad.Null and (Ad.HKS adenovirus into epididymal adipose tissue and fed with a high-fat diet (HFD). Insulin resistance-related proteins, AKT and IRS1, were detected in the liver, subcutaneous fat, and skeletal muscle by western blotting after one month of HFD. Epididymal adipose tissue was isolated after 24 h for culture, and exosomes were extracted by differential centrifugation. Enzyme-linked immunosorbent assay detected the expression of HKS protein in serum and exosomes. To examine the role of exosomes in AML12 insulin resistance, we used epididymal adipose tissue-derived exosomes or transfected (Ad.HKS into mature 3T3L1-derived exosomes to interfere with palmitic acid (PA)-induced mouse AML12 insulin resistance model. GW4869 was used to inhibit exosome biogenesis and release. Results: Our results showed that HFD-induced mice with high expression of HKS in epididymal adipose tissue had slower weight gain, lower serum triglycerides, reduced free fatty acids, and improved liver insulin resistance compared with the (Ad.Null group. We also demonstrated that HKS was enriched in epididymal adipose tissue-derived exosomes and released through the exosome pathway. In PA-induced AML12 cells, insulin resistance was alleviated after incubation of the HKS-related exosome; this effect was reversed with GW4869. Conclusion: High expression of HKS in epididymal adipose tissue could lead to its exocrine secretion in the form of exosomes and improve liver insulin resistance by promoting the phosphorylation of AKT. Production of high HKS vesicles might be a possible way to alleviate insulin resistance associated with obesity.