Insulin resistance (IR) is an important pathological basis of obesity, diabetes and cardiovascular diseases, and emerging evidence demonstrates aerobic exercise as an efficient therapeutical tool in the management of IR and IR-related metabolic disease. Interleukin-4 (IL-4), an important anti-inflammatory cytokine, was recently proved to be involved in regulation of IR, yet the effect of IL-4 on exercise-induced insulin sensitivity and underlying mechanism was less investigated. In this study, using a mouse model of swimming exercise training (60 min/day, 5 days/week for 8 weeks), we found that long-term swimming exercise promoted insulin sensitivity compared with sedentary groups as indexed by the homeostasis model assessment of insulin resistance (HOMA-IR), glucose and insulin tolerance test. Accompanying with increased insulin sensitivity, swimming exercise increased serum IL-4 levels as well as insulin receptor substrate 1 (IRS-1) and protein kinase B (Akt) phosphorylation. Mechanistically, IL-4 treatment increased insulin-stimulated glucose uptake and Akt phosphorylation in skeletal muscle C2C12 cells, and inhibition of IL-4 signaling via ruxolitinib, a Janus kinase OAK) inhibitor, attenuated IL-4-induced insulin sensitivity. Taken together, our results demonstrated IL-4 as a novel exercise factor contributing to exercise-induced insulin sensitivity, providing a potential therapeutical target of IR and related metabolic disease. (C) 2020 Elsevier Inc. All rights reserved.