EPA but not DHA improve systemic IR through activating muscle IL-6/AMPK pathway in high-fat diet-fed mice

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been reported to improve insulin resistance (IR), but the mechanisms and differences remain unclear. Our results showed that EPA and DHA activated muscle IL-6 and improved IR in high-fat diet-fed mice. After knocking out muscle IL-6, the effect of EPA on improving systemic IR was abolished, but the effect of DHA was restored; however, neither EPA nor DHA improved muscle IR through activating AMPK. Furthermore, EPA and DHA activated IL-6 and improved palmitic acid-induced IR in C2C12 myotube cells. After silencing IL-6, neither EPA nor DHA improved IR through activating AMPK in myotube cells. Once AMPK was inhibited, the effect of EPA and DHA on improving IR was both abolished. Additionally, IL-6 activated AMPK and improved IR in myotube cells. In conclusion, EPA but not DHA improves systemic IR mainly due to attenuating muscle IR through IL-6/AMPK signaling pathway. Both EPA and DHA stimulate the expression and secretion of muscle IL-6, and thereby activate AMPK to attenuate muscle insulin resistance (IR) via PI3K/AKT pathway. However, after silencing muscle IL-6, the effect of EPA on improving systemic IR was abolished, but the effect of DHA was restored. Overall, EPA but not DHA improves systemic IR mainly due to attenuating muscle IR through IL-6/AMPK signaling pathway. “➞”: Activated; “ ⊥ ”: Inhibited. • Muscle IL-6 plays an important role in maintaining glucose homeostasis. • Both EPA and DHA improve IR in high-fat diet-fed mice. • EPA, but not DHA, improves systemic IR through activating muscle IL-6. • Both EPA and DHA improve muscle IR through IL-6/AMPK signaling pathway.