Resolvin D3 improves the impairment of insulin signaling in skeletal muscle and nonalcoholic fatty liver disease through AMPK/autophagy-associated attenuation of ER stress.

Resolvin D3 (RD3), an endogenous lipid mediator derived from omega-3 fatty acids, has been documented to attenuate inflammation in various disease models. Although it has been reported that omega-3 fatty acids attenuate metabolic disorders, the roles of RD3 in insulin signaling in skeletal muscle and hepatic lipid metabolism remain unclear. In the current study, we examined the role of RD3 in skeletal muscle insulin resistance and hepatic steatosis using in vitro and in vivo obesity models. In mouse primary hepatocytes, RD3 treatment reduced lipid accumulation and the production of lipogenic proteins (processed SREBP1 and SCD1) while improving insulin signaling in C2C12 myocytes. Furthermore, RD3 treatment ameliorated palmitate-induced ER stress markers (phospho-eIF2α and CHOP) in mouse primary hepatocytes and C2C12 myocytes. Treatment with RD3 increased phospho-AMPK expression and autophagy markers (LC3 conversion, p62 degradation, and autophagosome formation). AMPK siRNA or 3-MA reduced the effects of RD3 on C2C12 myocytes and mouse primary hepatocytes treated with palmitate. Finally, we confirmed the therapeutic effects of RD3 on skeletal muscle insulin resistance and hepatic lipid metabolism in high-fat diet (HFD)-fed mice. In vivo transfection-mediated suppression of AMPK restored all these changes in animal models. The results of the present study suggest that RD3 alleviates insulin resistance in skeletal muscle and hepatic steatosis via AMPK/autophagy signaling and provides an effective and safe therapeutic approach for treating metabolic disorders, including insulin resistance, type 2 diabetes, and NAFLD.