The regulatory role of the SIRT1/FoxO1 pathway in the prevention of insulin resistance in skeletal muscle by aerobic exercise in mice

Abstract

Silent information regulator proteins (SIRT) play key roles in glucose and lipid metabolism and homeostasis. The SIRT1 inhibitor was used to investigate the mechanism of the SIRT1/FoxO1 (Forkhead box O1) pathway in mice and its function in the prevention of insulin resistance in skeletal muscle. Forty male mice were randomly divided into a control group and three experimental groups (NH: high-fat diet, HE: high-fat diet plus exercise, and HES: high-fat diet plus exercise and SIRT1 inhibitor). After 14 weeks, the fat weight, blood glucose level, and HOMA-IR score in HES were significantly increased compared to those in HE (P < 0.01). The same parameters were significantly decreased in HE compared to those in the NH group (P < 0.01). Mitochondrial 8-OHdG (8-hydroxy-2 deoxyguanosine) level of the HES group was significantly higher than that of the HE group (P < 0.01). Compared with NH, the 8-OHdG and 4-HNE (4-hydroxynonenal) level were significantly decreased in HE (P < 0.01). Histologic evaluation demonstrated mitochondrial vacuoles in HES, while a clean arrangement of mitochondrial cristae was observed in HE. FoxO1 acetylation was enhanced in HES compared to that in HE (P < 0.01). The insulin resistance was induced in mice after 14-week high-fat diet, while glucose metabolism was significantly improved by aerobic exercise. The physiologic adaptations induced by exercise were not observed in the presence of an SIRT1 inhibitor. Thus, the SIRT1/FoxO1 pathway effectively regulates glucose metabolism during aerobic exercise and also prevents fat-induced peroxidation injury in skeletal muscles.