〔Abstract〕 Objective To investigate the mechanism of resveratrol promoting fibronectin type Ⅲ domain-containing 5(FNDC5) degradation in skeletal muscle of male obese mice. Methods Six-week-old male C57BL/6 mice were randomly divided into three groups: standard control diet(SCD), high-fat diet(HFD) and high-fat diet treated with resveratrol(HFD+RES). HFD+RES group was intervened with resveratrolviagavage [400 mg/kg·d)] while fed HFD for 20 weeks. The body mass, serum TG, TC, LDL-C and HDL-C levels were detected. The pathological changes in skeletal muscle were detected by HE staining. The expression of FNDC5, SIRT1, SIRT2, LC3, p62, Beclin-1, ATG5, ATG7 was assessed by immunohistochemistry, RT-PCR and Western blot respectively. Results The body mass, serum TG, TC and LDL-C levels increased significantly, meanwhile HDL-C levels decreased in HFD group. Lipid deposition between skeletal muscle fibers were obvious in HFD group. The immunohistochemistry results showed that protein expression levels of SIRT1, SIRT2 and LC3 obviously decreased, while the protein levels of FNDC5 and p62 obviously increased. The expression levels of FNDC5 significantly increased, while the gene expression levels of SIRT1, SIRT2, LC3, Atg7 and Beclin-1 obviously decreased. All these responses were attenuated by treatment with RES. Conclusion RES has obvious effects of lipid-lowering and promoting FNDC5 degradation in skeletal muscle tissues, which may be related with SIRT1 and SIRT2-induced autophagy, thus resulting in degradation of FNDC5.