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Hyperuricemia is closely associated with insulin resistance. Xanthine oxidoreductase (XOR), a key enzyme known to catalyze purines to uric acid, is expressed in ubiquitous tissues. In addition, XOR expression is upregulated in obesity. Therefore, we speculated that XOR may exacerbate insulin resistance. But, the effects of XOR on insulin sensitivity have not been fully elucidated. Febuxostat is a selective XOR inhibitor. In this study we investigated the effect of suppression of XOR using febuxostat on insulin sensitivity in vivo and in vitro. Male Wistar rats were fed with 60% high fat diet containing with either febuxostat or not, for 4 weeks. Euglycemic-hyperinsulinemic clamp studies were performed after an 8-h fast. Differentiated C2C12 cells were incubated with 0 or 10 μM febuxostat. For Xor silencing experiments, we used the Xor RNAi adenovirus. The glucose infusion rate and insulin stimulated-glucose disposal rate were significantly increased by 12% (P<0.05) and 17% (P<0.05), respectively, in febuxostat fed rats. But the clamp hepatic glucose output was no significant change between two groups. Consistent with the clamp data, the insulin-stimulated phosphorylation of Akt and AMPK were significantly increased by 90% (P<0.05) and 53% (P<0.05), respectively, in skeletal muscle of febuxostat fed rats. In differentiated C2C12 cells, febuxostat treatment significantly increased the insulin-stimulated phosphorylation of Akt and AMPK by 65% (P<0.05) and 43% (P<0.05), respectively. Furthermore, knockdown of XOR with XOR RNAi adenovirus significantly increased the insulin-stimulated phosphorylation of Akt by 60% (P<0.05). These results suggest that the suppression of XOR in skeletal muscle improves the skeletal muscle insulin resistance. In conclusion, our findings demonstrated that suppression of XOR had beneficial effects on skeletal muscle insulin sensitivity in an insulin resistant state. The upregulation of XOR in skeletal muscle might cause the insulin resistance. Disclosure: C.T. Moriya: None. H. Satoh: None. S. Kakehi: None. H. Watada: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kissei Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Pfizer Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Kowa Pharmaceutical Europe Co. Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanwa Chemical Industry Co. Ltd., Takeda Pharmaceutical Company Limited. [ABSTRACT FROM AUTHOR]