It has been known that the increase of visceral fat is closely involved in abnormal glucose tolerance, hypertension, and hyperlipidemia, leading to the other diseases, such as atherosclerosis and type 2 diabetes. Recent reports have shown that serum copper concentration was increased in obese and/or diabetic patients. Here, we investigated the effects of copper chelator, cuprizone on high fat diet (HFD)-induced obesity in mice. We administered cuprizone (0.2%w) mixed in food pellets. Mice were divided in 4 groups, fed with (1) normal chow (NCD), (2) NCD with cuprizone (NCD+C), (3) HFD or (4) HFD with cuprizone (HFD+C) for 4 weeks, and then metabolic parameters were obtained. Serum copper levels were decreased in both cuprizone groups. Cuprizone significantly decreased the body weight in HFD+C without changes of food intake. Specifically in HFD+C, cuprizone decreased 60% of epididymal and inguinal fat weights, but did not change the weight of skeletal muscle, both soleus and gastrocnemius. Furthermore, we found that cuprizone ameliorated HFD-induced insulin resistance (ipGTT and ITT) with the modifications of gene expression pattern in liver, based on the comparison between NCD, HFD and HFD+C. These results suggest that cuprizone would be a candidate of leading compounds for anti-obesity agent.