We examined the preventive effect of Momordica charantia L. fruit (bitter melon) on hyperglycemia and insulin resistance in C57BL/6J mice fed with a high-fat (HF) diet. Firstly, mice were divided randomly into two groups: the control group was fed low-fat (LF) diet, whereas the experimental group was fed with a 45% HF diet last for 12 weeks. After 8 week of induction, the HF group was subdivided into six groups and was given orally with or without M. charantia or rosiglitazone 4 weeks afterward. We demonstrated that bitter melon was effective in ameliorating the HF diet-induced hyperglycemia, hyperleptinemia, and decreased the levels of blood glycated hemoglobin (HbA1c) and free fatty acid (FFA) (P<0.01, P<0.05, P<0.05, respectively), whereas increased the adipose PPARgamma and liver PPARalpha mRNA levels. Additionally, bitter melon significantly decreased the weights of epididymal white adipose tissue and visceral fat, and decreased the adipose leptin and resistin mRNA levels. It is tempting to speculate that at least a portion of bitter melon effects is due to be through PPARgamma-mediated pathways, resulting in lowering glucose levels and improving insulin resistance, and partly be through PPARalpha-mediated pathways to improve plasma lipid profiles. This is the first report demonstrating that bitter melon, is a food factor, but not a medicine, itself could influence dual PPARalpha/PPARgamma expression and the mediated gene expression, is effective in ameliorating insulin resistance and visceral obesity.