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Background: Bitter gourd (BG) fruit powder was previously showed to prevent high-fat diet (HFD)-induced metabolic disorders in mice. In current study, we investigated the beneficial difference of the water soluble (S-BG) and insoluble fractions (IS-BG) of bitter gourd. Results: Compared to normal chow diet, the HFD induced greater body weight gain and increased fat mass accompanied by impaired insulin sensitivity, elevated serum lipids and inflammation. Supplementation of BG, S-BG, and IS-BG showed similar beneficial effects and restored the metabolic changes in mice. Interestingly, BG showed no effect on fat mass, which was decreased by both S-BG and IS-BG. Additionally, S-BG and IS-BG inhibited the SREBP-1/FAS pathway, thereby decreasing liver cholesterol accumulation, while only BG showed improvement on mitochondrial activity. Conclusion: These results further support the position that bitter gourd has multiple active ingredients and that both fractions have beneficial effects on metabolic disorders.