During the screening of a variety of plant sources for their anti-obesity activity, it was found that a water-soluble extract, named PG105, prepared from stem parts of Cucurbita moschata, contains potent anti-obesity activities in a high fat diet-induced obesity mouse model. In this animal model, increases in body weight and fat storage were suppressed by 8-week oral administration of PG105 at 500 mg/kg, while the overall amount of food intake was not affected. Furthermore, PG105 protected the development of fatty liver and increased the hepatic beta-oxidation activity. Results from blood analysis showed that the levels of triglyceride and cholesterol were significantly lowered by PG105 administration, and also that the level of leptin was reduced, while that of adiponectin was increased. To understand the underlying mechanism at the molecular level, the effects of PG105 were examined on the expression of the genes involved in lipid metabolism by Northern blot analysis. In the liver of PG105-treated mice, the mRNA level of lipogenic genes such as SREBP-1c and SCD-1 was decreased, while that of lipolytic genes such as PPARalpha, ACO-1, CPT-1, and UCP-2 was modestly increased. Our data suggest that PG105 may have great potential as a novel anti-obesity agent in that both inhibition of lipid synthesis and acceleration of fatty acid breakdown are induced by this reagent.