During repeated preparations of high-fat diet (HFD)-induced obese mice, we have reproducibly observed both obesity-resistant (HFD_lean) and obesity-prone (HFD_fat) subpopulations in ddY mice, an outbred strain. To investigate metabolic characteristics of the subpopulations, we analyzed liver gene expression and glucose- and fat metabolisms. Hepatic steatosis was attenuated in HFD_lean even after ingestion of HFD for 15 weeks, whereas HFD_fat formed severe fatty liver. HFD_lean showed normal glucose tolerance and insulin sensitivity, whereas HFD_fat showed severe diabetes. Expression of genes for fatty acid transport (CD36), cytoplasmic triglyceride synthesis (DGAT2), fat synthesis (SREBP-I, PPARγ, PPARα) and β-oxidation (CPT-1a, acyl CoA oxidase) were significantly attenuated in HFD_lean as compared with those in HFD_fat. Low expression of apoB and MTP in HFD_lean consisted with their lower plasma LDL concentration. Also, plasma leptin concentration and liver β₂ adrenoceptor (β₂AdR) expression were significantly low, and hepatic glycogen content of HFD_lean was higher than that of HFD_fat. These results suggest that lower hepatic steatosis of HFD_lean was due to the decreased incorporation of fatty acid into the liver and suppression of triglyceride synthesis therein; and that inefficient glycogenolysis by less sympathetic activation in the liver of HFD_lean.