We have isolated inbred mouse strains that stably express either obesity-prone (ddY-H) or obesity-resistant (ddY-L) phenotypes. The ddY-H mice spontaneously develop hyperglycemia and hepatic steatosis along with a significant increase in body weight and fat mass even by fed with normal diet, whereas the ddY-L mice hardly develop these metabolic syndrome-like phenotypes. To investigate metabolic differences between ddY-H and ddY-L mice during high-fat diet (HFD) feeding, we analyzed the expression of transcripts related to glucose- and fat-metabolisms in the liver and adipose tissues. At 6 weeks of age with normal diet, no significant difference was observed in the expression of CD36, a major fatty acid transporter, in the liver of both strains, although the expression of PPARγ, a key transcription factor for fat synthesis, tended to be higher in the liver of ddY-H mice than that of ddY-L mice. Afterward, ingestion of HFD from 6 to 9 and 12 weeks of age dramatically induced the expression of PPARγ and CD36 in the liver of ddY-H mice. Neither PPARγ nor CD36 was induced in the liver of HFD-fed ddY-L mice, however, both transcripts were induced significantly in epididymal fat tissue. These results suggest that the low efficiency of hepatic expression of PPARγ and CD36 may be involved in the obesity-resistant phenotype of ddY-L mice.