The authors investigated strain-specific cell proliferation and differentiation differences in the dentate gyri of C57BL/6N (susceptible strain to obesity) and C3H/HeN (resistant strain to obesity) mice. In addition, the influences of a high fat diet (HD) on neuronal differentiation in C57BL/6N and C3H/HeN mice fed a low-fat diet (LD) or HD for 4 or 12 weeks were investigated. Body weight and body weight gains were significantly higher in HD-fed C57BL/6N and C3H/HeN mice than in LD-fed C57BL/6N and C3H/HeN mice. In particular, body weight gains were significantly higher in C57BL/6N mice than in C3H/HeN mice. In both of HD- and LD-fed C57BL/6N and C3H/HeN mice for 4 weeks, some Ki67 and many DCX immunoreactive cells were detected in the subgranular zone of the dentate gyrus. In HD-fed C57BL/6N and C3H/HeN mice, the number of Ki67 immunoreactive cells and DCX immunoreactivities in the dentate gyri were significantly lower than in LD-fed C57BL/6N and C3H/HeN mice. However, the number of Ki67 immunoreactive cells and DCX immunoreactivities in HD-fed C57BL/6N mice were significantly lower than in HD-fed C3H/HeN mice. These results suggest that C57BL/6N mice are more vulnerable to HD induced obesity than C3H/HeN mice. In addition, the feeding of HD was found to exacerbate reduced cell proliferation and differentiation in the dentate gyri of C57BL/6N mice as compared with that in C3H/HeN mice.