Although abnormal metabolism in metabolic syndrome and tumours has been well described, the relationship between oxoglutarate dehydrogenase (OGDH) and obesity-related diseases is still largely unknown. This study aimed to investigate whether it was possible to use transcription activator-like effector nuclease (TALEN) technology to establish OGDH^−/− rats and then study the effect of a high-fat diet (HFD) on these rats. However, after OGDH^+/−rats were generated, we were unable to identify any OGDH^−/− rats by performing mating experiments with the OGDH^+/− rats for almost one year. During the past three years, only OGDH^+/− rats were stably established, and correspondingly reduced OGDH expression in the tissues of the OGDH^+/− rats was verified. No significant abnormal behaviour was observed in the OGDH^+/− rats compared to the wild-type (WT) control rats. However, the OGDH^+/− rats were revealed to have higher body weight, and the difference was even significantly greater under the HFD condition. Furthermore, blood biochemical and tissue histological examinations uncovered no abnormalities with normal diets, but a HFD resulted in liver dysfunction with pathological alterations in the OGDH^+/− rats. Our results strongly indicate that OGDH homologous knockout is lethal in rats but heterologous OGDH knockout results in vulnerable liver lesions with a HFD. Therefore, the current study may provide a useful OGDH^+/− rat model for further investigations of metabolic syndrome and obesity-related hepatic carcinogenesis.