Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) are closely associated with the regulation of energy homeostasis, but their roles in diet-induced obesity have not been explored. Using dietary interventions, this study examined regional changes of BDNF and TrkB mRNA expression in different brain regions of diet-induced obese (DIO) and resistant (DR) mice in response to high-fat (HF), energy-restricted pair-feeding and low fat (LF) diets. Using in situ hybridization, DIO mice had significantly decreased levels of BDNF mRNA expression (ÃÂÃÂÃÂÃÂ¿32% to ÃÂÃÂÃÂÃÂ¿37%) and TrkB (ÃÂÃÂÃÂÃÂ¿21% to ÃÂÃÂÃÂÃÂ¿23%) in the hippocampus compared to DR mice on an HF diet, but not on energy-restricted pair-feeding and LF diets. In the ventromedial hypothalamic nucleus (VMH), BDNF expression was decreased in DIO mice on HF (ÃÂÃÂÃÂÃÂ¿23%) and energy-restricted pair-feeding (ÃÂÃÂÃÂÃÂ¿21%) diets. Furthermore, the VMH BDNF expression was negatively correlated with blood glucose but positively correlated with plasma adiponectin. These findings suggest that decreased hippocampal BDNF and TrkB expression plays an important role in high-fat diet induced obesity. A lower baseline BDNF mRNA expression in the VMH of DIO mice after normalization of body weight may indicate their intrinsic nature or an elevated body weight set point to drive body weight gain.