The main findings in our present study include (1) high-fat diet can lead to the development of depression through the use of behavioral paradigms; (2) its mechanism is related to the up-regulation of hippocampal GPAT4 expression and hippocampal inflammation; (3) in situ hybridization shows BDNF mRNA expression level, down-regulated in hippocampus and VMH; (4) Real-time quantitative PCR detects the down-regulation of hippocampal AMPK and CREB expression levels in the HFD fed mice. This evidence concerns the gene CREB1 and depressive disorder.