Investigation of the mechanism involved in high-fat diet-induced depressive behavior based on energy metabolism.

Abstract

BACKGROUND: The specific mechanisms underlying high-fat diet (HFD) and depressive behaviors remain elusive. Meanwhile, the impact of calorie restriction (CR) on the development of depression has not been explored in-depth. Thus, we aimed to examine the pathways underlying how long-term HFD intake leads to depression, focusing on energy metabolism. METHODS: C57BL/6J mice were randomly divided into four groups-control (CK) group, CR group, HFD group, and chronic unpredictable mild stress (CUMS) group. Enzyme-linked immunosorbent assay, western blot, metabolomics and 16s rRNA gene sequencing analysis were undertaken to investigate the 5-hydroxytryptamine system, glucolipid metabolism, brain energy metabolism and gut microbiome. RESULTS: Mice with HFD- and CUMS-induced depressive-like symptoms exhibited a significant decrease in serotonergic activity in the hippocampus. The behaviors of CR mice did not differ significantly from CK mice. Fasting blood glucose levels, fatty acid contents, and reactive oxygen species (ROS) levels were all negatively affected in unrestricted HFD and CUMS mice, suggestive of energy metabolism disruption. Metabolomic analysis revealed that tricarboxylic acid cycle activity was inhibited in the HFD and CUMS groups but not in the CR group. Additionally, analysis of the gut microbiome revealed that [Ruminococcus] gnavus exhibited higher predictive potential for HFD-induced depression, while Allobaculum showed greater predictive potential for stress-induced depression. LIMITATIONS: Causal relationship between brain energy metabolism and gut microbiome unclear. CONCLUSION: An unrestricted HFD promotes dysbiosis of the gut microbiota, impairs energy metabolism in the brain, affects the serotonergic system, and ultimately induces depressive-like behaviors.