Effects of High-fat Diet and Chronic Mild Stress on Depression-like Behaviors and Levels of Inflammatory Cytokines in the Hippocampus and Prefrontal Cortex of Rats

Obesity and depression tend to co-occur, and obese patients with chronic low-grade inflammation have a higher risk of developing depression. However, mechanisms explaining these connections have not been fully elucidated. Here, an animal model of comorbid obesity and depression induced by high-fat diet (HFD) combined with chronic unpredictable mild stress (CUMS) was used, and sucrose preference, open field, elevated plus maze and Morris water maze tests were used to detected depression-and anxiety-like behaviors and spatial memory. The levels of inflammatory cytokines and NF-κB and microglial activation in the hippocampus and prefrontal cortex were examined in the study. Our results revealed that the comorbidity group exhibited the most severe depression-like behavior. Obesity but unstressed rats had the highest serum lipid levels among groups. The HFD and CUMS alone and combination of them increased levels of IL-1β, IL-6 and TNF-α in the hippocampus and prefrontal cortex, which was significantly related to depression-like behaviors. Further, NF-κB protein and mRNA levels and microglial activation in the hippocampus and prefrontal cortex significantly increased in stressed, obese and comorbid groups, with animals in comorbid group having the highest NF-κB mRNA levels in the hippocampus and level of NF-κB proteins in the prefrontal cortex, and the highest microglial activation in both brain areas. The study concluded that HFD and CUMS alone and combination induce depression-like symptoms, abnormal serum lipid levels, microglial activation and increased inflammatory cytokines in the brain, effects that are possibly mediated by TLR4-NF-κB signaling.