Lipopolysaccharide exacerbates depressive‐like behaviors in obese rats through complement C1q‐mediated synaptic elimination by microglia

Abstract Aim Prolonged high‐fat diet (HFD) consumption has been shown to impair cognition and depression. The combined effects of HFD and lipopolysaccharide (LPS) administration on those outcomes have never been thoroughly investigated. This study investigated the effects of LPS, HFD consumption, and a combination of both conditions on microglial dysfunction, microglial morphological alterations, synaptic loss, cognitive dysfunction, and depressive‐like behaviors. Methods Sixty‐four male Wistar rats were fed either a normal diet (ND) or HFD for 12 weeks, followed by single dose‐subcutaneous injection of either vehicle or LPS. Then, cognitive function and depressive‐like behaviors were assessed. Then, rats were euthanized, and the whole brain, hippocampus, and spleen were collected for further investigation, including western blot analysis, qRT‐PCR, immunofluorescence staining, and brain metabolome determination. Results HFD‐fed rats developed obese characteristics. Both HFD‐fed rats with vehicle and ND‐fed rats with LPS increased cholesterol and serum LPS levels, which were exacerbated in HFD‐fed rats with LPS. HFD consumption, but not LPS injection, caused oxidative stress, blood–brain barrier disruption, and decreased neurogenesis. Both HFD and LPS administration triggered an increase in inflammatory genes on microglia and astrocytes, increased c1q colocalization with microglia, and increased dendritic spine loss, which were exacerbated in the combined conditions. Both HFD and LPS altered neurotransmitters and disrupted brain metabolism. Interestingly, HFD consumption, but not LPS, induced cognitive decline, whereas both conditions individually induced depressive‐like behaviors, which were exacerbated in the combined conditions. Conclusions Our findings suggest that LPS aggravates metabolic disturbances, neuroinflammation, microglial synaptic engulfment, and depressive‐like behaviors in obese rats.