Extra virgin olive oil supplementation attenuates hippocampal inflammation in high-fat diet-induced obesity animals with a depressive phenotype

Obesity and depression are major public health concerns that often co-occur. High-fat diets (HFD) in rodents are commonly used to model both conditions, triggering hippocampal inflammation. In this context, extra virgin olive oil (EVOO) supplementation, with its anti-obesogenic, anti-inflammatory, antioxidant and neuroprotective properties, shows potential as a therapeutic intervention. This study investigates the effects of EVOO supplementation in adult male and female rats receiving HFD. Depressive-like behavior was assessed through the Porsolt forced swim and splash tests, while neuroinflammation, activation of glial cells, and neuroplasticity-related proteins, were evaluated in the hippocampus. Our results showed that HFD induced depressive-like-behavior, which EVOO supplementation significantly alleviated by reducing immobility time and anhedonia. EVOO supplementation also reduced IL-1β, IL-6 and TNF-α levels and increased the immunocontent of neuroplasticity-related proteins in the hippocampus of female rats. In males with obesity, EVOO supplementation decreased glial fibrillary acidic protein (GFAP) and IL-6 levels in the hippocampus. Additionally, EVOO decreased the immunoreactivity of Toll-like receptor-4 (TLR-4) and ionized calcium-binding adaptor molecule-1 (IBA-1) in the hippocampus of both sexes. The clustering analysis made using the behavioral and neurochemical parameters measured in these animals further highlight the effectiveness of EVOO in attenuating HFD effects on these markers, with females displaying greater heterogeneity forming four distinct clusters and males exhibiting a clearer separation between groups. These findings suggest EVOO supplementation as a promising non-pharmacological strategy to counteract factors associated with obesity and depression, particularly by modulation of hippocampal neuroinflammation, astrocytic reactivity, and neuroplasticity. Hippocampal glial cells—microglia and astrocytes—respond to dietary lipids, establishing a reactive state with the release of inflammatory cytokines and reducing synaptic plasticity. This scenario is attenuated by extra virgin olive oil (EVOO) supplementation in the hippocampus of male and female rats. Especially in females, the main compounds in EVOO act on anti-inflammatory pathways that interact strongly with estradiol receptors (ESR1 and ESR2), attenuating the inflammatory context induced by HFD. • EVOO supplementation attenuated depressive phenotype in female rats after chronic High fat diet exposure. • EVOO supplementation mitigates increased inflammatory markers in the hippocampus of male and female rats with obesity. • EVOO supplementation prevent the increased IBA-1 and TLR4 immunoreactivity in the CA1 hippocampus of rats with obesity. • EVOO supplementation increased the immunocontent of proteins related to plasticity in hippocampus, especially in females.