Exploring the Impact of a High‐Fat Diet on Brain Homeostasis: A Comprehensive Analysis of the Absence of Inflammation

Excessive fat consumption increases the risk of Alzheimer's disease (AD), potentially through diet‐induced neuroinflammation. Microglia, the brain's immune cells, are affected by obesity and diet. Phytosterols (PS), plant‐derived cholesterol‐like compounds, accumulate in the brain with age, and their content correlates with dietary intake. We hypothesize that the accumulation of PS modulates microglial activation and exerts anti‐inflammatory effects. We investigated the effects of a normal diet (ND), high‐fat diet (HFD), HFD with 2% PS (HFD+2% PS), and HFD with 4% PS (HFD+4% PS) on neuroinflammation in female and male C57BL/6J mice. Flow cytometry (FC) of microglia showed no significant regulation of pro‐ (IFN‐γ, IL‐1β, TNF‐α) and anti‐inflammatory (IL‐10) cytokines due to diet, but sex‐ and age‐dependent differences were observed. Immunofluorescence staining showed no TREM2 upregulation, indicating a lack of microglial activation in response to HFD. PS supplementation significantly reduced HFD‐induced weight gain, suggesting metabolic effects. Contrary to existing research, we found no evidence of HFD‐induced neuroinflammation or microglial activation. However, the reduction in weight gain with PS supplementation suggests potential metabolic benefits, which could have implications for the treatment of obesity. The potential effects on neuroinflammation remain unclear.