Highlights: What are the main findings? A high-fat diet markedly amplifies LPS-induced neuroinflammatory responses in a brain-region-specific manner, especially in the frontal cortex and hypothalamus. L-alliin significantly reduces cytokine overactivation, with stronger anti-inflammatory effects in metabolically stressed (HFD-fed) animals. What are the implications of the main findings? L-alliin acts as a context-dependent modulator, selectively normalizing cytokine pathways according to the metabolic load and neural region involved. These results support the therapeutic potential of L-alliin for targeting obesity-related neuroinflammation and highlight the need for region-specific strategies in CNS immunometabolic disorders. Background/Objectives: A high-fat diet disrupts metabolic and neuroimmune balance in the brain, making neural tissue more reactive to inflammatory challenges. However, it is not well understood how this vulnerability varies across brain regions or how natural anti-inflammatory compounds influence it. Methods: In this study, we examined how the garlic-derived molecule L-alliin modulates the inflammatory response triggered by lipopolysaccharide in the frontal cortex, hippocampus, and hypothalamus of mice fed either a standard or high-fat diet. Results: Measurements of cytokine gene expression showed that the high-fat diet greatly increased the inflammatory response in the frontal cortex and hypothalamus, with the hypothalamus displaying the strongest overall activation. Treatment with L-alliin significantly reduced elevated cytokine levels in both regions, with the reductions most pronounced in animals on the high-fat diet. In contrast, the hippocampus showed a distinct pattern: expression of TNF-¿ and IL-1ß changed very little across diets or treatments, whereas IL-6 and CCL2 were selectively altered by L-alliin, depending on the animals¿ metabolic state. Conclusions: These findings demonstrate that diet-induced obesity does not affect the entire brain uniformly. Instead, inflammatory pathways are altered region-specifically, and L-alliin modulates these pathways with sensitivity to both brain region and metabolic condition. This work emphasizes the importance of accounting for neuroanatomical differences when developing strategies to reduce inflammation in obesity-associated conditions.
