Diet-Driven Microglial Activation: Region-Specific Neuroinflammation in the Mouse Brain

<b>Background</b>: High-fat diet (HFD) consumption is commonly linked to low-grade brain inflammation and increased risk of neurodegeneration. However, in our previous research, HFD exposure for up to 24 weeks did not increase pro-inflammatory cytokine expression or impair learning and spatial memory. To further investigate neuroimmune responses, we examined microglial activation at the transcriptional level. <b>Methods</b>: Male C57BL/6J mice were fed either a normal diet (ND) or HFD for 4, 12, or 24 weeks. Bulk RNA sequencing was performed across four brain regions (cerebellum, hippocampus, hypothalamus, cortex) to assess region-specific transcriptional responses. <b>Results</b>: HFD induced region- and time-dependent transcriptional changes. In the hypothalamus, 0/11/37 differentially expressed genes (DEGs; <i>p</i>-value < 0.05; fold change > 1.5) were detected at 4, 12, and 24 weeks, respectively. In the hippocampus, 2/41/42 DEGS were observed; in the cortex, 1/3/68 DEGS; and in the cerebellum, 27/0/0 DEGS at the respective time points, indicating minimal cerebellar involvement beyond the early time point. Across all conditions, three genes (<i>Lcn2</i>, <i>Ch25h</i>, <i>Gimap9</i>) were consistently regulated. Several DEGs were linked to microglial activation and inflammatory signaling. In the manuscript, we discuss 33 biologically relevant DEGs in detail. Transcriptomic signatures and pathway enrichment analyses suggest potential engagement of NF-κB-related pathways, although this interpretation remains indirect. <b>Conclusions</b>: These findings demonstrate that HFD selectively alters brain homeostasis by inducing region-specific transcriptional changes associated with microglial activation and inflammatory processes. While NF-κB-related pathways emerged as recurrent candidates, direct mechanistic validation is required.