Western Diet-induced Visceral Adipose Tissue Inflammation Promotes Alzheimer's Disease Pathology via Microglial Activation in a Mouse Model

Introduction: Western diet (WD)-induced visceral adipose tissue (VAT) inflammation is characterized by adipocyte hypertrophy, hypoxia, and apoptosis. Epididymal white adipose tissue (eWAT), a representative VAT depot in rodents, plays a central role in WD-induced inflammation by secreting pro-inflammatory cytokines that contribute to systemic and neuroinflammation. However, the mechanistic link between WD-driven eWAT inflammation and Alzheimer's disease (AD) pathology remains unclear. Methods: WD feeding for 20 weeks was conducted to evaluate its effects on AD-related neuroinflammation and pathology in mice. Cerebral glucose metabolism was assessed using F-18 FDG-PET. RNA sequencing of eWAT and plasma cytokine profiling identified inflammation-associated factors. In vitro assays were performed to examine the effects of these cytokines on microglial activation, neuronal viability, and IL-6/STAT3 signaling. Results: WD group exhibited significantly increased levels of neuroinflammatory markers and increased hippocampal levels of AD-related proteins including amyloid-beta oligomers, amyloid precursor protein, and phosphorylated tau. Additionally, F-18 FDG PET imaging revealed reduced glucose metabolism in the thalamus and hippocampus of WD group compared to controls. RNA sequencing of eWAT and cytokine profiling of plasma identified CCL8, CCL9, CXCL13, and IL-18 as significantly elevated pro-inflammatory cytokines. In vitro analyses demonstrated that these eWAT-associated cytokines directly activate microglial cells via the IL-6/STAT3 signaling pathway, promoting hippocampal neuronal death. Discussion: These findings elucidate a critical pathway through which WD-induced eWAT inflammation exacerbates AD pathology through a systemic–to–neuroinflammation axis, highlighting the therapeutic potential of targeting eWAT-associated cytokines to mitigate diet-associated AD progression. Overall design: Eighteen male C57BL/6J mice were randomly assigned to either the normal diet group (control) or WD group (n = 9, Western diet for 20 weeks) to assess the impact of eWAT inflammation on AD-related pathology. Body weight, food intake, and fasting glucose were monitored, followed by behavioral tests and F-18 fluorodeoxyglucose (FDG) brain positron emission tomography (PET) imaging to evaluate cognitive function and cerebral glucose metabolism, respectively. Following the intervention, epididymal fat (as a representative of eWAT), plasma, and brain tissues were collected for analysis. eWAT inflammation, systemic cytokine levels, neuroinflammatory responses, hippocampal neuronal damage, and AD-related protein expression were comprehensively evaluated using molecular and histological techniques. eWAT-associated proinflammatory cytokines were identified through transcriptomic and proteomic analyses and validated across tissues. To confirm their eWAT origin, eWAT-removal surgery was performed in a subset of WD group, resulting in a marked reduction of these cytokines in plasma. In vitro experiments further demonstrated that eWAT-associated cytokines promoted neurotoxicity via microglial activation. Specifically, the interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) pathway was implicated in mediating this effect, as pharmacological inhibition of STAT3 attenuated microglia-induced neuronal damage.