Supporting data for "Investigating the vulnerability of neuroinflammation and neurodegeneration by systemic inflammation in zebrafish with high-fat diet"

The research investigates the impact of systemic inflammation on neuroinflammation in an obesity model using zebrafish. Obesity was established by feeding adult and larval zebrafish a tailor-made high-fat diet. The model of high-fat diet-induced obesity was validated through Oil Red-O staining in larvae and adults, body mass index measurements in adults, and BODIPY staining of the liver in larvae.
In one experimental model, fin amputation was performed on both obese larvae and adults, while in a second model, intraperitoneal lipopolysaccharide injection was administered to obese adult zebrafish. Neuroinflammation was observed in high-fat diet-induced obese zebrafish larvae and adults. In the model involving fin amputation of obese zebrafish, altered adipokine expression was noted. Additionally, neuroinflammation, increased microglia, and elevated Lipocalin-2 expression in the posterior tuberculum were recorded. Cognitive decline and anxiety-like behavior were observed in obese zebrafish following fin amputation.
In the model of obese zebrafish injected intraperitoneally with lipopolysaccharide, altered metabolic pathways, iron accumulation, increased Lipocalin-2 expression, macrophage infiltration in the posterior tuberculum, and neuroinflammation were reported. Autophagy was also investigated. The IL-1β gene was specifically knocked out in macrophages to assess whether its deletion could ameliorate inflammation and neuroinflammation. Results indicated that IL-1β knockout in macrophages led to improved cognition and reduced neuroinflammation following systemic inflammation.
Collectively, these data identify macrophage-derived IL-1β as a pivotal mediator connecting systemic inflammation, lipid metabolism, and neuroinflammatory outcomes during obesity. The coordinated suppression of cytokine, adipokine, and iron metabolism disturbances in IL-1β knockout zebrafish underscores the systemic regulatory role of IL-1β. By bridging behavioral, molecular, and imaging analyses, comprehensive evidence is provided that IL-1β-dependent pathways integrate peripheral metabolic inflammation with CNS pathology. These findings highlight IL-1β as a promising therapeutic target for dissociating systemic metabolic inflammation from neurodegenerative risk, advancing the understanding of sex-specific immune–metabolic–neural interactions in obesity and inflammatory disease contexts.

本研究以斑马鱼为模型，探究全身性炎症对肥胖状态下神经炎症的影响。研究通过向成年及幼年斑马鱼饲喂定制化高脂饲料，构建肥胖模型。本高脂饮食诱导肥胖模型的有效性，通过幼年与成年斑马鱼的油红O（Oil Red-O）染色、成年斑马鱼的体质量指数测定，以及幼年斑马鱼肝脏的BODIPY染色得以验证。
在第一组实验模型中，研究对肥胖幼年及成年斑马鱼实施鳍切除术；在第二组模型中，则向肥胖成年斑马鱼腹腔注射脂多糖（lipopolysaccharide）。研究观察到高脂饮食诱导的肥胖斑马鱼幼体与成体均出现神经炎症。在肥胖斑马鱼鳍切除术模型中，研究人员发现脂肪因子表达发生改变。此外，还记录到神经炎症、小胶质细胞（microglia）增殖，以及后脑结节处脂质运载蛋白2（Lipocalin-2）表达上调。鳍切除术后的肥胖斑马鱼表现出认知功能下降与类焦虑行为。
在脂多糖腹腔注射的肥胖斑马鱼模型中，研究发现代谢通路异常、铁蓄积、脂质运载蛋白2（Lipocalin-2）表达上调、后脑结节处巨噬细胞（macrophage）浸润，以及神经炎症。同时本研究还对细胞自噬（autophagy）进行了探究。为明确巨噬细胞特异性敲除白细胞介素1β（IL-1β）是否可缓解炎症与神经炎症，研究人员构建了巨噬细胞IL-1β基因特异性敲除模型。结果显示，全身性炎症发生后，巨噬细胞IL-1β敲除可改善认知功能并减轻神经炎症。
综合来看，本研究数据证实，巨噬细胞来源的IL-1β（IL-1β）是连接肥胖状态下全身性炎症、脂质代谢与神经炎症结局的关键介导因子。IL-1β敲除斑马鱼中细胞因子、脂肪因子及铁代谢紊乱得到协同抑制，这一结果凸显了IL-1β的全身性调控作用。本研究通过整合行为学、分子生物学与影像学分析，为IL-1β依赖通路将外周代谢炎症与中枢神经系统（Central Nervous System）病理联系起来提供了全面证据。上述研究结果表明，IL-1β是极具潜力的治疗靶点，可用于分离全身性代谢炎症与神经退行性疾病风险，同时推动了肥胖与炎症性疾病背景下性别特异性免疫-代谢-神经交互作用的认知进展。