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式生物，探究全身性炎症（systemic inflammation）对肥胖模型中神经炎症的影响。研究通过定制化高脂饲料喂养成体及幼体斑马鱼以构建肥胖模型，并通过多项实验验证该高脂饮食诱导的肥胖模型：幼体与成体的油红O（Oil Red-O）染色、成体的体质量指数（body mass index, BMI）检测，以及幼体肝脏的BODIPY（BODIPY staining）染色。本研究设置两组实验模型：第一组对肥胖幼体及成体斑马鱼实施鳍切除术；第二组向肥胖成体斑马鱼腹腔注射脂多糖（lipopolysaccharide, LPS）。在高脂饮食诱导的肥胖斑马鱼中可观察到神经炎症现象。在肥胖斑马鱼鳍切除术模型中，研究人员发现脂肪因子（adipokine）表达发生异常。此外，研究还记录到神经炎症、小胶质细胞（microglia）增殖增多，以及后脑结节（posterior tuberculum）中脂质运载蛋白-2（Lipocalin-2）表达上调；鳍切除术后的肥胖斑马鱼出现认知功能下降及类焦虑行为。在腹腔注射脂多糖的肥胖斑马鱼模型中，研究人员观测到代谢通路异常、铁蓄积、脂质运载蛋白-2表达上调、后脑结节处巨噬细胞（macrophage）浸润，以及神经炎症；同时本研究还对自噬（autophagy）进行了探究。为明确巨噬细胞来源的白细胞介素1β（interleukin-1β, IL-1β）能否缓解炎症及神经炎症，研究人员构建了巨噬细胞IL-1β基因特异性敲除的斑马鱼模型，结果显示巨噬细胞IL-1β敲除可改善全身性炎症后的认知功能，并减轻神经炎症。综合以上数据，本研究确认巨噬细胞来源的IL-1β是连接肥胖进程中全身性炎症、脂质代谢与神经炎症结局的关键介导因子。巨噬细胞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、分子生物学及影像学分析，为依赖IL-1β的信号通路连接外周代谢炎症与中枢神经系统（central nervous system, CNS）病理过程提供了充分证据。本研究结果提示，IL-1β是极具潜力的治疗靶点，可用于区分全身性代谢炎症与神经退行性疾病风险，同时加深了我们对肥胖及炎症性疾病背景下性别特异性免疫-代谢-神经相互作用的理解。