Minneapolis Veterans Affairs Health Care System, Minneapolis, MN 55417, USA.
Department of Neuroscience, University of Minnesota Twin Cities, Minneapolis, MN 55455, USA.
Int J Mol Sci. 2023 Feb 8;24(4):3381. doi: 10.3390/ijms24043381.
Microglial fatty-acid binding protein 4 (FABP4) is a regulator of neuroinflammation. We hypothesized that the link between lipid metabolism and inflammation indicates a role for FABP4 in regulating high fat diet (HFD)-induced cognitive decline. We have previously shown that obese FABP4 knockout mice exhibit decreased neuroinflammation and cognitive decline. FABP4 knockout and wild type mice were fed 60% HFD for 12 weeks starting at 15 weeks old. Hippocampal tissue was dissected and RNA-seq was performed to measure differentially expressed transcripts. Reactome molecular pathway analysis was utilized to examine differentially expressed pathways. Results showed that HFD-fed FABP4 knockout mice have a hippocampal transcriptome consistent with neuroprotection, including associations with decreased proinflammatory signaling, ER stress, apoptosis, and cognitive decline. This is accompanied by an increase in transcripts upregulating neurogenesis, synaptic plasticity, long-term potentiation, and spatial working memory. Pathway analysis revealed that mice lacking FABP4 had changes in metabolic function that support reduction in oxidative stress and inflammation, and improved energy homeostasis and cognitive function. Analysis suggested a role for WNT/β-Catenin signaling in the protection against insulin resistance, alleviating neuroinflammation and cognitive decline. Collectively, our work shows that FABP4 represents a potential target in alleviating HFD-induced neuroinflammation and cognitive decline and suggests a role for WNT/β-Catenin in this protection.
小胶质细胞脂肪酸结合蛋白 4（FABP4）是神经炎症的调节剂。我们假设脂质代谢和炎症之间的联系表明 FABP4 在调节高脂肪饮食（HFD）诱导的认知衰退中发挥作用。我们之前已经表明，肥胖的 FABP4 基因敲除小鼠表现出神经炎症减少和认知衰退减少。从 15 周龄开始，将 FABP4 基因敲除和野生型小鼠喂食 60%的 HFD 12 周。分离海马组织并进行 RNA-seq 以测量差异表达的转录物。利用 Reactome 分子途径分析来检查差异表达的途径。结果表明，喂食 HFD 的 FABP4 基因敲除小鼠的海马转录组与神经保护一致，包括与促炎信号、内质网应激、细胞凋亡和认知衰退减少相关的关联。这伴随着上调神经发生、突触可塑性、长时程增强和空间工作记忆的转录本增加。途径分析显示，缺乏 FABP4 的小鼠在代谢功能上发生了变化，这些变化支持减少氧化应激和炎症，并改善能量稳态和认知功能。分析表明 WNT/β-连环蛋白信号在抵抗胰岛素抵抗、减轻神经炎症和认知衰退方面发挥作用。总之，我们的工作表明 FABP4 代表了缓解 HFD 诱导的神经炎症和认知衰退的潜在靶点，并表明 WNT/β-连环蛋白在这种保护中发挥作用。
