The role of interferon regulatory factors in tanycytes during HFD-induced inflammation, obesity and glucose dysregulation

干扰素调节因子在 HFD 诱导的炎症、肥胖和葡萄糖失调过程中的作用

• 批准号: 10446598
• 负责人: Linus Tzu-Yen Tsai
• 金额: $ 57.45万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446598
• 关键词: ATAC-seq; Address; Adult; Anatomy; Astrocytes; Atlases; Autopsy; Behavior; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; CRISPR/Cas technology; Cell Communication; Cell Nucleus; Cell physiology; Cells; Ceramides; Communication; Complex; Continuous Capillary; Cues; Data; Desire for food; Diet; Effector Cell; Endothelium; Ependymal Cell; Epidemic; Face; Fenestrated Capillary; Fertility; Gene Expression Profiling; Genes; Genetic Models; Genetic Transcription; Genetic study; Glucose; Healthcare Systems; High Fat Diet; Homeostasis; Human; Hypothalamic structure; IRF3 gene; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Interferon Activation; Interferons; Lactation; Life; Location; LoxP-flanked allele; MAPK8 gene; Magnetic Resonance Imaging; Mediating; Mediator of activation protein; Metabolic dysfunction; Methods; Microglia; Modeling; Molecular; Molecular Target; Mus; Neurons; Nutritional; Obesity; Overnutrition; Participant; Pathologic; Pathway Analysis; Pathway interactions; Peripheral; Pharmacological Treatment; Phenotype; Physiological; Physiology; Play; Positioning Attribute; Process; RNA; Regulation; Regulator Genes; Regulatory Element; Rodent Model; Role; Sentinel; Side; Signal Transduction; Stream; Structure of nucleus infundibularis hypothalami; TLR4 gene; Testing; Therapeutic; Tissues; Transcriptional Activation; Ventricular; Weight Gain; Work; brain parenchyma; cell type; combat; design; endoplasmic reticulum stress; energy balance; epigenomics; glucose metabolism; improved; insulin sensitivity; knockout gene; median eminence; metabolic phenotype; neurogenesis; obesogenic; passive transport; peripheral blood; progenitor; programs; receptor; response; single cell sequencing; single-cell RNA sequencing; transcriptome sequencing

Project Abstract The arcuate nucleus-median eminence complex (Arc-ME) is an evolutionarily conserved region of the hypothalamus that plays important roles in physiology and behavior, including control of appetite, energy balance, insulin sensitivity, fertility and lactation. In rodent models, the initiation of a high fat diet (HFD) rapidly induces inflammation specifically within Arc-ME, well in advance of inflammation observed in peripheral tissues. Genetic studies disrupting this inflammation protect from obesity, suggesting the inflammation is causal, and studies in humans show a correlation between arcuate inflammation and obesity. The arcuate has a unique anatomical relationship with bloodstream, as there is no classic endothelial Blood-Brain-Barrier (BBB) separating it from the median eminence, which is invaginated by fenestrated capillaries that are continuous with the peripheral circulation. Here, tanycytes, specialized ependymal cells found lining the ventricular wall of the basal hypothalamus, extend elaborate processes that separate the Arc and ME, thereby partitioning the ME, CSF, and brain parenchyma into distinct compartments. Studies of hypothalamic inflammation have not previously addressed a role for tanycytes, despite their unique localization. Using single cell RNA-seq, we observe that HFD induces an interferon response pathway specifically in 2 tanycytes, the subpopulation that contacts the peripheral circulation. We hypothesize that 2 tanycytes are sentinel cells that respond to signals associated with HFD by upregulating an inflammatory gene program and initiates hypothalamic inflammation. We propose to test this hypothesis by examining whether genetic models in which the interferon response program is specifically induced or disrupted in tanycytes is sufficient/necessary for induction of hypothalamic inflammation. We further propose to define specific interferon regulatory factor targets by which tanycytes elicit inflammation using a combination of transcriptional and epigenomic profiling within tanycytes and estimation of cell- cell communication from single cell sequencing of our perturbed models. Together, these studies will demonstrate a new role for tanycytes in initiating HFD-induced hypothalamic inflammation and identify specific molecular targets that enable them to do so. As 2 tanycytes are located outside of the BBB, they provide an attractive and specific target cell type modulating energy homeostasis against which to design therapeutics to combat obesity.

项目摘要 弓状核-正中隆起复合体(Arc-ME)是一个进化保守区 在生理和行为中起重要作用的下丘脑，包括控制 食欲、能量平衡、胰岛素敏感性、生育和哺乳。在啮齿动物模型中，启动 高脂饮食(HFD)提前很久迅速诱导Arc-ME内的炎症 周围组织中观察到的炎症反应。破坏这种炎症的基因研究 预防肥胖，这表明炎症是有原因的，而对人类的研究表明 弓状体炎与肥胖的相关性。弓形有一种独特的解剖结构 与血流的关系，因为没有经典的内皮血脑屏障(BBB) 将它与中间隆起分开，中间隆起被有窗口的毛细血管内陷，这些毛细血管是 与周围循环连续不断。在这里，发现了张力细胞，特化的室管膜细胞 衬里底部下丘脑的室壁，延伸出精细的突起，将 Arc和ME，从而将ME、CSF和脑实质划分为不同的 车厢。对下丘脑炎症的研究以前并没有涉及到 松弛细胞，尽管它们有独特的定位。利用单细胞RNA-seq，我们观察到HFD 在2张力细胞中特异性地诱导干扰素反应途径，该亚群 接触外周循环。我们假设2伸缩细胞是前哨细胞 通过上调炎症基因程序来响应与HFD相关的信号，并 引发下丘脑发炎。我们建议检验这一假说是否 干扰素反应程序被特异性诱导或中断的遗传模型 伸展细胞是诱导下丘脑炎症的充分/必需细胞。我们进一步建议 要确定特定的干扰素调节因子靶点，柔韧性细胞通过这些靶点引发炎症 柔韧细胞内转录和表观基因组图谱的组合以及细胞- 从我们的受扰模型的单细胞测序得到的细胞通讯。总而言之，这些研究 将展示伸缩细胞在启动HFD诱导的下丘脑炎症中的新作用 并确定特定的分子靶标，使他们能够做到这一点。随着2伸缩细胞的定位 在血脑屏障之外，它们提供了一种有吸引力的和特定的靶细胞类型的调节能量 动态平衡是设计对抗肥胖的治疗药物所依据的。