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）是一个进化上保守的区域 下丘脑在生理和行为中发挥重要作用，包括控制 食欲、能量平衡、胰岛素敏感性、生育力和哺乳期。在啮齿动物模型中，起始 高脂肪饮食 (HFD) 会提前迅速诱发 Arc-ME 内的炎症 周围组织中观察到的炎症。基因研究破坏了这种炎症 防止肥胖，表明炎症是因果关系，并且对人类的研究表明 弓形炎症与肥胖之间的相关性。弓形具有独特的解剖结构 与血液的关系，因为不存在经典的内皮血脑屏障（BBB） 将其与正中隆起分开，正中隆起由有孔毛细血管内陷， 与末梢循环连续。在这里，发现了特化的室管膜细胞 tanycytes 衬在基底下丘脑的心室壁上，延伸出分离的复杂过程 Arc 和 ME，从而将 ME、CSF 和脑实质划分为不同的区域 隔间。下丘脑炎症的研究此前尚未阐明其作用 tanycytes，尽管其独特的定位。使用单细胞 RNA-seq，我们观察到 HFD 诱导干扰素反应途径，特别是在 2 tanycytes 中，该亚群 接触末梢循环。我们假设 2 tanycytes 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， 引发下丘脑炎症。我们建议通过检查是否 干扰素反应程序在其中被特异性诱导或破坏的遗传模型 tanycytes对于诱导下丘脑炎症是充分/必要的。我们进一步建议 定义特定的干扰素调节因子靶标，通过该靶标单胞细胞可引发炎症 单细胞内转录和表观基因组分析以及细胞估计的组合 来自扰动模型的单细胞测序的细胞通信。这些研究共同 将证明 tanycytes 在引发 HFD 诱导的下丘脑炎症中的新作用 并确定使他们能够做到这一点的特定分子目标。由于 2 tanycytes 位于 在 BBB 之外，它们提供有吸引力且特定的靶细胞类型调节能量 体内平衡是设计对抗肥胖疗法的依据。