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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

基本信息

批准号：
10621286
负责人：
Linus Tzu-Yen Tsai
金额：
$ 55.1万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10621286
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 Line Cell physiology Cells Ceramides Circulation Communication Complex Continuous Capillary Cues Data Desire for food Diet Disparate Endothelium Ependymal Cell Epidemic Face Fenestrated Capillary Fertility Gene Expression Profiling Genes Genetic Models 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 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 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 constitutive expression design endoplasmic reticulum stress energy balance epigenomic profiling 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 nucleus RNA-sequencing single-cell RNA sequencing transcriptome sequencing

项目摘要

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