Tanycytes and Hypothalamic Inflammation Associated with Obesity

与肥胖相关的单细胞和下丘脑炎症

• 批准号: 9032508
• 负责人: RONALD Michael LECHAN
• 金额: $ 20.42万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9032508
• 关键词: Adaptor Signaling Protein; Adipose tissue; Adult; Affect; Animals; Appetite Regulation; Area; Binding; Blood; Blood Vessels; Body Weight; Brain; Cell Line; Cell Nucleus; Cells; Cerebrospinal Fluid; Chemotactic Factors; Chronic; Comorbidity; Coronary heart disease; Development; Eating; Energy Metabolism; Ependymal Cell; Epidemic; Fatty acid glycerol esters; Floor; Functional disorder; Gene Expression Profile; Genes; Health; High Fat Diet; Homeostasis; Hypertension; Hypothalamic structure; Image; Inflammation; Inflammation Mediators; Insulin; Insulin Resistance; Intervention; Knowledge; Leptin; Leptin resistance; Life; Liver; Location; Metabolic syndrome; Modality; Molecular Target; Morbidity - disease rate; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Overweight; Pathogenesis; Pathway interactions; Prevalence; Public Health; Receptor Signaling; Risk; Role; Satiation; Saturated Fatty Acids; Signal Pathway; Signal Transduction; Skeletal Muscle; Structure of nucleus infundibularis hypothalami; TLR2 gene; TLR4 gene; Testing; Third ventricle structure; Toll-like receptors; Transgenic Animals; Visceral; Weight Gain; Weight maintenance regimen; base; blood glucose regulation; cell type; chemokine; cytokine; feeding; inflammatory marker; insulin sensitivity; mortality; obesity in children; obesity management; obesity treatment; response; success; transcriptome sequencing

 DESCRIPTION (provided by applicant): We hypothesize that hypothalamic inflammation associated with high fat feeding arises as a result of Toll-like receptor (TLR) signaling in a specialized cell type lining the inferolateral walls of the third ventricle, the alpha tanycyte. We propose that the activation of NF-κB in these cells releases inflammatory mediators into feeding-related centers in the mediobasal hypothalamus, increasing feeding and/or altering the sensitivity of arcuate/ventromedial nucleus neurons to leptin and/or insulin. To test this hypothesis, RNA-Seq analysis will be used to identify the complete gene expression profile of alpha tanycytes in response to a HFD, with particular emphasis given to the identification of genes and pathways involved in inflammation. Based on this analysis, the effect of a HFD on food intake, energy expenditure, glucose homeostasis, leptin and insulin sensitivity, and other parameters of hypothalamic inflammation will be studied in transgenic animals with conditional KO in alpha tanycytes of selected genes identified in the RNA-Seq analysis. We propose that these studies will demonstrate a critical role of tanycytes in the pathophysiology of hypothalamic inflammation associated with high fat feeding, uncovering new knowledge in understanding the pathogenesis of obesity and a potentially new pharmacologic target for the treatment of obesity.

 描述（由适用提供）：我们假设在第三个心室的专门细胞类型中，由于Toll样受体（TLR）信号传导而导致下丘脑炎症与高脂肪进食相关，这是由于Toll样受体（TLR）信号传导的结果，即第三个心室的下外侧壁，Alpha tanycyte。我们 提出，这些细胞中NF-κB的激活将炎症介质释放到中层下丘脑中与喂养相关的中心中，从而增加了喂食和/或改变弧形/腹膜核神经元对瘦素和/或胰岛素的敏感性。为了检验这一假设，RNA-SEQ分析将用于鉴定响应于HFD的α胞囊的完整基因表达谱，并特别强调鉴定炎症中包含的基因和途径。基于此分析，HFD对食物摄入，能量消耗，葡萄糖稳态，瘦素和胰岛素敏感性以及下丘脑炎症的其他参数的影响将在转基因动物中研究，在RNA-seq分析中鉴定出的αtanycytes中的有条件KO。我们建议这些研究将证明丹麦氏症在与高脂肪喂养相关的下丘脑炎症的病理生物生物生物生物学中的关键作用，从而在理解肥胖症的发病机理和治疗肥胖症治疗的潜在新的药理学靶点方面发现了新知识。