Tanycytes and Hypothalamic Inflammation Associated with Obesity

与肥胖相关的单细胞和下丘脑炎症

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：我们研究发现，与高脂肪喂养相关的下丘脑炎症是由第三脑室下侧壁内衬的一种特殊细胞类型（α tanycyte We）中的 Toll 样受体 (TLR) 信号传导引起的。提出这些细胞中 NF-κB 的激活将炎症介质释放到内侧下丘脑的进食相关中心，增加进食和/或改变弓状/腹内侧核神经元对瘦素和/或胰岛素的敏感性。 RNA-Seq 分析将用于鉴定 α tanycytes 响应 HFD 的完整基因表达谱，特别强调鉴定与炎症相关的基因和途径。我们建议在转基因动物中研究 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其他参数的影响，并在 RNA-Seq 分析中确定的选定基因的 α 单胞中进行条件性敲除。这些研究将证明单细胞在与高脂肪喂养相关的下丘脑炎症的病理生理学中发挥关键作用，揭示了解肥胖发病机制的新知识以及治疗的潜在新药理学靶点肥胖症。