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: 8852848
• 负责人: RONALD Michael LECHAN
• 金额: $ 24.75万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852848
• 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; Diet; Eating; Energy Metabolism; Ependymal Cell; Epidemic; Fatty acid glycerol esters; Floor; Functional disorder; Gene Expression Profile; Genes; Health; 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 Receptor 2; 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; public health relevance; 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(申请人提供)：我们假设，与高脂肪喂养相关的下丘脑炎症是由于Toll样受体(TLR)信号在第三脑室下外侧壁上的一种特殊细胞类型，即α-tanycell中的信号所致。我们 推测这些细胞中的NF-κB的激活释放炎症介质到下丘脑内侧基底核的摄食相关中心，增加摄食和/或改变弓状核/腹内侧核神经元对瘦素和/或胰岛素的敏感性。为了验证这一假设，将使用RNA-Seq分析来确定阿尔法伸缩细胞对HFD的反应的完整基因表达谱，并特别强调识别参与炎症的基因和途径。在这一分析的基础上，将在RNA-Seq分析中确定的选定基因的阿尔法张力细胞中存在条件性KO的转基因动物中，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其他下丘脑炎症参数的影响。我们认为，这些研究将证明伸展细胞在与高脂饮食相关的下丘脑炎症的病理生理学中发挥关键作用，揭示理解肥胖发病机制的新知识，并为肥胖的治疗提供潜在的新的药理靶点。