Tanycytes and Hypothalamic Inflammation Associated with Obesity

 描述（由申请人提供）：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）信号传导导致的，该信号传导位于第三脑室下侧壁的一种特化细胞类型，即α-伸展细胞。我们 提出这些细胞中NF-κB的激活将炎症介质释放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。为了检验这一假设，将使用RNA-Seq分析来鉴定α-伸长细胞响应HFD的完整基因表达谱，特别强调鉴定炎症相关的基因和途径。基于该分析，将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的其他参数的影响，所述转基因动物在RNA-Seq分析中鉴定的所选基因的α-tanycytes中具有条件性KO。我们认为，这些研究将证明在下丘脑炎症的病理生理学与高脂肪喂养，揭示了新的知识，了解肥胖症的发病机制和一个潜在的新的药理学治疗肥胖症的目标的关键作用。

 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.