Regulation of energy and glucose homeostasis by endogenous hypothalamic FGF1

项目摘要 在过去的30年里，肥胖和2型糖尿病（T2D）已经成为最常见和最常见的糖尿病之一。 现代社会所面临的昂贵的慢性病。肥胖患者的治疗结局，或 由于缺乏非手术药物治疗，T2D显示出最小的改善， 持续的功效。因此，迫切需要新的、更有效的治疗选择， 针对大脑的战略具有满足这一需求的重要潜力。作为相关临床前 工作，我们的小组最近表明，信号在大脑中的外源性管理的成员， 成纤维细胞生长因子（FGF）家族产生有效的减肥和抗糖尿病作用。我们的K08提案 集中在持续的抗糖尿病作用的基础上的综合中枢和外周机制 在肥胖和T2D啮齿动物模型中的外源性FGF 1。在这个应用中，我们提出了一个平行的研究路线， 该研究将研究内源性下丘脑FGF 1信号传导在能量和葡萄糖调节中的作用 体内平衡我们最近发现，FGF 1是内源性表达的伸长细胞和细胞分布， 在许多关键的下丘脑区域，涉及体重和葡萄糖的控制。您因前述 观察到内源性下丘脑FGF1表达受禁食和再喂养的调节， 研究表明，从下丘脑神经元或伸长细胞中删除FGF1会导致体重增加和葡萄糖 对食物不耐受。这些数据支持了内源性下丘脑FGF 1信号传导发挥作用的前提， 在能量和葡萄糖稳态调节中的生理作用。我们将调查这一假设， 确定表达FGF 1的特定下丘脑核和细胞类型， 人群对代谢状态和饮食的急性和慢性变化的反应，以及干扰的程度。 内源性下丘脑FGF 1信号传导足以促进肥胖和葡萄糖代谢的发展。 不容忍从这些调查中获得的数据将形成一个新的研究路线的基础， 内源性下丘脑FGF1信号传导作为治疗肥胖和T2D的新靶点。

Project Summary Over the past 3 decades, obesity and type 2 diabetes (T2D) have emerged as among the most common and costly chronic diseases confronting modern society. Treatment outcomes for patients affected with obesity or T2D have shown minimal improvement due to the absence of non-surgical medical treatments that have sustained efficacy. Therefore, an urgent need for new, more effective treatment options therefore exists, and strategies targeting the brain have important potential to meet this need. As one example of relevant preclinical work, our group has recently shown that signaling in the brain by exogenous administration of members of the fibroblast growth factor (FGF) family produces potent weight-loss and anti-diabetic effects. Our K08 proposal focused on the integrated central and peripheral mechanisms underlying the sustained anti-diabetic action of exogenous FGF1 in rodent models of obesity and T2D. In this application, we propose a parallel line of studies that will investigate the role of endogenous hypothalamic FGF1 signaling in the regulation of energy and glucose homeostasis. We have recently found that FGF1 is endogenously expressed by tanycytes and cells distributed in a number of key hypothalamic areas implicated in the control of body weight and glucose. Further, we have observed that endogenous hypothalamic FGF1 expression is regulated fasting and refeeding and in preliminary studies that deleting FGF1 from either hypothalamic neurons or tanycytes induces weight gain and glucose intolerance on chow diet. These data support the premise that endogenous hypothalamic FGF1 signaling plays a physiologic role in the regulation of energy and glucose homeostasis. We will investigate this hypothesis by determining the specific hypothalamic nuclei and cell types that express FGF1, identify which of these populations respond to acute and chronic changes in metabolic status and diet, and the extent to which disrupting endogenous hypothalamic FGF1 signaling is sufficient to promote the development of obesity and glucose intolerance. The data obtained from these investigations will form the basis of a new line of research centered on endogenous hypothalamic FGF1 signaling as a novel target to treat obesity and T2D.