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 现代社会面临的代价高昂的慢性病。受肥胖或肥胖影响的患者的治疗结果 由于缺乏非手术治疗，T2D的改善微乎其微 持久的疗效。因此，迫切需要新的、更有效的治疗办法， 针对大脑的策略具有满足这一需求的重要潜力。作为相关临床前研究的一个例子 最近，我们的研究小组发现，大脑中的信号是通过外源性给药 成纤维细胞生长因子(FGF)家族具有强大的减肥和抗糖尿病作用。我们的K08提案 集中于持续抗糖尿病作用的中枢和外周综合机制 外源性FGF1在肥胖和T2D啮齿动物模型中的作用在这一应用中，我们提出了一条平行的研究路线 这将研究内源性下丘脑FGF1信号在能量和葡萄糖调节中的作用 动态平衡。我们最近发现，FGF1由内源性的伸缩细胞和分布的细胞表达 在一些关键的下丘脑区域涉及控制体重和血糖。此外，我们还拥有 观察到内源性下丘脑FGF1的表达受禁食和再摄食的调节，并在 从下丘脑神经元或松弛细胞中删除FGF1会导致体重增加和血糖升高的研究 对食物饮食的不容忍。这些数据支持内源性下丘脑FGF1信号发挥作用的前提 在调节能量和葡萄糖动态平衡方面的生理作用。我们将通过以下方式研究这一假设 确定表达FGF1的特定下丘脑核和细胞类型，识别以下哪些 人们对代谢状态和饮食的急性和慢性变化以及干扰的程度做出反应 内源性下丘脑FGF1信号足以促进肥胖和血糖的发展 不宽容。从这些调查中获得的数据将构成一个新的研究方向的基础 内源性下丘脑FGF1信号作为治疗肥胖和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.