Neuronal FGF21 Signaling in the Detection of Dietary Protein Restriction

项目摘要/摘要 中枢神经系统被认为是能量和葡萄糖的主要调节器。 动态平衡。我们的数据表明，限制饮食蛋白质会增加能量消耗和 改善葡萄糖的动态平衡，这种作用在很大程度上是由代谢激素介导的 FGF21.事实上，我们的数据表明，FGF21是唯一已知的具有特异性的内分泌激素 协调对蛋白质限制的适应性反应。因此，本项目采用了饮食模式 蛋白质限制探讨FGF21影响能量的生理机制 支出和血糖稳态，特别是测试中枢神经系统内的FGF21信号是否 蛋白质限制的代谢效应所必需的。此模型将通过删除 需要来自神经元的成纤维细胞生长因子共同受体β-Klotho(KLb)，并确定是否有CNS FGF21缺失的小鼠 信号不能表现出增加能量消耗或改善血糖稳态 低蛋白质饮食。考虑到我们目前缺乏关于通过哪些机制 FGF21的作用，这项工作将既定义中枢神经系统对FGF21信号的贡献，同时也 描绘了第一个已知的解释协调代谢变化的神经内分泌模型 由限制饮食蛋白质引起的。

PROJECT SUMMARY/ABSTRACT The central nervous system is acknowledged as a major regulator of both energy and glucose homeostasis. Our data demonstrates that dietary protein restriction increases energy expenditure and improves glucose homeostasis, and that this effect is largely mediated by the metabolic hormone FGF21. Indeed, our data suggest that FGF21 is the only known endocrine hormone that specifically coordinates adaptive responses to protein restriction. Therefore, this project uses the model of dietary protein restriction to probe the physiological mechanisms through which FGF21 influences energy expenditure and glucose homeostasis, specifically testing whether FGF21 signaling within the CNS is required for the metabolic effects of protein restriction. This model will be tested by deleting the required FGF co-receptor beta-Klotho (Klb) from neurons, and determining if mice lacking CNS FGF21 signaling fail to exhibit increased energy expenditure or improved glucose homeostasis when placed on a low protein diet. Considering our current lack of certainty regarding the mechanisms through which FGF21 acts, this work will both define the contribution of the CNS to FGF21 signaling while also delineating the first known neuroendocrine model to explain the coordinated metabolic changes induced by dietary protein restriction.