FGF21-dependent mechanisms driving changes in energy expenditure during dietary protein restriction

项目摘要 膳食蛋白质摄入改变能量消耗并重塑脂肪组织，但其细胞机制 调解这些影响在很大程度上是未知的。我们最近发现，荷尔蒙FGF21非常强健 由于限制饮食蛋白质而增加，缺乏FGF21的小鼠未能表现出预期的变化 生长、能量消耗或葡萄糖稳态对饮食限制的反应。此外，有选择性地 大脑中FGF21共受体β-Klotho(KLb)的缺失也会阻止对 蛋白质限制。这一发现重新定义了成纤维细胞生长因子21的生理作用，表明它直接作用于 大脑协调对蛋白质限制的适应性、动态平衡反应。本项目扩展了这些功能 数据通过1)确定调节能量变化的依赖于FGF21的神经生物学机制 蛋白质限制期间的支出，以及2)确定蛋白质限制的机制，通过 大脑FGF21信号，重塑脂肪组织，从而影响能量消耗和代谢 健康。这个项目将定义动物感知和响应蛋白质限制的机制。 同时也描绘了FGF21在大脑中刺激能量消耗的机制。

Project Summary Dietary protein intake alters energy expenditure and remodels adipose tissue, but the cellular mechanisms mediating these effects are largely undescribed. We recently discovered that the hormone FGF21 is robustly increased by dietary protein restriction and that mice lacking FGF21 fail to exhibit the expected changes in growth, energy expenditure or glucose homeostasis in response to dietary restriction. In addition, selective deletion of the FGF21 co-receptor beta-Klotho (Klb) from the brain also blocks the metabolic response to protein restriction. This discovery has redefined FGF21's physiological role by suggesting that it acts directly in the brain to coordinate the adaptive, homeostatic response to protein restriction. This project extends these data by 1) Identifying the FGF21-dependent neurobiological mechanisms that mediate changes in energy expenditure during protein restriction, and 2) Determining the mechanism through which protein restriction, via brain FGF21 signaling, remodels adipose tissue and thereby influences energy expenditure and metabolic health. This project will define the mechanism through which animals sense and respond to protein restriction while also delineating the mechanisms through which FGF21 acts in the brain to stimulate energy expenditure.