FGF21 is an endocrine signal of protein restriction

 描述(由申请人提供)：限制饮食蛋白质摄入会导致新陈代谢的适应性变化并延长寿命，但调节饮食蛋白质限制的细胞机制及其对健康和长寿的影响几乎没有描述。我们最近发现，激素FGF21是由饮食蛋白质限制强烈诱导的，而缺乏FGF21的小鼠无法改变食物摄入量、能量消耗或体重对饮食蛋白质限制的反应。这些数据不仅重新定义了FGF21的生理作用，还识别了一种全新的内分泌机制，似乎可以解释蛋白质限制对代谢的影响。该项目通过以下方式扩展这些数据 1)确定限制饮食蛋白质增加肝脏FGF21的细胞机制，2)确定限制饮食蛋白质对能量消耗的影响是否需要中枢或脂肪组织内的FGF21信号，以及3)描述限制蛋白质预防高脂饮食诱导的肥胖和葡萄糖耐量异常的机制。该项目将重新定义FGF21在营养限制适应性反应中的生理作用，并为饮食蛋白质、代谢和健康之间的关系提供新的机制解释。

 DESCRIPTION (provided by applicant): The restriction of dietary protein intake induces adaptive changes in metabolism and increases lifespan, but the cellular mechanisms mediating the detection of dietary protein restriction and its effects on health and longevity are virtually undescribed. We recently discovered that the hormone FGF21 is robustly induced by dietary protein restriction, and that mice lacking FGF21 fail to alter food intake, energy expenditure or body weight in response to dietary protein restriction. These data not only redefine the physiological role for FGF21, they also identify a fundamentally novel endocrine mechanism that appears to explain the metabolic effects of protein restriction. This project extends these data by 1) Identifying the cellular mechanism whereby dietary protein restriction increases hepatic FGF21, 2) Determining whether FGF21 signaling within the CNS or adipose tissue is required for the effects of dietary protein restriction on energy expenditure, and 3) Delineating the mechanisms through which protein restriction protects against HFD-induced obesity and glucose intolerance. This project will redefine the physiological role of FGF21 in the adaptive responses to nutrient restriction and provide a novel mechanistic explanation for the relationship between dietary protein, metabolism and health.