Department of Neurobiology, Physiology, and Behavior, College of Biological Sciences, University of California, Davis, Davis, California.
Endocrinology. 2019 May 1;160(5):1069-1080. doi: 10.1210/en.2018-01056.
Whereas carbohydrates and lipids are stored as glycogen and fat, there is no analogous inert storage form of protein. Therefore, continuous adjustments in feeding behavior are needed to match amino acid supply to ongoing physiologic need. Neuroendocrine mechanisms facilitating this behavioral control of protein and amino acid homeostasis remain unclear. The hepatokine fibroblast growth factor-21 (FGF21) is well positioned for such a role, as it is robustly secreted in response to protein and/or amino acid deficit. In this study, we tested the hypothesis that FGF21 feeds back at its receptors in the nervous system to shift macronutrient selection toward protein. In a series of behavioral tests, we isolated the effect of FGF21 to influence consumption of protein, fat, and carbohydrate in male mice. First, we used a three-choice pure macronutrient-diet paradigm. In response to FGF21, mice increased consumption of protein while reducing carbohydrate intake, with no effect on fat intake. Next, to determine whether protein or carbohydrate was the primary-regulated nutrient, we used a sequence of two-choice experiments to isolate the effect of FGF21 on preference for each macronutrient. Sweetness was well controlled by holding sucrose constant across the diets. Under these conditions, FGF21 increased protein intake, and this was offset by reducing the consumption of either carbohydrate or fat. When protein was held constant, FGF21 had no effect on macronutrient intake. Lastly, the effect of FGF21 to increase protein intake required the presence of its co-receptor, β-klotho, in neurons. Taken together, these findings point to a novel liver→nervous system pathway underlying the regulation of dietary protein intake via FGF21.
虽然碳水化合物和脂肪被储存为糖原和脂肪，但蛋白质没有类似的惰性储存形式。因此，需要不断调整进食行为，以匹配氨基酸供应与持续的生理需求。促进这种蛋白质和氨基酸动态平衡的行为控制的神经内分泌机制仍不清楚。肝源细胞因子成纤维细胞生长因子 21（FGF21）非常适合发挥这种作用，因为它对蛋白质和/或氨基酸缺乏有强烈的分泌反应。在这项研究中，我们检验了 FGF21 通过其在神经系统中的受体反馈，将宏量营养素选择转向蛋白质的假设。在一系列行为测试中，我们分离了 FGF21 影响雄性小鼠对蛋白质、脂肪和碳水化合物的消费的作用。首先，我们使用了三选一的纯宏量营养素饮食范式。FGF21 促使小鼠增加蛋白质的摄入，同时减少碳水化合物的摄入，对脂肪的摄入没有影响。接下来，为了确定蛋白质或碳水化合物是主要调节营养素，我们使用了一系列的二选一实验来分离 FGF21 对每种宏量营养素的偏好的影响。在这些饮食中，通过保持蔗糖在整个饮食中的恒定来很好地控制甜味。在这些条件下，FGF21 增加了蛋白质的摄入，而通过减少碳水化合物或脂肪的消耗来抵消这种增加。当蛋白质保持恒定时，FGF21 对宏量营养素的摄入没有影响。最后，FGF21 增加蛋白质摄入的作用需要其共同受体 β-klotho 存在于神经元中。总之，这些发现指向了一个新的肝脏→神经系统途径，通过 FGF21 调节膳食蛋白质摄入。
