Despite the different physiologic functions of FGF19 and FGF21 as hormonal regulators of fed and fasted metabolism, their pharmacologic administration causes similar increases in energy expenditure, weight loss, and enhanced insulin sensitivity in obese animals. Here, in genetic loss-of-function studies of the shared co-receptor β-Klotho, we show that these pharmacologic effects are mediated through a common, tissue-specific pathway. Surprisingly, FGF19 and FGF21 actions in liver and adipose tissue are not required for their longer-term weight loss and glycemic effects. In contrast, β-Klotho in neurons is essential for both FGF19 and FGF21 to cause weight loss and lower glucose and insulin levels. We further show an FGF21 mimetic antibody that activates the FGF receptor 1/β-Klotho complex also requires neuronal β-Klotho for its metabolic effects. These studies highlight the importance of the nervous system in mediating the beneficial weight loss and glycemic effects of endocrine FGF drugs.

中文翻译：

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FGF19，FGF21和FGFR1 /β-Klotho激活抗体作用于神经系统以调节体重和糖血症

尽管FGF19和FGF21作为进食和禁食新陈代谢的激素调节剂具有不同的生理功能，但它们的药理作用导致肥胖动物的能量消耗，体重减轻和胰岛素敏感性增加。在这里，在对共有的共受体β-Klotho进行基因功能丧失研究中，我们显示了这些药理作用是通过共同的组织特异性途径介导的。出人意料的是，由于它们的长期减肥和血糖作用，它们在肝和脂肪组织中不需要FGF19和FGF21的作用。相反，神经元中的β-Klotho对于FGF19和FGF21引起体重减轻以及降低葡萄糖和胰岛素水平至关重要。我们进一步显示了激活FGF受体1 /β-Klotho复合物的FGF21模拟抗体，还需要神经元β-Klotho才能发挥其代谢作用。