Fibroblast growth factor 21 (FGF21) as a metabolic stress hormone, is mainly secreted by the liver. In addition to its well‐defined roles in energy homeostasis, FGF21 has been shown to promote remyelination after injury in the central nervous system. In the current study, we sought to examine the potential roles of FGF21 in the peripheral nervous system (PNS) myelination. In the PNS myelin development, Fgf21 expression was reversely correlated with myelin gene expression. In cultured primary Schwann cells (SCs), the application of recombinant FGF21 greatly attenuates myelination‐associated gene expression, including Oct6, Krox20, Mbp, Mpz, and Pmp22. Accordingly, the injection of FGF21 into neonatal rats markedly mitigates the myelination in sciatic nerves. On the contrary, the infusion of the anti‐FGF21 antibody accelerates the myelination. Mechanistically, both extracellular signal‐regulated kinase (ERK) and p38 mitogen‐activated protein kinase (MAPK) were stimulated by FGF21 in SCs and sciatic nerves. Following experiments including pharmaceutical intervention and gene manipulation revealed that the p38 MAPK/c‐Jun axis, rather than ERK, is targeted by FGF21 for mediating its repression on myelination in SCs. Taken together, our data provide a new aspect of FGF21 by acting as a negative regulator for the myelin development process in the PNS via activation of p38 MAPK/c‐Jun.

中文翻译：

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FGF21 通过刺激 p38 MAPK/c-Jun 轴阻碍外周髓鞘发育。

成纤维细胞生长因子 21 (FGF21) 作为一种代谢应激激素，主要由肝脏分泌。除了在能量稳态中的明确作用外，FGF21 已被证明可促进中枢神经系统损伤后的髓鞘再生。在当前的研究中，我们试图检查 FGF21 在外周神经系统 (PNS) 髓鞘形成中的潜在作用。在 PNS 髓鞘发育中，Fgf21表达与髓鞘基因表达呈负相关。在培养的原代雪旺细胞 (SCs) 中，重组 FGF21 的应用大大减弱了髓鞘形成相关基因的表达，包括Oct6、Krox20、Mbp、Mpz和Pmp22. 因此，将 FGF21 注射到新生大鼠中显着减轻了坐骨神经的髓鞘形成。相反，抗 FGF21 抗体的输注会加速髓鞘形成。从机制上讲，细胞外信号调节激酶（ERK）和 p38 丝裂原活化蛋白激酶（MAPK）都受到 SCs 和坐骨神经中的 FGF21 的刺激。包括药物干预和基因操作在内的实验表明，FGF21 靶向 p38 MAPK/c-Jun 轴，而不是 ERK，以介导其对 SCs 髓鞘形成的抑制。总之，我们的数据通过激活 p38 MAPK/c-Jun 充当 PNS 髓鞘发育过程的负调节因子，为 FGF21 提供了一个新的方面。