Objective

Insulin-like growth factor 1 (IGFI) is one of several growth factors which is induced by growth hormone (GH), which activates the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) pathway, and plays crucial roles in normal human growth, metabolism, and systemic energy homeostasis. However, little is known about the negative regulation of IGF-I production under different physiological or pathological conditions. Herein, we explore whether activation of endoplasmic reticulum (ER) stress regulates IGF-I production and normal body growth.

Materials and methods

C57BL/6 J mice were challenged with tunicamycin (Tm) to induce ER stress activation. 24 h after stimulation, hepatic mRNA expression was analyzed by RNA-Seq and validated by qPCR. Enzyme-linked immunosorbent assay (ELISA) was performed 24 h after Tm stimulation. Body growth was determined 16 days after Tm stimulation. Animals were then sacrificed and liver tissues were collected for further analysis.

Results

Mice challenged with Tm displayed a retardation of growth. Molecularly, we found that ER stress inhibited phosphorylation of STAT5. IGF-I transcription and circulating IGF-I were also dramatically decreased under ER stress activation. Moreover, our results demonstrate that IGF-I administration ameliorates Tm-induced growth retardation.

Conclusions

ER stress induces growth retardation. ER stress inhibits hepatic GH-JAK2 signaling activation and its downstream target gene expression. These results warrant further research to explore the crosstalk between ER stress and growth hormone signaling in improving body growth.

中文翻译：

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内质网应激通过抑制生长激素 IGF-I 轴诱导生长迟缓。

客观的

胰岛素样生长因子 1 (IGF I) 是由生长激素 (GH) 诱导的几种生长因子之一，可激活 Janus 激酶 2 (JAK2)-信号转导和转录激活因子 5 (STAT5) 通路，并发挥在正常人类生长、新陈代谢和全身能量稳态中发挥关键作用。然而，在不同生理或病理条件下对 IGF-I 产生的负调控知之甚少。在此，我们探讨了内质网 (ER) 应激的激活是否调节 IGF-I 的产生和正常的身体生长。

材料和方法

C57BL/6 J 小鼠接受衣霉素 (Tm) 攻击以诱导 ER 应激激活。刺激后 24 小时，通过 RNA-Seq 分析肝脏 mRNA 表达并通过 qPCR 验证。Tm 刺激后 24 小时进行酶联免疫吸附测定 (ELISA)。在 Tm 刺激后 16 天确定身体生长。然后处死动物并收集肝组织用于进一步分析。

结果

用 Tm 攻击的小鼠表现出生长迟缓。在分子上，我们发现内质网应激抑制了 STAT5 的磷酸化。内质网应激激活下 IGF-I 转录和循环 IGF-I 也显着降低。此外，我们的结果表明 IGF-I 给药改善了 Tm 诱导的生长迟缓。

结论

内质网应激导致生长迟缓。ER 应激抑制肝脏 GH-JAK2 信号激活及其下游靶基因表达。这些结果值得进一步研究，以探索内质网应激和生长激素信号之间在改善身体生长方面的相互作用。