Hepatic c-Jun regulates glucose metabolism via FGF21 and modulates body temperature through the neural signals
Hepatic c-Jun regulates glucose metabolism via FGF21 and modulates body temperature through the neural signals
复制标题
肝脏 c-Jun 通过 FGF21 调节葡萄糖代谢，并通过神经信号调节体温。
DOI：
10.1016/j.molmet.2018.12.003
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发表时间：
2019
影响因子：
8.1
通讯作者：
Guo Feifan
中科院分区：
文献类型：
--
作者：
Xiao Fei;Guo Yajie;Deng Jiali;Yuan Feixiang;Xiao Yuzhong;Hui Lijian;Li Yu;Hu Zhimin;Zhou Yuncai;Li Kai;Han Xiao;Fang Qichen;Jia Weiping;Chen Yan;Ying Hao;Zhai Qiwei;Chen Shanghai;Guo Feifan
Jun是激活蛋白1（AP-1）家族的重要成员，参与细胞死亡和存活等多种生理过程。然而，肝脏c-Jun在全身代谢中的作用知之甚少。MethodsWe产生肝脏特异性c-Jun基因敲除（c-Jun△li）小鼠，以研究肝脏c-Jun对全身生理学的影响，特别是在血糖和体温。结果sc-jun △ li小鼠的肝细胞增殖能力明显高于对照组，体外实验结果与对照组相似。此外，c-Jun基因敲低可直接抑制成纤维细胞生长因子21（FGF 21）的表达，腺病毒介导的肝脏FGF 21过表达可阻断c-Jun对inc-jun△ li小鼠胚胎发生的影响。有趣的是，c-jun△ li小鼠也表现出较高的体温，诱导产热和解偶联蛋白1（UCP 1）在棕色脂肪组织（BAT）的表达。此外，在热中性温度（30 °C）下，-jun △ li和对照小鼠之间的体温变得相当。此外，注射β-肾上腺素能受体阻滞剂还可增加小鼠交感神经系统（SNS）的活动，并抑制小鼠体温升高。最后，SNS的激活和inc-jun△limice小鼠体温的升高很可能是由来自脑和肝迷走神经的信号引起的，作为c-Fos的表达（神经元激活的分子标志物）在控制体温的几个脑区发生了变化，选择性肝迷走神经切断术降低了体温。Jun通过FGF 21和神经信号调节胚胎发生和体温。我们的研究结果也提供了新的见解器官串扰的调节全身生理。
Objectivec-Jun, a prominent member of the activator protein 1 (AP-1) family, is involved in various physiology processes such as cell death and survival. However, a role of hepatic c-Jun in the whole-body metabolism is poorly understood.MethodsWe generated liver-specific c-Jun knock-out (c-jun△li) mice to investigate the effect of hepatic c-Jun on the whole-body physiology, particularly in blood glucose and body temperature. Primary hepatocytes were also used to explore a direct regulation of c-Jun in gluconeogenesis.Resultsc-jun△limice showed higher hepatic gluconeogenic capacity compared with control mice, and similar results were obtained in vitro. In addition, fibroblast growth factor 21 (FGF21) expression was directly inhibited by c-Jun knockdown and adenovirus-mediated hepatic FGF21 over-expression blocked the effect of c-Jun on gluconeogenesis inc-jun△limice. Interestingly,c-jun△limice also exhibited higher body temperature, with induced thermogenesis and uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT). Furthermore, the body temperature became comparable betweenc-jun△liand control mice at thermoneutral temperature (30 °C). Moreover, the activity of sympathetic nervous system (SNS) was increased inc-jun△limice and the higher body temperature was inhibited by beta-adrenergic receptor blocker injection. Finally, the activated SNS and increased body temperature inc-jun△limice was most likely caused by the signals from the brain and hepatic vagus nerve, as the expression of c-Fos (the molecular marker of neuronal activation) was changed in several brain areas controlling body temperature and body temperature was decreased by selective hepatic vagotomy.ConclusionsThese data demonstrate a novel function of hepatic c-Jun in the regulation of gluconeogenesis and body temperature via FGF21 and neural signals. Our results also provide novel insights into the organ crosstalk in the regulation of the whole-body physiology.