Chronic mild stress alters circadian expressions of molecular clock genes in the liver.
Chronic mild stress alters circadian expressions of molecular clock genes in the liver.
复制标题
DOI：
10.1152/ajpendo.00388.2012
复制
发表时间：
2013-02
期刊：
影响因子：
--
通讯作者：
Kei Takahashi;Tetsuya Yamada;Sohei Tsukita;Keizo Kaneko;Yuta Shirai;Yuichiro Munakata;Y. Ishigaki;Junta Imai;Kenji Uno;Yutaka Hasegawa;Shojiro Sawada;Y. Oka;H. Katagiri
中科院分区：
文献类型：
--
作者：
Kei Takahashi;Tetsuya Yamada;Sohei Tsukita;Keizo Kaneko;Yuta Shirai;Yuichiro Munakata;Y. Ishigaki;Junta Imai;Kenji Uno;Yutaka Hasegawa;Shojiro Sawada;Y. Oka;H. Katagiri
众所周知，慢性压力会影响代谢调节。然而，相互联系的应激反应系统和代谢调节的分子机制尚未阐明。包括葡萄糖/脂质代谢在内的各种生理过程受昼夜节律钟调节，据报道核心时钟基因失调导致代谢紊乱。糖皮质激素作为下丘脑-垂体-肾上腺（HPA）轴的末端效应物，通过相移核心时钟基因表达来控制外周器官（包括肝脏）的昼夜节律。因此，我们研究是否慢性应激影响昼夜表达的核心时钟基因和代谢相关基因在肝脏中使用慢性轻度应激（CMS）的程序。在BALB/c小鼠中，CMS升高和相移血清皮质酮水平，表明HPA轴过度激活。核心时钟基因的节律表达，例如，Clock、Npas 2、Bmal 1、Per 1和Cry 1在肝脏中发生改变，而在下丘脑视交叉上核（SCN）中完全保留，这表明SCN不参与肝脏核心时钟基因表达的改变。此外，葡萄糖和脂质代谢相关基因的昼夜节律模式，过氧化物酶体增殖物激活受体（Ppar）α、Pparγ-1、Pparγ-辅激活因子-1 α和磷酸烯醇丙酮酸羧激酶也受到CMS的干扰。相反，在C57 BL/6小鼠中，相同的CMS程序既不改变血清皮质酮水平，也不改变肝脏核心时钟基因和代谢相关基因的节律表达。因此，慢性应激可以干扰核心时钟基因和代谢相关基因在肝脏中的昼夜表达，可能涉及HPA轴过度激活。这种机制可能会导致现代社会压力巨大的代谢紊乱。
Chronic stress is well known to affect metabolic regulation. However, molecular mechanisms interconnecting stress response systems and metabolic regulations have yet to be elucidated. Various physiological processes, including glucose/lipid metabolism, are regulated by the circadian clock, and core clock gene dysregulation reportedly leads to metabolic disorders. Glucocorticoids, acting as end-effectors of the hypothalamus-pituitary-adrenal (HPA) axis, entrain the circadian rhythms of peripheral organs, including the liver, by phase-shifting core clock gene expressions. Therefore, we examined whether chronic stress affects circadian expressions of core clock genes and metabolism-related genes in the liver using the chronic mild stress (CMS) procedure. In BALB/c mice, CMS elevated and phase-shifted serum corticosterone levels, indicating overactivation of the HPA axis. The rhythmic expressions of core clock genes, e.g., Clock, Npas2, Bmal1, Per1, and Cry1, were altered in the liver while being completely preserved in the hypothalamic suprachiasmatic nuculeus (SCN), suggesting that the SCN is not involved in alterations in hepatic core clock gene expressions. In addition, circadian patterns of glucose and lipid metabolism-related genes, e.g., peroxisome proliferator activated receptor (Ppar) α, Pparγ-1, Pparγ-coactivator-1α, and phosphoenolepyruvate carboxykinase, were also disturbed by CMS. In contrast, in C57BL/6 mice, the same CMS procedure altered neither serum corticosterone levels nor rhythmic expressions of hepatic core clock genes and metabolism-related genes. Thus, chronic stress can interfere with the circadian expressions of both core clock genes and metabolism-related genes in the liver possibly involving HPA axis overactivation. This mechanism might contribute to metabolic disorders in stressful modern societies.