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Studies of association of metabolic syndrome and circadian rhythms

代谢综合征与昼夜节律关联的研究

基本信息

批准号：
15390074
负责人：
SHIBATA Shigenobu
金额：
$ 8.45万
依托单位：
Faculty of Scienceand Engineering Waseda University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390074/
关键词：
circadian Biological rhythm Obesity Hypercholesterol diabetes liver Pai-1 suprachiasmatic

项目摘要

Myocardial infarction frequently occurs in the morning, a phenomena in part resulting from the down regulation of fibrinolytic activity. Plasminogen activator inhibitor-1(PAI-1) is a key factor behind fibrinolytic activity, and its gene expression shows circadian change in the mouse heart and liver. Hypercholesterolaemia has been associated with impaired fibrinolysis due to enhanced PAI-1, which has also been implicated in atherosclerosis. The aim of this study was to decipher whether the Pai-1 gene is still expressed daily with hypercholesterolaemia. We found that a diet containing 1 % cholesterol (hypercholesterolaemia) strongly enhanced daily expression of the Pai-1 gene in the mouse liver but not the heart. Hypercholesterolaemia did not affect the daily expression of clock genes (Per2 and Bmal1) and clock-controlled genes (Dbp and E4bp4) in the liver ; however daily expression of Pai-1 promoter regulating factor genes such as Nr4a1 and TNF-alpha but not the VLDL receptor, was up-re … More gulated. Daily restricted feeding for 4 hrs during the day reset the gene expression of Per2, Pai-1, Nr4a1, and TNF-alpha. Lesion of the suprachiasmatic nucleus, location of the main clock system, led to loss of Per2 and Pai-1 daily expression. The present experiment demonstrates that hypercholesterolaemia enhanced daily expression of Pai-1, TNF-alpha, and Nr4a1 gene expression in the mouse liver without affecting clock and clock-controlled genes. Thus, the risk or high frequency of acute atherothrombotic events in the morning still seems to be factor that may be augmented under hypercholesterolaemia conditions.Mouse Pai-1 shows a daily rhythm in vivo, and its transcription is seems to be controlled not only by clock genes but also by humoral factors such as insulin and triglyceride. Thus, we investigated daily clock genes and mPai-1 mRNA expression in the liver of db/db mice exhibiting high levels of glucose, insulin, and triglyceride. db/db mice showed attenuated locomotor activity rhythms. The rhythmic expression of mPer2 mRNA was severely dampened, and the phase of mBmal1 oscillation was advanced in the db/db mouse liver, while mPai-1 mRNA was highly and constitutively expressed. Night-time restricted feeding led to a recovery from not only the dampened locomotor activity, but also from the dampened mPer2 and advanced mBmal1 mRNA rhythms. mPai-1 mRNA expression in db/db mice was reduced far below normal levels. We demonstrated that insulin-independent diabetes impaired the oscillation of the peripheral oscillator. Night-time restricted feeding rather than pioglitazone injection led to a recovery from the dampened locomotor activity and altered oscillation of the peripheral clock and mPai-1 mRNA rhythm. Thus, we conclude that scheduled restricted food-intake may be a useful form of treatment for diabetes. Less

心肌梗塞常发生在早晨，这一现象部分是由于纤溶活性下调所致。纤溶酶原激活物抑制剂-1（派-1）是纤溶活性背后的关键因子，其基因表达在小鼠心脏和肝脏中呈现昼夜变化。高胆固醇血症与由于增强的PAI-1引起的纤维蛋白溶解受损相关，PAI-1也与动脉粥样硬化有关。本研究的目的是破译是否派-1基因仍然表达的高胆固醇血症的日常。我们发现含有1%胆固醇的饮食（高胆固醇血症）强烈增强小鼠肝脏中派-1基因的每日表达，但不增强心脏。高胆固醇血症并不影响肝脏中时钟基因（Per 2和Bmal 1）和时钟控制基因（Dbp和E4 bp 4）的每日表达;然而，派-1启动子调节因子基因（如Nr 4a 1和TNF-α）的每日表达增加，而VLDL受体的表达没有增加。 ...更多信息 gulated.白天每天限制喂养4小时重置Per 2、派-1、Nr 4a 1和TNF-α的基因表达。视交叉上核（主时钟系统的位置）的损伤导致Per 2和派-1的日常表达的丧失。本实验表明，高胆固醇血症增强小鼠肝脏中派-1，TNF-α和Nr 4a 1基因表达的每日表达，而不影响时钟和时钟控制的基因。因此，早晨急性动脉粥样硬化血栓形成事件的风险或高频率似乎仍然是在高胆固醇血症条件下可能增加的因素。小鼠派-1在体内表现出日节律，其转录似乎不仅受时钟基因控制，还受体液因子如胰岛素和甘油三酯的调控。因此，我们研究了表现出高水平葡萄糖、胰岛素和甘油三酯的db/db小鼠肝脏中的每日时钟基因和mPai-1 mRNA表达。db/db小鼠表现出减弱的自发活动节律。db/db小鼠肝脏中mPer 2 mRNA的节律性表达受到严重抑制，mBmal 1振荡的相位提前，而mPai-1 mRNA高度组成性表达。夜间限制喂养导致的恢复，不仅从抑制的自发活动，但也从抑制mPer 2和先进的mBmal 1 mRNA的节奏。db/db小鼠中mPai-1 mRNA表达降低至远低于正常水平。我们证明，胰岛素非依赖性糖尿病损害了周边振荡器的振荡。夜间限制喂养而不是吡格列酮注射导致从抑制的运动活动中恢复，并改变外周时钟和mPai-1 mRNA节律的振荡。因此，我们得出结论，计划限制食物摄入量可能是治疗糖尿病的一种有用的形式。少