Studies of association of metabolic syndrome and circadian rhythms

心肌梗死常发生在早晨，部分原因是由于纤溶活性下调。纤溶酶原激活物抑制剂-1（PAI-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PAI-1增强引起的纤维蛋白溶解受损有关，这也与动脉粥样硬化有关。这项研究的目的是破译Pai-1基因是否仍然在高胆固醇血症中每天表达。我们发现含有1%胆固醇（高胆固醇血症）的饮食强烈增强了小鼠肝脏中Pai-1基因的日常表达，而不是心脏。高胆固醇血症不影响肝脏生物钟基因（Per2和Bmal1）和生物钟控制基因（Dbp和E4bp4）的日常表达；而Pai-1启动子调节因子基因如Nr4a1和tnf - α的日常表达则被上调，而VLDL受体未被上调。白天每天限饲4小时，重置Per2、Pai-1、Nr4a1和tnf - α的基因表达。主要时钟系统所在地视交叉上核的病变导致Per2和Pai-1日常表达的丧失。本实验表明，高胆固醇血症增强了小鼠肝脏中Pai-1、tnf - α和Nr4a1基因的日常表达，但不影响生物钟和生物钟控制基因。因此，早晨急性动脉粥样硬化血栓事件的风险或高频率似乎仍然是高胆固醇血症条件下可能增加的因素。小鼠Pai-1在体内表现出每日节律，其转录似乎不仅受到时钟基因的控制，还受到胰岛素和甘油三酯等体液因子的控制。因此，我们研究了葡萄糖、胰岛素和甘油三酯水平高的db/db小鼠肝脏中每日时钟基因和mPai-1 mRNA的表达。Db / Db小鼠的运动活动节律减弱。在db/db小鼠肝脏中，mPer2 mRNA的节律性表达被严重抑制，mBmal1的振荡期提前，而mpi -1 mRNA的高表达和组成性表达。夜间限制进食不仅会导致运动活动的抑制，还会导致mPer2和mBmal1 mRNA节律的抑制。mPai-1 mRNA在db/db小鼠中的表达明显低于正常水平。我们证明胰岛素非依赖型糖尿病损害了外周振荡器的振荡。与吡格列酮注射相比，夜间限制进食导致运动活动减弱和外周时钟振荡和mpi -1 mRNA节律改变的恢复。因此，我们得出结论，计划限制食物摄入可能是治疗糖尿病的一种有效形式。少

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