Circadian contol of metabolism: implications for health and disease

日常24小时节律几乎存在于我们行为和生理的各个方面，例如睡眠/觉醒，喂养和体温周期。这些节律是由内在的定时系统（生物钟）支撑的，这些系统在整个身体中运行，并在每个组织中起作用，以协调许多器官功能和节律活动（例如肝脏中的葡萄糖稳态）。在哺乳动物中，昼夜节律是由位于大脑中一个叫做视交叉上核（SCN）的小区域中的“主时钟”领导的。SCN使身体其他部分的时钟同步，使不同器官系统的功能相互协调，以及覆盖行为周期（例如进食，睡眠）。最近已经很清楚，我们的生物钟与能量代谢密切相关，并且昼夜节律性减弱现在被认为是肥胖和糖尿病等代谢疾病的标志性特征。因此，我们必须了解我们的内部时钟如何调节能量代谢，以及昼夜节律时间的破坏如何导致代谢疾病。在许多组织中，生物钟基因（驱动生物钟的机制）与代谢途径密切相关。重要的是，这种联系是相互的，这意味着生物钟不仅驱动关键代谢基因的节律活动，而且本身也受到代谢和细胞能量状态的强烈影响。例如，当夜间实验室小鼠被迫只在白天进食时，它们生理学的许多方面（以及这些生理学的基础时钟）变得不稳定并与SCN断开连接，SCN仍然锁定在环境光周期中。因此，饮食和饮食行为对生物钟的强烈影响表明，异常的能量供应（过度消耗高热量食物，或与正常行为模式不同步的饮食习惯）将有效抑制甚至阻止新陈代谢的昼夜节律控制。这就提出了三个重要的问题：1）我们的一些生物钟是否特别容易受到饮食诱导的干扰; 2）这些“易受影响”的生物钟中生物钟功能的丧失如何影响整体代谢或行为节律; 3）在这些组织中，什么关键成分形成了生物钟-代谢界面。我的研究计划旨在解决这些问题。具体来说，我将研究饮食引起的肥胖如何影响行为（睡眠，喂养）和生理过程（代谢率，体温，血糖）在一天中，使用最先进的监测设备。大脑和外周器官不同区域的时钟基因的遗传图谱将用于识别在肥胖期间受影响最大的时钟，以便这些时钟结构可以在体内（动物）或体外（切除的组织培养物）直接靶向。体内靶向将采用小鼠的优雅遗传修饰，使得在大脑、大脑的特定区域或外周器官中选择性地去除或加速（20小时对24小时）时钟。这将使我能够研究组织时钟如何相互作用，以决定代谢节奏。体外研究将通过操纵生物钟的特定组分（例如REV-ERBa）或特性（例如速度），靶向生物钟与模型组织（例如白色脂肪组织中的脂肪储存/分解）连接并调节模型组织内代谢功能的机制。我的初步数据表明，生物钟基因REV-ERBa代表了生物钟和代谢途径之间的关键连接点。缺乏这种基因的小鼠是肥胖的，表现出抑制的代谢节律，并且在白色脂肪组织中明显地显示出没有时钟基因节律。最后，我将研究是否药物加强昼夜节律系统可以改善肥胖的代谢后果。

Daily 24-hour rhythms are present in virtually all aspects of our behaviour and physiology such as sleep/wake, feeding and body temperature cycles. These rhythms are underpinned by inherent timing systems (circadian clocks) which run throughout the body, and act within each tissue to orchestrate many organ functions and rhythmic activities (e.g. glucose homeostasis in the liver). In mammals, circadian timing is headed by a 'master clock' located in a small area of the brain called the suprachiasmatic nucleus (SCN). The SCN synchronises clocks in the rest of the body, so that functioning of different organ systems are coordinated with each other, as well as overriding behavioural cycles (e.g. feeding, sleeping). It has recently become clear that our circadian clocks are intimately linked to energy metabolism, and diminished circadian rhythmicity is now considered a hallmark feature of metabolic diseases such as obesity and diabetes. It is therefore critical that we understand how our internal clocks regulate energy metabolism, and how a disruption of circadian timing may contribute to metabolic disease. In many tissues, circadian clock genes (the machinery that drives the clock) are closely connected to metabolic pathways. Importantly this connection is reciprocal, meaning that the clock not only drives the rhythmic activity of key metabolic genes, but is itself strongly influenced by metabolism and cellular energy status. For example, when nocturnal laboratory mice are forced to feed only during the day, many aspects of their physiology (and the clocks that underlie these physiologies) become desynchronised and disconnected from the SCN, which remains locked to environmental light cycles. Thus, the strong influence of diet and eating behaviour on circadian clocks suggests that abnormal energy supply (over consumption of high-calorie foods, or eating habits that are out of synchrony with normal patterns of behaviour) will be effective at dampening or even blocking circadian control of metabolism. This raises three important questions: 1) are some of our body clocks particularly susceptible to diet-induced disruption; 2) how does the loss of clock function within these 'susceptible' clocks impact on overall metabolic or behavioural rhythms; 3) what critical components form the clock-metabolic interface in such tissues. My research proposal aims to address these questions. Specifically, I will investigate how diet-induced obesity impacts on behavioural (sleep, feeding) and physiological processes (metabolic rate, body temperature, blood glucose) across the day, using state-of-the-art monitoring equipment. Genetic mapping of clock genes in different regions of the brain and peripheral organs will be used to identify clocks that are most affected during obesity, so that these clock structure may be directly targeted in vivo (in animal) or in vitro (excised tissue cultures). In vivo targeting will employ elegant genetic modification of mice, such that the clock has been removed or accelerated (20hr vs 24hr) selectively within the brain, specific regions of the brain, or in peripheral organs. This will allow me to investigate how tissue clocks interact with each other to dictate metabolic rhythms. In vitro studies will target the mechanisms by which the clock is connected to and regulates metabolic functions within a model tissue (e.g. fat storage/breakdown in white adipose tissue) by manipulating specific components (e.g. REV-ERBa) or properties (e.g. speed) of the clock pharmacologically. My preliminary data suggests that the circadian clock gene REV-ERBa represents a critical connection point between the clock and metabolic pathways. Mice lacking this gene are obese, exhibit dampened metabolic rhythms, and remarkably show no clock gene rhythms in white adipose tissue. Finally, I will examine whether pharmacological strengthening of the circadian system can improve the metabolic consequences of obesity.