Circadian contol of metabolism: implications for health and disease

新陈代谢的昼夜节律控制:对健康和疾病的影响

基本信息

  • 批准号:
    BB/I018654/1
  • 负责人:
  • 金额:
    $ 120.77万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Fellowship
  • 财政年份:
    2012
  • 资助国家:
    英国
  • 起止时间:
    2012 至 无数据
  • 项目状态:
    已结题

项目摘要

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.
每天24小时的节律存在于我们行为和生理的方方面面,比如睡眠/觉醒、进食和体温循环。这些节律是由内在的计时系统(昼夜节律时钟)支撑的,它贯穿全身,并在每个组织内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,昼夜节律是由一个“主时钟”控制的,这个“主时钟”位于大脑中一个被称为视交叉上核(SCN)的小区域。SCN与身体其他部分的时钟同步,因此不同器官系统的功能相互协调,以及压倒一切的行为周期(例如进食、睡眠)。我们的生物钟与能量代谢密切相关,这一点最近变得很清楚,而昼夜节律性减弱现在被认为是代谢性疾病(如肥胖和糖尿病)的一个标志性特征。因此,至关重要的是,我们要了解我们的内部时钟是如何调节能量代谢的,以及昼夜节律的破坏是如何导致代谢疾病的。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性活动,而且本身也受到代谢和细胞能量状态的强烈影响。例如,当夜间活动的实验室小鼠被迫只在白天进食时,它们的生理机能(以及构成这些生理机能的生物钟)的许多方面变得不同步,并与SCN断开连接,SCN仍然被环境光周期所锁定。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(高热量食物的过度消耗,或与正常行为模式不同步的饮食习惯)将有效地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引起的干扰;2)这些“易感”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,哪些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遗传图谱将用于识别肥胖期间受影响最大的时钟,因此这些时钟结构可能直接针对体内(动物)或体外(切除组织培养)。体内靶向将采用对小鼠进行优雅的基因修饰,从而在大脑、大脑的特定区域或周围器官中选择性地去除或加速时钟(20小时vs 24小时)。这将使我能够研究组织时钟是如何相互作用来决定代谢节律的。体外研究将通过药理学上操纵时钟的特定成分(例如REV-ERBa)或特性(例如速度),以时钟连接和调节模型组织内代谢功能(例如白色脂肪组织中的脂肪储存/分解)的机制为目标。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。缺乏该基因的小鼠肥胖,表现出抑制的代谢节律,并且在白色脂肪组织中明显没有时钟基因节律。最后,我将研究是否加强昼夜节律系统的药理学可以改善肥胖的代谢后果。

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Deficient copper concentrations in dried-defatted hepatic tissue from ob/ob mice: A potential model for study of defective copper regulation in metabolic liver disease.
ob/ob小鼠干燥的肝组织中的铜浓度不足:研究代谢肝病中有缺陷的铜调节的潜在模型。
  • DOI:
    10.1016/j.bbrc.2015.03.067
  • 发表时间:
    2015-05-08
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    Church, Stephanie J.;Begley, Paul;Kureishy, Nina;McHarg, Selina;Bishop, Paul N.;Bechtold, David A.;Unwin, Richard D.;Cooper, Garth J. S.
  • 通讯作者:
    Cooper, Garth J. S.
Bright daytime light enhances circadian amplitude in a diurnal mammal.
明亮的白天光线可以增强昼夜哺乳动物中的昼夜节律幅度。
The circadian clock regulates inflammatory arthritis.
Adiponectin induces A20 expression in adipose tissue to confer metabolic benefit.
  • DOI:
    10.2337/db13-1835
  • 发表时间:
    2015-01
  • 期刊:
  • 影响因子:
    7.7
  • 作者:
    Hand LE;Usan P;Cooper GJ;Xu LY;Ammori B;Cunningham PS;Aghamohammadzadeh R;Soran H;Greenstein A;Loudon AS;Bechtold DA;Ray DW
  • 通讯作者:
    Ray DW
REVERBa couples the circadian clock to hepatic glucocorticoid action.
  • DOI:
    10.1172/jci96138
  • 发表时间:
    2018-10-01
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Caratti G;Iqbal M;Hunter L;Kim D;Wang P;Vonslow RM;Begley N;Tetley AJ;Woodburn JL;Pariollaud M;Maidstone R;Donaldson IJ;Zhang Z;Ince LM;Kitchen G;Baxter M;Poolman TM;Daniels DA;Stirling DR;Brocker C;Gonzalez F;Loudon AS;Bechtold DA;Rattray M;Matthews LC;Ray DW
  • 通讯作者:
    Ray DW
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David Bechtold其他文献

David Bechtold的其他文献

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{{ truncateString('David Bechtold', 18)}}的其他基金

Rhythms in the beat: Circadian Clock Regulation of Cardiac Electrophysiology
节拍中的节律:心脏电生理学的昼夜节律时钟调节
  • 批准号:
    BB/V002651/1
  • 财政年份:
    2021
  • 资助金额:
    $ 120.77万
  • 项目类别:
    Research Grant
Metabolic and behavioural phenotyping system
代谢和行为表型系统
  • 批准号:
    BB/V019198/1
  • 财政年份:
    2021
  • 资助金额:
    $ 120.77万
  • 项目类别:
    Research Grant
REVing-down: targeting the circadian clock in metabolic disease
REVing-down:针对代谢疾病中的生物钟
  • 批准号:
    MR/P00279X/1
  • 财政年份:
    2017
  • 资助金额:
    $ 120.77万
  • 项目类别:
    Research Grant
Biological resonance: matching internal timing to environmental fluctuations
生物共振:将内部时间与环境波动相匹配
  • 批准号:
    BB/J017744/1
  • 财政年份:
    2013
  • 资助金额:
    $ 120.77万
  • 项目类别:
    Research Grant

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