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
• 负责人: David Bechtold
• 金额: $ 59.84万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ017744%2F1
• 关键词: Biological; resonance; matching; internal; timing

In virtually all organisms, inherent timing systems (circadian clocks) orchestrate rhythmic patterns of physiology and behaviour across the day. These timers are also responsive to external environmental cues, such as cycles in light and food availability. In mammals, the circadian clockwork regulates our daily patterns of behaviour (when and how long we sleep, when we eat), and also the underlying physiologies that support such behaviour (e.g. rhythms in body temperature, hormone release and liver function). Unfortunately, it now seems clear that disruption of our bodies' 'natural' rhythms by modern societies' 24h lifestyle (shift work, sleep restriction, disrupted eating patterns) is associated with metabolic disease (obesity, diabetes). Therefore, it is critical that we understand the basic biology behind how internal timers align our physiology to the environment and what the consequences are when that alignment is disrupted.Until recently, it was believed that circadian timing in mammals was determined wholly by a small area of the brain, the suprachiasmatic nucleus (SCN). We now know this not to be true, and that clocks reside in many areas of the brain and virtually all peripheral organs. Within each tissue, many functions are controlled by the local clockwork, such as daily rhythms in liver glucose production. These peripheral tissue clocks are strongly influenced by rhythmic feeding activity (normally governed by the SCN) and hence rhythmic energy flux. As a consequence, many behavioural and physiological processes can be decoupled from the SCN when feeding does not adhere to an SCN driven rhythm. This can be modelled easily in laboratory mice using restricted feeding schedules, which force these nocturnal animals to eat in the day.To understand how our physiology, and especially our ability to maintain energy balance, is affected by disrupted activity or feeding patterns, we will examine what happens when the external environment is put in opposition to internal clocks in the brain and liver, or when different clocks in the body are not able to keep in time with one another. This is especially important in tissues such as the liver, which must cope with large fluctuations in energy supply (due to feeding/fasting cycles). We will use genetically modified mice in which we have changed the speed of the clock (20h vs 24h per cycle) in all tissues or selectively in either the SCN or the liver. Our aim is not to stop or remove the clock within the mice (nor in any of their tissue systems), but reveal the consequences to energy metabolism when we run these clocks at different rates or phases to the external environment (light and meal times). This is much closer to the real world. We will also challenge these mice will high fat diet to determine their ability to cope with vastly altered energy intake. This may be particularly relevant to the real world, where large high calorie meals are often eaten at inappropriate times (such as before bed). To date, it has been very hard to measure rhythmic responses in a particular tissue. However, we will use an exciting new method to track liver oscillations in free-moving mice. This is achieved by injecting a virus containing a light-emitting gene, which oscillates in response to activation of a specific metabolic pathway. Thus, we can track how the core clockwork of the liver responds to altered feeding schedules, or even of how metabolic genes regulating glucose production, fatty acid synthesis or protein metabolism change their expression. We are confident that this remarkable new technology will greatly increase understanding of how tissues such as liver respond to environmental cues, and be of wide-spread application, and also potentially lead to reduced animal usage as greatly more information can now be obtained from one animal than before.

在几乎所有的生物体中，内在的计时系统（生物钟）在一天中协调生理和行为的节奏模式。这些计时器也对外部环境线索做出反应，比如光照周期和食物供应。在哺乳动物中，生物钟调节着我们的日常行为模式（我们什么时候睡觉，睡多久，什么时候吃饭），以及支持这些行为的潜在生理学（例如体温、激素释放和肝功能的节律）。不幸的是，现在似乎很清楚，现代社会24小时的生活方式（轮班工作、睡眠限制、饮食模式紊乱）扰乱了我们身体的“自然”节奏，这与代谢疾病（肥胖、糖尿病）有关。因此，至关重要的是，我们要了解内部计时器如何使我们的生理与环境保持一致，以及当这种一致被破坏时会产生什么后果。直到最近，人们还认为哺乳动物的昼夜节律完全由大脑的一个小区域——视交叉上核（SCN）决定。我们现在知道这不是真的，时钟存在于大脑的许多区域和几乎所有的外围器官中。在每个组织中，许多功能都是由局部的生物钟控制的，比如肝脏葡萄糖产生的日常节律。这些外周组织时钟受到节律性进食活动（通常由SCN控制）的强烈影响，因此也受到节律性能量通量的影响。因此，当进食不遵循SCN驱动的节奏时，许多行为和生理过程可以与SCN分离。这可以很容易地在实验室老鼠身上进行模拟，使用限制进食时间表，迫使这些夜行动物在白天进食。为了了解我们的生理，尤其是我们维持能量平衡的能力是如何受到活动或进食模式中断的影响的，我们将研究当外部环境与大脑和肝脏的内部时钟相反时，或者当体内不同的时钟不能彼此保持同步时，会发生什么。这在肝脏等组织中尤其重要，因为肝脏必须应对能量供应的大幅波动（由于喂养/禁食周期）。我们将使用转基因小鼠，我们已经改变了所有组织中的时钟速度（每个周期20小时对24小时），或者选择性地在SCN或肝脏中进行。我们的目的不是停止或移除小鼠体内的时钟（也不是在它们的任何组织系统中），而是揭示当我们以不同的速率或阶段运行这些时钟对外部环境（光照和用餐时间）时对能量代谢的影响。这更接近真实世界。我们还将挑战这些高脂肪饮食的小鼠，以确定它们应对巨大变化的能量摄入的能力。这可能与现实世界特别相关，在现实世界中，人们经常在不合适的时间（比如睡觉前）吃大量高热量的食物。迄今为止，很难测量特定组织的节律性反应。然而，我们将使用一种令人兴奋的新方法来跟踪自由运动小鼠的肝脏振荡。这是通过注射一种含有发光基因的病毒来实现的，该基因会随着特定代谢途径的激活而振荡。因此，我们可以追踪肝脏的核心生物钟如何对改变的进食时间表做出反应，甚至可以追踪调节葡萄糖生产、脂肪酸合成或蛋白质代谢的代谢基因如何改变其表达。我们相信，这项非凡的新技术将大大增加对肝脏等组织如何对环境线索作出反应的理解，并得到广泛的应用，并且还可能导致减少动物的使用，因为现在可以从一只动物身上获得比以前更多的信息。

项目成果

Adipocyte NR1D1 dictates adipose tissue expansion during obesity.

• DOI: 10.7554/elife.63324
• 发表时间: 2021-08-05
• 期刊: eLife
• 影响因子: 7.7
• 作者: Hunter AL;Pelekanou CE;Barron NJ;Northeast RC;Grudzien M;Adamson AD;Downton P;Cornfield T;Cunningham PS;Billaud JN;Hodson L;Loudon AS;Unwin RD;Iqbal M;Ray DW;Bechtold DA
• 通讯作者: Bechtold DA

The circadian clock regulates inflammatory arthritis.

• DOI: 10.1096/fj.201600353r
• 发表时间: 2016-11
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Hand LE;Hopwood TW;Dickson SH;Walker AL;Loudon AS;Ray DW;Bechtold DA;Gibbs JE
• 通讯作者: Gibbs JE

Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia.

• DOI: 10.1038/s41467-021-22788-8
• 发表时间: 2021-04-30
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Hayter EA;Wehrens SMT;Van Dongen HPA;Stangherlin A;Gaddameedhi S;Crooks E;Barron NJ;Venetucci LA;O'Neill JS;Brown TM;Skene DJ;Trafford AW;Bechtold DA
• 通讯作者: Bechtold DA