Biological resonance: matching internal timing to environmental fluctuations

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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.