Circadian contol of metabolism: implications for health and disease

点击翻译按钮获取中文摘要

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.