Biological and medical relevance of circadian and metabolic cycles

Abstract

The circadian clock is an intrinsic timing system operative in evolutionarily divergent species, ranging from cyanobacteria to humans (Hastings et al. 2003; Lowrey and Takahashi 2004; Wijnen and Young 2006). This clock drives endogenous daily oscillations of biological processes to anticipate and respond to changes in the environment induced by the rotation of the earth. Consistent with its adaptive function, the clock exhibits three defining features. First, the intrinsic free-running period under constant conditions is close to, but not precisely, 24 hours. Second, the clock can be synchronized by external entraining stimuli to exactly 24 hours, or as defined by the period length of the environmental cycle. These stimuli, commonly referred to as zeitgebers (German, time giver), can also reset the phase as a function of the circadian time. Finally, the period of the clock remains largely constant over a wide range of temperatures. This “temperature compensation” helps maintain physiological homeostasis against temperature fluctuation during the day.Circadian rhythms are important for the growth and survival of many organisms. Competitive co-culture experiments have shown that, when intrinsic rhythms are aligned with external light–dark rhythms, cyanobacteria maintain a selective growth advantage over those in the same culture with longer or shorter periods (Woelfle et al. 2004). Clock-dependent growth and survival advantages have also been reported in plants whose clocks are closely synchronized with environmental cycles (Dodd et al. 2005; Green et al. 2002). For animals, foraging behavior and predator avoidance also follow circadian patterns. In an experiment conducted in their natural habitats, chipmunks with intact clocks showed significantly higher survival rates than the ones whose central pacemaker tissues had been surgically removed (DeCoursey and Krulas 1998). Although genetic disruption of clock genes in laboratory animals does not lead to lethality, an intact clock is almost certainly important for having a competitive advantage in the wild.In mammals, circadian clocks modulate a wide spectrum of essential molecular and physiological processes, including gene expression, metabolism, cell cycle progression, sleep–wake cycles, body temperature, hormonal secretion, heart rate, blood pressure, and mood. Consequently, disruption of rhythms has been linked with a number of diseases, such as mood disorders (Bunney and Bunney 2000; McClung 2007), metabolic syndromes (Wijnen and Young 2006; Ramsey et al. 2007), sleep disorders (Mahowald and Schenck 2005), cancer (Canaple et al. 2003; Lévi 2006), and cardiovascular diseases (Curtis and Fitzgerald 2006). Much interest has thus been directed toward studies of the clock and potential therapeutic applications that might be achieved by manipulating the clock.Metabolism is likely a major driving force during the evolution of the circadian clock (Tu and McKnight 2006). Cyanobacteria have occupied our planet for almost 4 billion years, and their circadian clocks may have evolved as a means to segregate photosynthesis from biochemically incompatible nitrogen fixation during the day/night cycle. This ancient metabolic function of the circadian clock is preserved in present-day photosynthetic plants. In animals, the clock also orchestrates complex or even incompatible metabolic activities, such as glycolysis and gluconeogenesis in liver and muscle. On the other hand, evidence has also been accumulating indicating that metabolism can feed back to drive the clock (Rutter et al. 2002; Tu and McKnight 2006; Wijnen and Young 2006).In this chapter, we review current knowledge of the mammalian circadian clock, and provide examples of how the clock is an important factor contributing to human health. We also review evidence supporting a metabolic basis for the circadian clock, including significant insights from research into a bona fide metabolic cycle in a simple model organism, the budding yeast Saccharomyces cerevisiae. The reciprocal relationship between metabolism and the circadian clock could provide a unified conceptual framework to understand complex circadian biology and to guide future therapeutic strategies.