ReviewMetabolic regulation of circadian clocks
Introduction
The genetic components of extant circadian clocks share few similarities suggesting that circadian clocks evolved independently in the Kingdoms [1]. This independent evolution of gene networks forming circadian systems has converged on similarities in basic architecture but there is little conservation of the individual components (Fig. 1). Circadian clocks are phase-matched to the local environment through entrainment by input signals called zeitgebers, such as light and temperature. The core circadian oscillator generates rhythmic outputs which in plants include rhythmic expression of at least 30% of the genome [2], [3], [4], [5], movements of the leaves and petals, oscillations in the cytosolic concentration of free calcium ([Ca2+]cyt) and changes in stomatal aperture [6]. Circadian regulation of many aspects of plant metabolism is also observed, including photosynthesis [7], redox homeostasis [8], starch metabolism [9], [10], nutrient assimilation [11] and secondary metabolism [12]. We summarise the role of the circadian clock in regulating metabolism and consider the accumulating evidence that metabolic rhythms contribute to circadian timing. In the context of understanding the role of metabolism in regulating plant circadian networks, we highlight similarities between divergent circadian systems despite very different physiology and varied cellular metabolism. These similarities might imply a conserved role for fundamental aspects of metabolism in circadian function across Kingdoms, lending support to the notion that metabolic rhythms provided a foundation for the evolution of molecular clocks [1], [13].
Genetic screens in Arabidopsis, mice, Drosophila, Neurospora and other species have provided compelling evidence for a pervasive role for transcription–translation feedback loops (TTFLs) in circadian timing. These TTFLs are formed by rhythmic transcription and translation of transcriptional activators and repressors acting in regulatory feedback loops (Fig. 1). For example, in Arabidopsis feedback loops exist between the morning-expressed myb-like transcription factors, CIRCADIAN CLOCK ASSOCIATED1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY) and PSEUDO RESPONSE REGULATOR9 (PRR9), PRR7, PRR5 and PRR1 (also known as TIMING OF CAB1) [14], [15], [16], [17]. TOC1 also forms a feedback loop with GIGANTEA (GI), a protein of unknown biochemical function, through interactions with the F-box protein ZEITLUPE (ZTL) [18]. In addition, EARLY FLOWERING3 (ELF3), ELF4 and LUX ARRYHTHMO (LUX) form the so-called evening complex (EC), which represses the PRR9 promoter during the night [19], [20]. Many additional proteins contribute to the complex circadian network and for detailed descriptions of the current model of TTFLs within plant circadian clocks see other reviews in this issue [21], [22]. It is believed this basic machinery operates in all plant cells, possibly with cell-specific modification in the roots [23] and vasculature [24]. In animals, there is a master oscillator in the brain, driven by light input from the retina whereas TTFL in peripheral tissues function as slave oscillators, or are absent altogether.
Another level of complexity in circadian timing mechanisms arises from the role of non-nuclear events and the existence of “metabolic clocks”. For example, circadian rhythms of [Ca2+]cyt, peroxiredoxin redox state, ATP, reactive oxygen species (ROS), and nicotinamide adenine dinucleotide (NAD+) have been identified [8], [25], [26], [27], [28], [29]. In most cases, there is evidence that these metabolic oscillations interact directly with TTFL, but in some cases it appears metabolic rhythms can be sustained independently of transcription–translation [30], [31]. Importantly, metabolic oscillators appear to be similar across Kingdoms and might predate the evolution of the classical TTFL structure of circadian clocks [1], [13].
Section snippets
Regulation of metabolism by the circadian clock
Metabolism is a crucial regulatory output of circadian clocks, which ensures optimal physiology, growth and behaviour in light–dark cycles [7], [32], [33]. The role of the circadian clock in regulation of metabolism in animals has received significant recent interest because of its implications for human health and disease, particularly with respect to diabetes and obesity [32], [34], [35]. Transcriptome studies in mammals revealed circadian regulation of transcripts, in many cases encoding
Sugar metabolism
In addition to the established role for the circadian clock in regulating glucose metabolism in mammals, nutrition also has profound effects on circadian clock function [49], [50], [51], [52]. In mice, inverse feeding cycles were able to reverse the phase of circadian clock gene expression in peripheral tissues, such as the liver, but did not affect phase in the master clock in the suprachiasmatic nucleus (SCN) [49]. Similarly, high-fat diet lengthened the circadian period of locomotor activity
Conclusion
The importance of circadian clocks for regulating metabolism in many organisms to optimise physiology is clear. There is also increasing evidence that rhythmic cellular metabolism can affect timing mechanisms driven by TTFL operating in the nucleus (Fig. 3). In humans, this has important implications for health and disease and in plants this contributes to biomass production and therefore crop yields. Furthermore, it is now apparent that evolutionarily conserved metabolic oscillators may act
Acknowledgements
Research in the Webb laboratory is supported by BBSRC grant BB/H006826/1 and BBSRC CASE studentships to TJH and LJB.
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