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AGING, February 2009, Vol. 2. No 2
                                            Research Perspective

Circadian clock‐coordinated hepatic lipid metabolism: only      transcriptional regulation?   
Frédéric Gachon1, Xavier Bonnefont2   
  1    Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, CH‐1005, Switzerland  2   CNRS, UMR 5203, Institut de Génomique Fonctionnelle, 34094 Montpellier, France   
Running title: Rhythmic post‐transcriptional regulation of lipid metabolism Key words: Circadian clock, Lipid metabolism, Unfolded protein response, IRE1α, autophagy, growth hormone Correspondence: Frédéric Gachon, PhD, Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Rue  du Bugnon, 27, CH‐1005, Switzerland  Received: 02/09/10; accepted: 02/16/10; published on line: 02/17/10  E‐mail:  Copyright: © Gachon and Bonnefont. This is an open‐access article distributed under the terms of the Creative Commons  Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author  and source are credited   Abstract: By regulating the metabolism of fatty acids, carbohydrates, and xenobiotic, the mammalian circadian clock plays a fundamental role on the liver physiology. At present, it is supposed that the circadian clock regulates metabolism mostly by  regulating  the  expression  of  liver  enzymes  at  the  transcriptional  level.  However,  recent  evidences  suggest  that  somesignaling pathways synchronized by the circadian clock can also influence metabolism at a post‐transcriptional level. In this context, we have recently shown that the circadian clock synchronizes the rhythmic activation of the IRE1α pathway in the endoplasmic reticulum. The absence of circadian clock perturbs this secondary clock, provokes deregulation of endoplasmic reticulum‐localized  enzymes,  and  leads  to  impaired  lipid  metabolism. We  will  describe  here  the  additional  pathways synchronized by the clock and discussed the influence of the circadian clock‐controlled feeding rhythm on them. 


Circadian clocks are operative in virtually all lightsensitive organisms, including cyanobacteria, fungi, plants, protozoans and metazoans. These timing devices allow their possessors to adapt their physiological needs to the timeof day in an anticipatory way. In mammals, circadian pacemakers regulate many systemic processes, such as sleep-wake cycles, body temperature, heartbeat, and many physiological outputs conducted by peripheral organs, such as liver, kidney and the digestive tract [1]. On the basis of surgical ablation and transplantation experiments, it was established that the suprachiasmatic nucleus (SCN) in thehypothalamus coordinates most of these daily rhythms [2], probably through both synaptic connections and humoral signals [3]. Interestingly, self-sustained and cell-autonomous molecular oscillators do not only exist in pacemaker cells such as SCN neurons, but are also operative in most peripheral, non-neuronal cell types [4]. These peripheral oscillators participate in the circadian control

ofanimal physiology. During the past few years, analysis of animal transcriptomes with the DNA microarray technology showed that many aspects of physiology are directly controlled by the circadian clock through control of the expression of enzymes and regulators involved in these physiological processes [5,6]. Although the mechanisms involved in these regulations are not yet understood in detail,it is likely that transcription factors whose expression is controlled by the circadian clock are involved [7]. Based on these circadian transcriptome profiling studies it is commonly thought that circadian metabolism is mainly the consequence of circadian transcription and possible effects of circadian clock-controlled post-transcriptional regulatory mechanisms have been largely...