REVIEW Clock Genes and Clock-Controlled Genes in the Regulation of Metabolic Rhythms Gianluigi Mazzoccoli, 1 Valerio Pazienza, 2 and Manlio Vinciguerra 3 1 Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza,” Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo (FG), Italy, 2 Research Laboratory and Division of Gastroenterology, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza,” Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo (FG), Italy, 3 Fatty Liver Unit, Institute of Hepatology, Foundation for Liver Research, Birkbeck University College, London, United Kingdom Daily rotation of the Earth on its axis and yearly revolution around the Sun impose to living organisms adaptation to nyctohemeral and seasonal periodicity. Terrestrial life forms have developed endogenous molecular circadian clocks to synchronize their behavioral, biological, and metabolic rhythms to environmental cues, with the aim to perform at their best over a 24-h span. The coordinated circadian regulation of sleep/wake, rest/activity, fasting/feeding, and catabolic/anabolic cycles is crucial for optimal health. Circadian rhythms in gene expression synchronize biochemical processes and metabolic fluxes with the external environment, allowing the organism to function effectively in response to predictable physiological challenges. In mammals, this daily timekeeping is driven by the biological clocks of the circadian timing system, composed of master molecular oscillators within the suprachiasmatic nuclei of the hypothalamus, pacing self-sustained and cell-autonomous molecular oscillators in peripheral tissues through neural and humoral signals. Nutritional status is sensed by nuclear receptors and coreceptors, transcriptional regulatory proteins, and protein kinases, which synchronize metabolic gene expression and epigenetic modification, as well as energy production and expenditure, with behavioral and light-dark alternance. Physiological rhythmicity characterizes these biological processes and body functions, and multiple rhythms coexist presenting different phases, which may determine different ways of coordination among the circadian patterns, at both the cellular and whole-body levels. A complete loss of rhythmicity or a change of phase may alter the physiological array of rhythms, with the onset of chronodisruption or internal desynchronization, leading to metabolic derangement and disease, i.e., chronopathology. (Author correspondence: g.mazzoccoli@operapadrepio.it) Keywords: Circulation rhythm, Clock genes, Glucose metabolism, Lipid metabolism, Metabolism, Nuclear receptors INTRODUCTION Since their appearance, primitive life forms have evolved in parallel with the geological history of the Earth, facing natural selection pressures imposed by periodic changes in the characteristic of their spatio/temporal niches and developing rhythmic variations in biology and behavior. Fitness advantage of organisms living in the wild is allowed by matching and maintaining the phase-relation- ship between biological rhythms and predictable environ- mental cycles. Free-living animals have to anticipate periodic events in their external geophysical environment, which might condition organism and species survival, impinging on feeding, predation, competition, and mating. The daily rotation of our planet on its axis determines the daily transition from darkness to solar illumination, and this cycle is a powerful environmental cue that exerts major impact on our health and well-being. The synchronization to the daily and seasonal changes in external time cues, most notably light and temperature, and the anticipation of environmental transitions, allows living organisms to perform activities at biologi- cally advantageous times during the day, and undergo characteristic seasonal responses. Daily and seasonal changes of light and temperature influence also human physiology, metabolism, and behavior (sleep/wakeful- ness alternation and fasting/feeding time) in health and disease (e.g., Takahashi et al., 2008; Kershenbaum et al., 2011). Time-dependent variations of environ- mental cues and biological processes may be character- ized by a predictable rhythmicity, and when the Address correspondence to Gianluigi Mazzoccoli, MD, Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza,” Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo (FG), 71013 Cappuccini Avenue, Italy. Tel.: 0039-0882-410289; Fax: 0039-0882-410563; Email: g.mazzoccoli@oper- apadrepio.it Submitted September 15, 2011, Returned for revision October 18, 2011, Accepted January 8, 2012 Chronobiology International, 29(3): 227–251, (2012) Copyright © Informa Healthcare USA, Inc. ISSN 0742-0528 print/1525-6073 online DOI: 10.3109/07420528.2012.658127  Chronobiol Int Downloaded from informahealthcare.com by Ospedale Casa Sollievo Della on 03/12/12 For personal use only.