Clock Genes and Clock-Controlled Genes in the Regulation of Metabolic Rhythms

Abstract

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: [email protected])

Keywords:

• Circulation rhythm, Clock genes, Glucose metabolism
• Lipid metabolism
• Metabolism, Nuclear receptors

ACKNOWLEDGMENTS

We apologize for not commenting on all of the relevant studies and not citing all pertinent references due to space limitations. We thank Ms. Christine Podrini for proofreading the manuscript. This work was supported by “Italian Ministry of Health” grant RC1103MI53 through the 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.

Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Notes

1 Three ER-localized transmembrane protein sensors start the main UPR signaling cascades in mammalian cells: IRE1α (inositol-requiring 1α, with protein-kinase and site-specific endoribonuclease activities), PERK (double-stranded RNA-dependent protein kinase-like ER kinase), and ATF6 (activating transcription factor 6). They sense unfolded proteins with an ER-luminal domain, and transmit signals to the transcriptional or translational apparatus by means of a cytosolic domain. In response to ER stress, IRE1α autophosphorylates, removes a 26-base intron from mRNA encoding X-box–binding protein 1 (XBP1), and leads to an XBP1 isoform with potent activity as a transcription factor. Xbp1 expression is induced by CCAAT/enhancer-binding protein β (C/EBPβ), a transcription factor that plays a key role in adipogenesis by activating the expression of PPARγ and C/EBPα, two key adipogenic transcription factors that positively regulate each other to promote and maintain adipocytes in the differentiated state, and, in turn, XBP1 transactivates the expression of C/EBPα. In response to ER stress, IRE1α binds to the adaptor protein tumor necrosis factor (TNF)-α-receptor–associated factor 2 (TRAF2), and the IRE1α-TRAF2 complex can recruit inhibitor of nuclear factor (NF)-κB (IκB) kinase (IKK), which phosphorylates IκB, leading to the degradation of IκB and the nuclear translocation of NF-κB. The IRE1α-TRAF2 complex can also recruit the c-Jun NH₂-terminal kinase (JNK), which activates and induces the expression of inflammatory genes by phosphorylating the transcription factor activator protein 1 (AP1). For an extensive discussion on the role played by ER stress and UPR in lipid metabolism, refer to the recent review by Gachon and Bonnefont (2010).