bims-ciryme Biomed News
on Circadian rhythms and metabolism
Issue of 2023‒05‒21
thirteen papers selected by
Gabriela Da Silva Xavier
University of Birmingham
  1. Astrocytic control of extracellular GABA drives circadian timekeeping in the suprachiasmatic nucleus.
  2. Singularity response reveals entrainment properties in mammalian circadian clock.
  3. Lipid metabolism around the body clocks.
  4. Mice with humanized livers reveal the role of hepatocyte clocks in rhythmic behavior.
  5. The Role of Circadian Rhythmicity and CLOCK Genes in Psychiatry.
  6. Prediction of mammalian tissue-specific CLOCK-BMAL1 binding to E-box DNA motifs.
  7. Ingrained city rhythms: flexible activity timing but more persistent circadian pace in urban birds.
  8. Timing Is Important-Management of Metabolic Syndrome According to the Circadian Rhythm.
  9. Preservation of ∼12-hour ultradian rhythms of gene expression of mRNA and protein metabolism in the absence of canonical circadian clock.
  10. Circadian glucocorticoids throughout development.
  11. Sexual dimorphism in the response to chronic circadian misalignment on a high-fat diet.
  12. N-methyl-D-aspartate receptor regulates the circadian clock in megakaryocytic cells and impacts cell proliferation through BMAL1.
  13. PERIOD phosphorylation leads to feedback inhibition of CK1 activity to control circadian period.
  1. Proc Natl Acad Sci U S A. 2023 05 23. 120(21): e2301330120
    Astrocytic control of extracellular GABA drives circadian timekeeping in the suprachiasmatic nucleus.
    Andrew P Patton, Emma L Morris, David McManus, Huan Wang, Yulong Li, Jason W Chin, Michael H Hastings.
      The hypothalamic suprachiasmatic nucleus (SCN) is the master mammalian circadian clock. Its cell-autonomous timing mechanism, a transcriptional/translational feedback loop (TTFL), drives daily peaks of neuronal electrical activity, which in turn control circadian behavior. Intercellular signals, mediated by neuropeptides, synchronize and amplify TTFL and electrical rhythms across the circuit. SCN neurons are GABAergic, but the role of GABA in circuit-level timekeeping is unclear. How can a GABAergic circuit sustain circadian cycles of electrical activity, when such increased neuronal firing should become inhibitory to the network? To explore this paradox, we show that SCN slices expressing the GABA sensor iGABASnFR demonstrate a circadian oscillation of extracellular GABA ([GABA]e) that, counterintuitively, runs in antiphase to neuronal activity, with a prolonged peak in circadian night and a pronounced trough in circadian day. Resolving this unexpected relationship, we found that [GABA]e is regulated by GABA transporters (GATs), with uptake peaking during circadian day, hence the daytime trough and nighttime peak. This uptake is mediated by the astrocytically expressed transporter GAT3 (Slc6a11), expression of which is circadian-regulated, being elevated in daytime. Clearance of [GABA]e in circadian day facilitates neuronal firing and is necessary for circadian release of the neuropeptide vasoactive intestinal peptide, a critical regulator of TTFL and circuit-level rhythmicity. Finally, we show that genetic complementation of the astrocytic TTFL alone, in otherwise clockless SCN, is sufficient to drive [GABA]e rhythms and control network timekeeping. Thus, astrocytic clocks maintain the SCN circadian clockwork by temporally controlling GABAergic inhibition of SCN neurons.
    Keywords:  GABA; GABA transporters; astrocytes; circadian rhythms; suprachiasmatic nucleus
    DOI:  https://doi.org/10.1073/pnas.2301330120
  2. Nat Commun. 2023 May 17. 14(1): 2819
    Singularity response reveals entrainment properties in mammalian circadian clock.
    Kosaku Masuda, Naohiro Kon, Kosuke Iizuka, Yoshitaka Fukada, Takeshi Sakurai, Arisa Hirano.
      Entrainment is characterized by phase response curves (PRCs), which provide a summary of responses to perturbations at each circadian phase. The synchronization of mammalian circadian clocks is accomplished through the receipt of a variety of inputs from both internal and external time cues. A comprehensive comparison of PRCs for various stimuli in each tissue is required. Herein, we demonstrate that PRCs in mammalian cells can be characterized using a recently developed estimation method based on singularity response (SR), which represents the response of desynchronized cellular clocks. We confirmed that PRCs can be reconstructed using single SR measurements and quantified response properties for various stimuli in several cell lines. SR analysis reveals that the phase and amplitude after resetting are distinguishable among stimuli. SRs in tissue slice cultures reveal tissue-specific entrainment properties. These results demonstrate that SRs can be employed to unveil entrainment mechanisms with diverse stimuli in multiscale mammalian clocks.
    DOI:  https://doi.org/10.1038/s41467-023-38392-x
  3. Prog Lipid Res. 2023 May 13. pii: S0163-7827(23)00025-5. [Epub ahead of print]91 101235
    Lipid metabolism around the body clocks.
    Volodymyr Petrenko, Flore Sinturel, Howard Riezman, Charna Dibner.
      Lipids play important roles in energy metabolism along with diverse aspects of biological membrane structure, signaling and other functions. Perturbations of lipid metabolism are responsible for the development of various pathologies comprising metabolic syndrome, obesity, and type 2 diabetes. Accumulating evidence suggests that circadian oscillators, operative in most cells of our body, coordinate temporal aspects of lipid homeostasis. In this review we summarize current knowledge on the circadian regulation of lipid digestion, absorption, transportation, biosynthesis, catabolism, and storage. Specifically, we focus on the molecular interactions between functional clockwork and biosynthetic pathways of major lipid classes comprising cholesterol, fatty acids, triacylglycerols, glycerophospholipids, glycosphingolipids, and sphingomyelins. A growing body of epidemiological studies associate a socially imposed circadian misalignment common in modern society with growing incidence of metabolic disorders, however the disruption of lipid metabolism rhythms in this connection has only been recently revealed. Here, we highlight recent studies that unravel the mechanistic link between intracellular molecular clocks, lipid homeostasis and development of metabolic diseases based on animal models of clock disruption and on innovative translational studies in humans. We also discuss the perspectives of manipulating circadian oscillators as a potentially powerful approach for preventing and managing metabolic disorders in human patients.
    Keywords:  Circadian clocks; circadian lipidomics; lipid metabolism; metabolic diseases; tissue-specific circadian regulation; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.plipres.2023.101235
  4. Sci Adv. 2023 May 19. 9(20): eadf2982
    Mice with humanized livers reveal the role of hepatocyte clocks in rhythmic behavior.
    Anne-Sophie Delbès, Mar Quiñones, Cédric Gobet, Julien Castel, Raphaël G P Denis, Jérémy Berthelet, Benjamin D Weger, Etienne Challet, Aline Charpagne, Sylviane Metairon, Julie Piccand, Marine Kraus, Bettina H Rohde, John Bial, Elizabeth M Wilson, Lise-Lotte Vedin, Mirko E Minniti, Matteo Pedrelli, Paolo Parini, Frédéric Gachon, Serge Luquet.
      The synchronization of circadian clock depends on a central pacemaker located in the suprachiasmatic nuclei. However, the potential feedback of peripheral signals on the central clock remains poorly characterized. To explore whether peripheral organ circadian clocks may affect the central pacemaker, we used a chimeric model in which mouse hepatocytes were replaced by human hepatocytes. Liver humanization led to reprogrammed diurnal gene expression and advanced the phase of the liver circadian clock that extended to muscle and the entire rhythmic physiology. Similar to clock-deficient mice, liver-humanized mice shifted their rhythmic physiology more rapidly to the light phase under day feeding. Our results indicate that hepatocyte clocks can affect the central pacemaker and offer potential perspectives to apprehend pathologies associated with altered circadian physiology.
    DOI:  https://doi.org/10.1126/sciadv.adf2982
  5. Pharmacopsychiatry. 2023 May;56(3): 85-86
    The Role of Circadian Rhythmicity and CLOCK Genes in Psychiatry.
    Denise Palm, Johannes Thome.
      Circadian rhythms are biological oscillations, that perpetuate themselves even in the absence of "zeitgebers" (external time cues), with a period of approximately 24 hours. The master pacemaker is the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN is entrained by environmental factors, particularly light, to the 24-hour light-dark cycle by the Earth's rotation. Peripheral circadian oscillators, located in multiple cell types and tissues, are controlled by signals arising from the SCN and from the environment, particularly food intake, hormonal signals and body-temperature fluctuations. Circadian rhythmicity is observable in almost every cell of living organisms including humans and, for example in cell cultures, these rhythms persist even without the SCN 1 2.
    DOI:  https://doi.org/10.1055/a-2078-4905
  6. Sci Rep. 2023 May 12. 13(1): 7742
    Prediction of mammalian tissue-specific CLOCK-BMAL1 binding to E-box DNA motifs.
    Daniel Marri, David Filipovic, Omar Kana, Shelley Tischkau, Sudin Bhattacharya.
      The Brain and Muscle ARNTL-Like 1 protein (BMAL1) forms a heterodimer with either Circadian Locomotor Output Cycles Kaput (CLOCK) or Neuronal PAS domain protein 2 (NPAS2) to act as a master regulator of the mammalian circadian clock gene network. The dimer binds to E-box gene regulatory elements on DNA, activating downstream transcription of clock genes. Identification of transcription factor binding sites and genomic features that correlate to DNA binding by BMAL1 is a challenging problem, given that CLOCK-BMAL1 or NPAS2-BMAL1 bind to several distinct binding motifs (CANNTG) on DNA. Using three different types of tissue-specific machine learning models with features based on (1) DNA sequence, (2) DNA sequence plus DNA shape, and (3) DNA sequence and shape plus histone modifications, we developed an interpretable predictive model of genome-wide BMAL1 binding to E-box motifs and dissected the mechanisms underlying BMAL1-DNA binding. Our results indicated that histone modifications, the local shape of the DNA, and the flanking sequence of the E-box motif are sufficient predictive features for BMAL1-DNA binding. Our models also provide mechanistic insights into tissue specificity of DNA binding by BMAL1.
    DOI:  https://doi.org/10.1038/s41598-023-34115-w
  7. Proc Biol Sci. 2023 May 31. 290(1999): 20222605
    Ingrained city rhythms: flexible activity timing but more persistent circadian pace in urban birds.
    Barbara M Tomotani, Fabian Timpen, Kamiel Spoelstra.
      Urbanization dramatically increases the amount of light at night, which may disrupt avian circadian organization. We measured activity patterns of great tits breeding in the city and forest, and subsequently measured two clock properties of these birds under controlled conditions: tau (endogenous circadian clock speed) and after-effects (history dependency of the clock relative to previous conditions). City and forest birds showed a high repeatability of activity onset (0.60 and 0.41, respectively), with no difference between habitats after controlling for date effects. Activity duration and offset showed more variance, without a difference between birds from the two habitats. Tau did not differ between city and forest birds, however, city birds showed stronger after-effects, taking more days to revert to their endogenous circadian period. Finally, onset of activity was correlated with clocks speed in both habitats. Our results suggest that potential differences in activity timing of city birds is not caused by different clock speeds, but by a direct response to light. Persistence in after-effects suggests a reduced sensitivity of the clock to light at night. Urbanization may select for clock properties that increase the inertia of the endogenous circadian system to improve accuracy of activity rhythms when exposed to noisier lighting cues.
    Keywords:  after-effects of entrainment; artificial light at night; free-running period; great tit; incubation; urbanization
    DOI:  https://doi.org/10.1098/rspb.2022.2605
  8. Biomedicines. 2023 Apr 13. pii: 1171. [Epub ahead of print]11(4):
    Timing Is Important-Management of Metabolic Syndrome According to the Circadian Rhythm.
    Ksenija Zečević, Nataša Popović, Aleksandra Vuksanović Božarić, Mihailo Vukmirović, Manfredi Rizzo, Emir Muzurović.
      Physiological processes occur in accordance with a rhythm regulated by the endogenous biological clock. This clock is programmed at the molecular level and synchronized with the daily light-dark cycle, as well as activities such as feeding, exercise, and social interactions. It consists of the core clock genes, Circadian Locomotor Output Cycles Protein Kaput (CLOCK) and Brain and Muscle Arnt-Like protein 1 (BMAL1), and their products, the period (PER) and cryptochrome (CRY) proteins, as well as an interlocked feedback loop which includes reverse-strand avian erythroblastic leukemia (ERBA) oncogene receptors (REV-ERBs) and retinoic acid-related orphan receptors (RORs). These genes are involved in the regulation of metabolic pathways and hormone release. Therefore, circadian rhythm disruption leads to development of metabolic syndrome (MetS). MetS refers to a cluster of risk factors (RFs), which are not only associated with the development of cardiovascular (CV) disease (CVD), but also with increased all-cause mortality. In this review, we consider the importance of the circadian rhythm in the regulation of metabolic processes, the significance of circadian misalignment in the pathogenesis of MetS, and the management of MetS in relation to the cellular molecular clock.
    Keywords:  chronotherapy; circadian clocks; diet; exercise therapy; metabolic syndrome; peroxisome proliferator-activated receptors
    DOI:  https://doi.org/10.3390/biomedicines11041171
  9. bioRxiv. 2023 May 02. pii: 2023.05.01.538977. [Epub ahead of print]
    Preservation of ∼12-hour ultradian rhythms of gene expression of mRNA and protein metabolism in the absence of canonical circadian clock.
    Bokai Zhu, Silvia Liu.
      Besides the ∼24-hour circadian rhythms, ∼12-hour ultradian rhythms of gene expression, metabolism and behaviors exist in animals ranging from crustaceans to mammals. Three major hypotheses were proposed on the origin and mechanisms of regulation of ∼12-hour rhythms, namely that they are not cell-autonomous and controlled by a combination of the circadian clock and environmental cues, that they are regulated by two anti-phase circadian transcriptional factors in a cell-autonomous manner, or that they are established by a cell-autonomous ∼12-hour oscillator. To distinguish among these possibilities, we performed a post-hoc analysis of two high temporal resolution transcriptome dataset in animals and cells lacking the canonical circadian clock. In both the liver of BMAL1 knockout mice and Drosophila S2 cells, we observed robust and prevalent ∼12-hour rhythms of gene expression enriched in fundamental processes of mRNA and protein metabolism that show large convergence with those identified in wild-type mice liver. Bioinformatics analysis further predicted ELF1 and ATF6B as putative transcription factors regulating the ∼12-hour rhythms of gene expression independently of the circadian clock in both fly and mice. These findings provide additional evidence to support the existence of an evolutionarily conserved 12-hour oscillator that controls ∼12-hour rhythms of gene expression of protein and mRNA metabolism in multiple species.
    DOI:  https://doi.org/10.1101/2023.05.01.538977
  10. Front Neurosci. 2023 ;17 1165230
    Circadian glucocorticoids throughout development.
    Marianne Lehmann, Katharina Haury, Henrik Oster, Mariana Astiz.
      Glucocorticoids (GCs) are essential drivers of mammalian tissue growth and maturation during one of the most critical developmental windows, the perinatal period. The developing circadian clock is shaped by maternal GCs. GC deficits, excess, or exposure at the wrong time of day leads to persisting effects later in life. During adulthood, GCs are one of the main hormonal outputs of the circadian system, peaking at the beginning of the active phase (i.e., the morning in humans and the evening in nocturnal rodents) and contributing to the coordination of complex functions such as energy metabolism and behavior, across the day. Our article discusses the current knowledge on the development of the circadian system with a focus on the role of GC rhythm. We explore the bidirectional interaction between GCs and clocks at the molecular and systemic levels, discuss the evidence of GC influence on the master clock in the suprachiasmatic nuclei (SCN) of the hypothalamus during development and in the adult system.
    Keywords:  circadian system; development; glucocorticoid receptor; glucocorticoids; hypothalamic-pituitary-adrenal axis; molecular clock; perinatal programming
    DOI:  https://doi.org/10.3389/fnins.2023.1165230
  11. Sci Transl Med. 2023 May 17. 15(696): eabo2022
    Sexual dimorphism in the response to chronic circadian misalignment on a high-fat diet.
    Seán T Anderson, Hu Meng, Thomas G Brooks, Soon Yew Tang, Ronan Lordan, Arjun Sengupta, Soumyashant Nayak, Antonijo Mřela, Dimitra Sarantopoulou, Nicholas F Lahens, Aalim Weljie, Gregory R Grant, Frederic D Bushman, Garret A FitzGerald.
      Longitudinal studies associate shiftwork with cardiometabolic disorders but do not establish causation or elucidate mechanisms of disease. We developed a mouse model based on shiftwork schedules to study circadian misalignment in both sexes. Behavioral and transcriptional rhythmicity were preserved in female mice despite exposure to misalignment. Females were protected from the cardiometabolic impact of circadian misalignment on a high-fat diet seen in males. The liver transcriptome and proteome revealed discordant pathway perturbations between the sexes. Tissue-level changes were accompanied by gut microbiome dysbiosis only in male mice, biasing toward increased potential for diabetogenic branched chain amino acid production. Antibiotic ablation of the gut microbiota diminished the impact of misalignment. In the United Kingdom Biobank, females showed stronger circadian rhythmicity in activity and a lower incidence of metabolic syndrome than males among job-matched shiftworkers. Thus, we show that female mice are more resilient than males to chronic circadian misalignment and that these differences are conserved in humans.
    DOI:  https://doi.org/10.1126/scitranslmed.abo2022
  12. Platelets. 2023 Dec;34(1): 2206918
    N-methyl-D-aspartate receptor regulates the circadian clock in megakaryocytic cells and impacts cell proliferation through BMAL1.
    James I Hearn, Mariam Alhilali, Minah Kim, Maggie L Kalev-Zylinska, Raewyn C Poulsen.
      Peripheral circadian clocks control cell proliferation and survival, but little is known about their role and regulation in megakaryocytic cells. N-methyl-D-aspartate receptor (NMDAR) regulates the central clock in the brain. The purpose of this study was to determine whether NMDAR regulates the megakaryocytic cell clock and whether the megakaryocytic clock regulates cell proliferation and cell death. We found that both the Meg-01 megakaryocytic cell line and native murine megakaryocytes expressed circadian clock genes. Megakaryocyte-directed deletion of Grin1 in mice caused significant disruption of the circadian rhythm pathway at the transcriptional level and increased expression of BMAL1 at the protein level. Similarly, both pharmacological (MK-801) and genetic (GRIN-/-) inhibition of NMDAR in Meg-01 cells in vitro resulted in widespread changes in clock gene expression including increased expression of BMAL1, the core clock transcription factor. BMAL1 overexpression reduced Meg-01 cell proliferation and altered the time-dependent expression of the cell cycle regulators MYC and WEE1, whereas BMAL1 knockdown led to increased cell death in Meg-01-GRIN1-/- cells. Our results demonstrate that NMDAR regulates the circadian clock in megakaryocytic cells and that the circadian clock component BMAL1 contributes to the control of Meg-01 cell proliferation and survival.
    Keywords:  BMAL1; NMDA receptor; cell cycle; cell proliferation; circadian rhythm; megakaryocyte; megakaryocytic leukemia cell line (Meg-01); peripheral clock
    DOI:  https://doi.org/10.1080/09537104.2023.2206918
  13. Mol Cell. 2023 May 18. pii: S1097-2765(23)00290-3. [Epub ahead of print]83(10): 1677-1692.e8
    PERIOD phosphorylation leads to feedback inhibition of CK1 activity to control circadian period.
    Jonathan M Philpott, Alfred M Freeberg, Jiyoung Park, Kwangjun Lee, Clarisse G Ricci, Sabrina R Hunt, Rajesh Narasimamurthy, David H Segal, Rafael Robles, Yao Cai, Sarvind Tripathi, J Andrew McCammon, David M Virshup, Joanna C Chiu, Choogon Lee, Carrie L Partch.
      PERIOD (PER) and Casein Kinase 1δ regulate circadian rhythms through a phosphoswitch that controls PER stability and repressive activity in the molecular clock. CK1δ phosphorylation of the familial advanced sleep phase (FASP) serine cluster embedded within the Casein Kinase 1 binding domain (CK1BD) of mammalian PER1/2 inhibits its activity on phosphodegrons to stabilize PER and extend circadian period. Here, we show that the phosphorylated FASP region (pFASP) of PER2 directly interacts with and inhibits CK1δ. Co-crystal structures in conjunction with molecular dynamics simulations reveal how pFASP phosphoserines dock into conserved anion binding sites near the active site of CK1δ. Limiting phosphorylation of the FASP serine cluster reduces product inhibition, decreasing PER2 stability and shortening circadian period in human cells. We found that Drosophila PER also regulates CK1δ via feedback inhibition through the phosphorylated PER-Short domain, revealing a conserved mechanism by which PER phosphorylation near the CK1BD regulates CK1 kinase activity.
    Keywords:  circadian rhythms; kinase; product inhibition, intrinsically disordered protein
    DOI:  https://doi.org/10.1016/j.molcel.2023.04.019
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