bims-ciryme Biomed News
on Circadian rhythms and metabolism
Issue of 2022–10–30
six papers selected by
Gabriela Da Silva Xavier, University of Birmingham
  1. Machine Learning Analyses Reveal Circadian Features Predictive of Risk for Sleep Disturbance.
  2. Suprachiasmatic to paraventricular nuclei interaction generates normal food searching rhythms in mice.
  3. Input integration by the circadian clock exhibits nonadditivity and fold-change detection.
  4. Aryl hydrocarbon receptor affects circadian-regulated lipolysis through an E-Box-dependent mechanism.
  5. The role of insufficient sleep and circadian misalignment in obesity.
  6. Palmitate impairs circadian transcriptomics in muscle cells through histone modification of enhancers.
  1. Nat Sci Sleep. 2022 ;14 1887-1900
    Machine Learning Analyses Reveal Circadian Features Predictive of Risk for Sleep Disturbance.
    Rebeccah Overton, Aziz Zafar, Ziad Attia, Ahmet Ay, Krista K Ingram.
       Introduction: Sleep disturbances often co-occur with mood disorders, with poor sleep quality affecting over a quarter of the global population. Recent advances in sleep and circadian biology suggest poor sleep quality is linked to disruptions in circadian rhythms, including significant associations between sleep features and circadian clock gene variants.
    Methods: Here, we employ machine learning techniques, combined with statistical approaches, in a deeply phenotyped population to explore associations between clock genotypes, circadian phenotypes (diurnal preference and circadian phase), and risk for sleep disturbance symptoms.
    Results: As found in previous studies, evening chronotypes report high levels of sleep disturbance symptoms. Using molecular chronotyping by measuring circadian phase, we extend these findings and show that individuals with a mismatch between circadian phase and diurnal preference report higher levels of sleep disturbance. We also report novel synergistic interactions in genotype combinations of Period 3, Clock and Cryptochrome variants (PER3B (rs17031614)/ CRY1 (rs228716) and CLOCK3111 (rs1801260)/ CRY2 (rs10838524)) that yield strong associations with sleep disturbance, particularly in males.
    Conclusion: Our results indicate that both direct and indirect mechanisms may impact sleep quality; sex-specific clock genotype combinations predictive of sleep disturbance may represent direct effects of clock gene function on downstream pathways involved in sleep physiology. In addition, the mediation of clock gene effects on sleep disturbance indicates circadian influences on the quality of sleep. Unraveling the complex molecular mechanisms at the intersection of circadian and sleep physiology is vital for understanding how genetic and behavioral factors influencing circadian phenotypes impact sleep quality. Such studies provide potential targets for further study and inform efforts to improve non-invasive therapeutics for sleep disorders.
    Keywords:  chronotype; circadian clock; circadian misalignment; machine learning; sleep disturbance; sleep quality
    DOI:  https://doi.org/10.2147/NSS.S379888
  2. Front Physiol. 2022 ;13 909795
    Suprachiasmatic to paraventricular nuclei interaction generates normal food searching rhythms in mice.
    Iwona Olejniczak, Benjamin Campbell, Yuan-Chen Tsai, Shiva K Tyagarajan, Urs Albrecht, Jürgen A Ripperger.
      Searching for food follows a well-organized decision process in mammals to take up food only if necessary. Moreover, scavenging is preferred during their activity phase. Various time-dependent regulatory processes have been identified originating from the suprachiasmatic nuclei (SCN), which convert external light information into synchronizing output signals. However, a direct impact of the SCN on the timing of normal food searching has not yet been found. Here, we revisited the function of the SCN to affect when mice look for food. We found that this process was independent of light but modified by the palatability of the food source. Surprisingly, reducing the output from the SCN, in particular from the vasopressin releasing neurons, reduced the amount of scavenging during the early activity phase. The SCN appeared to transmit a signal to the paraventricular nuclei (PVN) via GABA receptor A1. Finally, the interaction of SCN and PVN was verified by retrograde transport-mediated complementation. None of the genetic manipulations affected the uptake of more palatable food. The data indicate that the PVN are sufficient to produce blunted food searching rhythms and are responsive to hedonistic feeding. Nevertheless, the search for normal food during the early activity phase is significantly enhanced by the SCN.
    Keywords:  GABA; circadian; hedonistic; homeostat; suprachiasmatic nuclei
    DOI:  https://doi.org/10.3389/fphys.2022.909795
  3. Proc Natl Acad Sci U S A. 2022 Nov;119(44): e2209933119
    Input integration by the circadian clock exhibits nonadditivity and fold-change detection.
    Gal Manella, Nityanand Bolshette, Marina Golik, Gad Asher.
      Circadian clocks are synchronized by external timing cues to align with one another and the environment. Various signaling pathways have been shown to independently reset the phase of the clock. However, in the body, circadian clocks are exposed to a multitude of potential timing cues with complex temporal dynamics, raising the question of how clocks integrate information in response to multiple signals. To investigate different modes of signal integration by the circadian clock, we used Circa-SCOPE, a method we recently developed for high-throughput phase resetting analysis. We found that simultaneous exposure to different combinations of known pharmacological resetting agents elicits a diverse range of responses. Often, the response was nonadditive and could not be readily predicted by the response to the individual signals. For instance, we observed that dexamethasone is dominant over other tested inputs. In the case of signals administered sequentially, the background levels of a signal attenuated subsequent resetting by the same signal, but not by signals acting through a different pathway. This led us to examine whether the circadian clock is sensitive to relative rather than absolute levels of the signal. Importantly, our analysis revealed the involvement of a signal-specific fold-change detection mechanism in the clock response. This mechanism likely stems from properties of the signaling pathway that are upstream to the clock. Overall, our findings elucidate modes of input integration by the circadian clock, with potential relevance to clock resetting under both physiological and pathological conditions.
    Keywords:  circadian clocks; corticosteroids; fold-change detection; phase transition curve; signal transduction
    DOI:  https://doi.org/10.1073/pnas.2209933119
  4. Mol Cell Endocrinol. 2022 Oct 22. pii: S0303-7207(22)00257-X. [Epub ahead of print] 111809
    Aryl hydrocarbon receptor affects circadian-regulated lipolysis through an E-Box-dependent mechanism.
    Ali Qasim Khazaal, Nazmul Haque, Callie R Krager, Stacey L Krager, Christopher Chambers, Andrew Wilber, Shelley A Tischkau.
      An internal circadian clock regulates timing of systemic energy homeostasis. The central clock in the hypothalamic suprachiasmatic nucleus (SCN) directs local clocks in peripheral tissues such as liver, muscle, and adipose tissue to synchronize metabolism with food intake and rest/activity cycles. Aryl hydrocarbon receptor (AhR) interacts with the molecular circadian clockworks. Activation of AhR dampens rhythmic expression of core clock genes, which may lead to metabolic dysfunction. Given the importance of appropriately-timed adipose tissue function to regulation of energy homeostasis, this study focused on mechanisms by which AhR may influence clock-controlled adipose tissue activity. We hypothesized that AhR activation in adipose tissue would impair lipolysis by dampening adipose rhythms, leading to a decreased lipolysis rate during fasting, and subsequently, altered serum glucose concentrations. Levels of clock gene and lipolysis gene transcripts in mouse mesenchymal stem cells (BMSCs) differentiated into mature adipocytes were suppressed by the AhR agonist β-napthoflavone (BNF), in an AhR dependent manner. BNF altered rhythms of core clock gene and lipolysis gene transcripts in C57bl6/J mice. BNF reduced serum free fatty acids, glycerol and liver glycogen. Chromatin immunoprecipitation indicated that BNF increased binding of AhR to E-Box elements in clock gene and lipolysis gene promoters. These data establish a link between AhR activation and impaired lipolysis, specifically by altering adipose tissue rhythmicity. In response to the decreased available energy from impaired lipolysis, the body increases glycogenolysis, thereby degrading more glycogen to provide necessary energy.
    DOI:  https://doi.org/10.1016/j.mce.2022.111809
  5. Nat Rev Endocrinol. 2022 Oct 24.
    The role of insufficient sleep and circadian misalignment in obesity.
    Jean-Philippe Chaput, Andrew W McHill, Rebecca C Cox, Josiane L Broussard, Caroline Dutil, Bruno G G da Costa, Hugues Sampasa-Kanyinga, Kenneth P Wright.
      Traditional risk factors for obesity and the metabolic syndrome, such as excess energy intake and lack of physical activity, cannot fully explain the high prevalence of these conditions. Insufficient sleep and circadian misalignment predispose individuals to poor metabolic health and promote weight gain and have received increased research attention in the past 10 years. Insufficient sleep is defined as sleeping less than recommended for health benefits, whereas circadian misalignment is defined as wakefulness and food intake occurring when the internal circadian system is promoting sleep. This Review discusses the impact of insufficient sleep and circadian misalignment in humans on appetite hormones (focusing on ghrelin, leptin and peptide-YY), energy expenditure, food intake and choice, and risk of obesity. Some potential strategies to reduce the adverse effects of sleep disruption on metabolic health are provided and future research priorities are highlighted. Millions of individuals worldwide do not obtain sufficient sleep for healthy metabolic functions. Furthermore, modern working patterns, lifestyles and technologies are often not conducive to adequate sleep at times when the internal physiological clock is promoting it (for example, late-night screen time, shift work and nocturnal social activities). Efforts are needed to highlight the importance of optimal sleep and circadian health in the maintenance of metabolic health and body weight regulation.
    DOI:  https://doi.org/10.1038/s41574-022-00747-7
  6. Life Sci Alliance. 2023 Jan;pii: e202201598. [Epub ahead of print]6(1):
    Palmitate impairs circadian transcriptomics in muscle cells through histone modification of enhancers.
    Nicolas J Pillon, Laura Sardón Puig, Ali Altıntaş, Prasad G Kamble, Salvador Casaní-Galdón, Brendan M Gabriel, Romain Barrès, Ana Conesa, Alexander V Chibalin, Erik Näslund, Anna Krook, Juleen R Zierath.
      Obesity and elevated circulating lipids may impair metabolism by disrupting the molecular circadian clock. We tested the hypothesis that lipid overload may interact with the circadian clock and alter the rhythmicity of gene expression through epigenomic mechanisms in skeletal muscle. Palmitate reprogrammed the circadian transcriptome in myotubes without altering the rhythmic mRNA expression of core clock genes. Genes with enhanced cycling in response to palmitate were associated with post-translational modification of histones. The cycling of histone 3 lysine 27 acetylation (H3K27ac), a marker of active gene enhancers, was modified by palmitate treatment. Chromatin immunoprecipitation and sequencing confirmed that palmitate exposure altered the cycling of DNA regions associated with H3K27ac. The overlap between mRNA and DNA regions associated with H3K27ac and the pharmacological inhibition of histone acetyltransferases revealed novel cycling genes associated with lipid exposure of primary human myotubes. Palmitate exposure disrupts transcriptomic rhythmicity and modifies enhancers through changes in histone H3K27 acetylation in a circadian manner. Thus, histone acetylation is responsive to lipid overload and may redirect the circadian chromatin landscape, leading to the reprogramming of circadian genes and pathways involved in lipid biosynthesis in skeletal muscle.
    DOI:  https://doi.org/10.26508/lsa.202201598
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