bims-ciryme Biomed News
on Circadian rhythms and metabolism
Issue of 2022‒08‒21
six papers selected by
Gabriela Da Silva Xavier
University of Birmingham

  1. Proc Natl Acad Sci U S A. 2022 Aug 23. 119(34): e2203563119
      The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal clock driving circadian rhythms of physiology and behavior that adapt mammals to environmental cycles. Disruption of SCN-dependent rhythms compromises health, and so understanding SCN time keeping will inform management of diseases associated with modern lifestyles. SCN time keeping is a self-sustaining transcriptional/translational delayed feedback loop (TTFL), whereby negative regulators inhibit their own transcription. Formally, the SCN clock is viewed as a limit-cycle oscillator, the simplest being a trajectory of successive phases that progresses through two-dimensional space defined by two state variables mapped along their respective axes. The TTFL motif is readily compatible with limit-cycle models, and in Neurospora and Drosophila the negative regulators Frequency (FRQ) and Period (Per) have been identified as state variables of their respective TTFLs. The identity of state variables of the SCN oscillator is, however, less clear. Experimental identification of state variables requires reversible and temporally specific control over their abundance. Translational switching (ts) provides this, the expression of a protein of interest relying on the provision of a noncanonical amino acid. We show that the negative regulator Cryptochrome 1 (CRY1) fulfills criteria defining a state variable: ts-CRY1 dose-dependently and reversibly suppresses the baseline, amplitude, and period of SCN rhythms, and its acute withdrawal releases the TTFL to oscillate from a defined phase. Its effect also depends on its temporal pattern of expression, although constitutive ts-CRY1 sustained (albeit less stable) oscillations. We conclude that CRY1 has properties of a state variable, but may operate among several state variables within a multidimensional limit cycle.
    Keywords:  feedback; genetic code expansion; noncanonical amino acid; oscillator; transcriptional inhibition
  2. Cell Rep. 2022 Aug 16. pii: S2211-1247(22)01030-0. [Epub ahead of print]40(7): 111213
      High altitude exposes humans to hypobaric hypoxia, which induces various physiological and molecular changes. Recent studies point toward interaction between circadian rhythms and the hypoxic response, yet their human relevance is lacking. Here, we examine the effect of different high altitudes in conjunction with time of day on human whole-blood transcriptome upon an expedition to the highest city in the world, La Rinconada, Peru, which is 5,100 m above sea level. We find that high altitude vastly affects the blood transcriptome and, unexpectedly, does not necessarily follow a monotonic response to altitude elevation. Importantly, we observe daily variance in gene expression, especially immune-related genes, which is largely altitude dependent. Moreover, using a digital cytometry approach, we estimate relative changes in abundance of different cell types and find that the response of several immune cell types is time- and altitude dependent. Taken together, our data provide evidence for interaction between the transcriptional response to hypoxia and the time of day in humans.
    Keywords:  CIBERSORTx; CP: Molecular biology; circadian clocks; clock genes; daily rhythms; high altitude; humans; hypoxia; immune response; lowlanders; whole-blood transcriptomics
  3. Proc Natl Acad Sci U S A. 2022 Aug 23. 119(34): e2206066119
      The metronome-like circadian regulation of sleep timing must still adapt to an uncertain environment. Recent studies in Drosophila indicate that neuromodulation not only plays a key role in clock neuron synchronization but also affects interactions between the clock network and brain sleep centers. We show here that the targets of neuromodulators, G Protein Coupled Receptors (GPCRs), are highly enriched in the fly brain circadian clock network. Single-cell sequencing indicates that they are not only enriched but also differentially expressed and contribute to clock neuron identity. We generated a comprehensive guide library to mutagenize individual GPCRs in specific neurons and verified the strategy by introducing a targeted sequencing approach. Combined with a behavioral screen, the mutagenesis strategy revealed a role of dopamine in sleep regulation by identifying two dopamine receptors and a clock neuron subpopulation that gate the timing of sleep.
    Keywords:  circadian; clock neurons; dopamine; modulation; sleep
  4. Nutrition. 2022 Jun 17. pii: S0899-9007(22)00189-7. [Epub ahead of print]103-104 111776
      OBJECTIVES: Maternal circadian eating time and frequency are associated with altered glucose metabolism during pregnancy in humans. Research on long maternal fasting intervals is inconclusive, and little is known about the effect of maternal time feeding on offspring health. Therefore, the aim of the present study is to determine whether maternal time feeding influences the metabolic status of both male and female offspring.METHODS: Pregnant rats were provided ad libitum access to chow diet or fed during either the light phase (LP) or dark phase (DP) during embryonic development. At the age of 150 days, glucose tolerance, lipid concentrations, and insulin secretion were determined in adult male and female offspring.
    RESULTS: Both male and female offspring of LP and DP dams exhibited alterations in the lipid profile, and female offspring were glucose intolerant. Glucose-stimulated insulin secretion decreased in male and female offspring of LP and DP dams. Acetylcholine increased insulin secretion in male and female offspring. Islets from male and female offspring of DP dams exhibited less pronounced inhibition of insulin secretion by epinephrine, suggesting alterations in the cholinergic and adrenergic pathways in these animals.
    CONCLUSIONS: Our data suggest that a time-restricted feeding regimen during embryonic development could program rat offspring for metabolic dysfunction during adulthood.
    Keywords:  Circadian rhythms; Embryonic development; Insulin secretion; Offspring
  5. Commun Biol. 2022 Aug 19. 5(1): 846
      Every day, we sleep for a third of the day. Sleep is important for cognition, brain waste clearance, metabolism, and immune responses. The molecular mechanisms governing sleep are largely unknown. Here, we used a combination of single-cell RNA sequencing and cell-type-specific proteomics to interrogate the molecular underpinnings of sleep. Different cell types in three important brain regions for sleep (brainstem, cortex, and hypothalamus) exhibited diverse transcriptional responses to sleep need. Sleep restriction modulates astrocyte-neuron crosstalk and sleep need enhances expression of specific sets of transcription factors in different brain regions. In cortex, we also interrogated the proteome of two major cell types: astrocytes and neurons. Sleep deprivation differentially alters the expression of proteins in astrocytes and neurons. Similarly, phosphoproteomics revealed large shifts in cell-type-specific protein phosphorylation. Our results indicate that sleep need regulates transcriptional, translational, and post-translational responses in a cell-specific manner.
  6. Sleep Health. 2022 Aug 10. pii: S2352-7218(22)00101-2. [Epub ahead of print]
      Scientists in sleep and circadian rhythms, public health experts, healthcare providers, partners, and stakeholders convened in 2020 for a 2-day meeting organized by the Canadian Sleep and Circadian Network to develop a national strategy for the integration of sleep and circadian rhythms into public health and policies in Canada. The objective of this paper is to present the national strategy that emerged from this meeting of 60 participants from across Canada. The meeting focused on 4 key target priorities: (1) atypical working schedules, (2) sleep and circadian rhythms of children and adolescents, (3) insomnia, and (4) impact of sleep apnea on health. Following constructive discussions over 2 days, it was decided that the following 4 strategic objectives should be prioritized to accelerate the integration of sleep and circadian rhythms into public health policies in Canada: (1) Increase public health sleep and circadian rhythm research, (2) Increase public health education and knowledge mobilization on sleep, (3) Inform and support public health sleep interventions and policies, and (4) Promote sleep health training. The participants recommended that research and public health efforts should address the needs along the continuum of sleep health. The committee noted that strategies and interventions could differ across contexts, settings, sectors, and jurisdictions. The national strategy also identified high-priority research questions in public health and recommended mechanisms to build research capacity, providing a path forward for the integration of sleep and circadian rhythms into public health research and policies.
    Keywords:  Canada; Circadian rhythms; National strategy; Policy; Public health; Sleep health