bims-ciryme Biomed News
on Circadian rhythms and metabolism
Issue of 2020‒06‒21
eight papers selected by
Gabriela Da Silva Xavier
University of Birmingham

  1. Nat Commun. 2020 Jun 17. 11(1): 3071
      Unlimited access to calorie-dense, palatable food is a hallmark of Western societies and substantially contributes to the worldwide rise of metabolic disorders. In addition to promoting overconsumption, palatable diets dampen daily intake patterns, further augmenting metabolic disruption. We developed a paradigm to reveal differential timing in the regulation of food intake behavior in mice. While homeostatic intake peaks in the active phase, conditioned place preference and choice experiments show an increased sensitivity to overeating on palatable food during the rest phase. This hedonic appetite rhythm is driven by endogenous circadian clocks in dopaminergic neurons of the ventral tegmental area (VTA). Mice with disrupted clock function in the VTA lose their hedonic overconsumption rhythms without affecting homeostatic intake. These findings assign a functional role of VTA clocks in modulating palatable feeding behaviors and identify a potential therapeutic route to counteract hyperphagy in an obesogenic environment.
  2. J Biol Rhythms. 2020 Jun 15. 748730420932073
      The suprachiasmatic nucleus (SCN) drives circadian rhythms in locomotion through coupled, single-cell oscillations. Global genetic deletion of the neuropeptide Vip or its receptor Vipr2 results in profound deficits in daily synchrony among SCN cells and daily rhythms in locomotor behavior and glucocorticoid secretion. To test whether this phenotype depends on vasoactive intestinal polypeptide (VIP) neurons in the SCN, we ablated VIP SCN neurons in vivo in adult male mice through Caspase3-mediated induction of the apoptotic pathway in cre-expressing VIP neurons. We found that ablation of VIP SCN neurons in adult mice caused a phenotype distinct from Vip- and Vipr2-null mice. Mice lacking VIP neurons retained rhythmic locomotor activity with a shortened circadian period, more variable onsets, and decreased duration of daily activity. Circadian hormonal outputs, specifically corticosterone rhythms, were severely dampened. In contrast, deletion of neonatal SCN VIP neurons dramatically reduced circadian gene expression in the cultured SCN, mimicking the effects of global deletion of Vip or Vipr2. These results suggest that SCN VIP neurons play a role in lengthening circadian period and stimulating the daily surge in glucocorticoids in adults and in synchronizing and sustaining daily rhythms among cells in the developing SCN.
    Keywords:  caspase; suprachiasmatic nucleus; vasoactive intestinal peptide; vasopressin
  3. Obesity (Silver Spring). 2020 Jun 15.
      In mammals, time and metabolism are tightly coupled variables; this relationship can be illustrated by numerous examples, such as the circadian variation in food intake or the circadian response to a glucose bolus. We review evidence that the interaction between suprachiasmatic nucleus and arcuate nucleus plays a key role in the execution of these functions. The nuclei are reciprocally connected via different projections, and this interaction provides an ideal anatomical framework to modify the temporal output of the hypothalamus to metabolic organs as a consequence of the feedback from the periphery. The suprachiasmatic nucleus-arcuate nucleus relationship is essential to integrate metabolic information into the circadian system and thus adapt circadian rhythms in core body temperature, locomotor activity, food intake, and circulating molecules such as glucose and corticosterone. With the rise in obesity-associated diseases in the world population, gaining knowledge about this relationship, and the consequences of disturbing this liaison, is essential to understand the pathogenesis of obesity.
  4. J Biol Rhythms. 2020 Jun 16. 748730420923164
      Electric light has enabled humans to conquer the night, but light exposure at night can disrupt the circadian timing system and is associated with a diverse range of health disorders. To provide adequate lighting for visual tasks without disrupting the human circadian timing system, a precise definition of circadian spectral sensitivity is required. Prior attempts to define the circadian spectral sensitivity curve have used short (≤90-min) monochromatic light exposures in dark-adapted human subjects or in vitro dark-adapted isolated retina or melanopsin. Several lines of evidence suggest that these dark-adapted circadian spectral sensitivity curves, in addition to 430- to 499-nm (blue) wavelength sensitivity, may include transient 400- to 429-nm (violet) and 500- to 560-nm (green) components mediated by cone- and rod-originated extrinsic inputs to intrinsically photosensitive retinal ganglion cells (ipRGCs), which decay over the first 2 h of extended light exposure. To test the hypothesis that the human circadian spectral sensitivity in light-adapted conditions may have a narrower, predominantly blue, sensitivity, we used 12-h continuous exposures of light-adapted healthy human subjects to 6 polychromatic white light-emitting diode (LED) light sources with diverse spectral power distributions at recommended workplace levels of illumination (540 lux) to determine their effect on the area under curve of the overnight (2000-0800 h) salivary melatonin. We derived a narrow steady-state human Circadian Potency spectral sensitivity curve with a peak at 477 nm and a full-width half-maximum of 438 to 493 nm. This light-adapted Circadian Potency spectral sensitivity permits the development of spectrally engineered LED light sources to minimize circadian disruption and address the health risks of light exposure at night in our 24/7 society, by alternating between daytime circadian stimulatory white light spectra and nocturnal circadian protective white light spectra.
    Keywords:  circadian; human; light spectrum; melatonin; spectral sensitivity
  5. Sci Rep. 2020 Jun 18. 10(1): 9920
      Disruption of the circadian system caused by disordered exposure to light is pervasive in modern society and increases the risk of cardiovascular disease. The mechanisms by which this happens are largely unknown. ApolipoproteinE-deficient (ApoE-/-) mice are studied commonly to elucidate mechanisms of atherosclerosis. In this study, we determined the effects of light-induced circadian disruption on atherosclerosis in ApoE-/- mice. We first characterized circadian rhythms of behavior, light responsiveness, and molecular timekeeping in tissues from ApoE-/- mice that were indistinguishable from rhythms in ApoE+/+ mice. These data showed that ApoE-/- mice had no inherent circadian disruption and therefore were an appropriate model for our study. We next induced severe disruption of circadian rhythms by exposing ApoE-/- mice to constant light for 12 weeks. Constant light exposure exacerbated atherosclerosis in male, but not female, ApoE-/- mice. Male ApoE-/- mice exposed to constant light had increased serum cholesterol concentrations due to increased VLDL/LDL fractions. Taken together, these data suggest that ApoE-/- mice are an appropriate model for studying light-induced circadian disruption and that exacerbated dyslipidemia may mediate atherosclerotic lesion formation caused by constant light exposure.
  6. Biochem Biophys Res Commun. 2020 Jun 11. pii: S0006-291X(20)30921-9. [Epub ahead of print]
      ICER corresponds to a group of alternatively spliced Inducible cAMP Early Repressors with high similarity, but multiple roles, including in circadian rhythm, and are involved in attenuation of cAMP-dependent gene expression. We present experimental and in silico data revealing biological differences between the isoforms with exon gamma (ICER) or without it (ICERγ). Both isoforms are expressed in the liver and the adrenal glands and can derive from differential splicing. In adrenals the expression is circadian, with maximum at ZT12 and higher amplitude of Icerγ. In the liver, the expression of Icerγ is lower than Icer in the 24 h time frame. Icer mRNA has a delayed early response to forskolin. The longer ICER protein binds to three DNA grooves of the Per1 promoter, while ICERγ only to two, as deduced by molecular modelling. This is in line with gel shift competition assays showing stronger binding of ICER to Per1 promotor. Only Icerγ siRNA provoked an increase of Per1 expression. In conclusion, we show that ICER and ICERγ have distinct biochemical properties in tissue expression, DNA binding, and response to forskolin. Data are in favour of ICERγ as the physiologically important form in hepatic cells where weaker binding of repressor might be preferred in guiding the cAMP-dependent response.
    Keywords:  Circadian expression; ICER; ICERγ; Isoform; Splicing
  7. Proc Natl Acad Sci U S A. 2020 Jun 15. pii: 202004262. [Epub ahead of print]
      Organisms possess photoperiodic timing mechanisms to detect variations in day length and temperature as the seasons progress. The nature of the molecular mechanisms interpreting and signaling these environmental changes to elicit downstream neuroendocrine and physiological responses are just starting to emerge. Here, we demonstrate that, in Drosophila melanogaster, EYES ABSENT (EYA) acts as a seasonal sensor by interpreting photoperiodic and temperature changes to trigger appropriate physiological responses. We observed that tissue-specific genetic manipulation of eya expression is sufficient to disrupt the ability of flies to sense seasonal cues, thereby altering the extent of female reproductive dormancy. Specifically, we observed that EYA proteins, which peak at night in short photoperiod and accumulate at higher levels in the cold, promote reproductive dormancy in female D. melanogaster Furthermore, we provide evidence indicating that the role of EYA in photoperiodism and temperature sensing is aided by the stabilizing action of the light-sensitive circadian clock protein TIMELESS (TIM). We postulate that increased stability and level of TIM at night under short photoperiod together with the production of cold-induced and light-insensitive TIM isoforms facilitate EYA accumulation in winter conditions. This is supported by our observations that tim null mutants exhibit reduced incidence of reproductive dormancy in simulated winter conditions, while flies overexpressing tim show an increased incidence of reproductive dormancy even in long photoperiod.
    Keywords:  alternative splicing; circadian clock; photoperiod; seasonality; temperature
  8. PLoS Genet. 2020 Jun;16(6): e1008814
      The circadian clocks in chlorophyte algae have been studied in two model organisms, Chlamydomonas reinhardtii and Ostreococcus tauri. These studies revealed that the chlorophyte clocks include some genes that are homologous to those of the angiosperm circadian clock. However, the genetic network architectures of the chlorophyte clocks are largely unknown, especially in C. reinhardtii. In this study, using C. reinhardtii as a model, we characterized RHYTHM OF CHLOROPLAST (ROC) 75, a clock gene encoding a putative GARP DNA-binding transcription factor similar to the clock proteins LUX ARRHYTHMO (LUX, also called PHYTOCLOCK 1 [PCL1]) and BROTHER OF LUX ARRHYTHMO (BOA, also called NOX) of the angiosperm Arabidopsis thaliana. We observed that ROC75 is a day/subjective day-phase-expressed nuclear-localized protein that associates with some night-phased clock genes and represses their expression. This repression may be essential for the gating of reaccumulation of the other clock-related GARP protein, ROC15, after its light-dependent degradation. The restoration of ROC75 function in an arrhythmic roc75 mutant under constant darkness leads to the resumption of circadian oscillation from the subjective dawn, suggesting that the ROC75 restoration acts as a morning cue for the C. reinhardtii clock. Our study reveals a part of the genetic network of C. reinhardtii clock that could be considerably different from that of A. thaliana.