bims-ciryme Biomed News
on Circadian rhythms and metabolism
Issue of 2022‒01‒23
eight papers selected by
Gabriela Da Silva Xavier
University of Birmingham

  1. FASEB J. 2022 Feb;36(2): e22133
      Shift-workers show an increased incidence of type 2 diabetes mellitus (T2DM). A possible mechanism is the disruption of the circadian timing of glucose homeostasis. Skeletal muscle mitochondrial function is modulated by the molecular clock. We used time-restricted feeding (TRF) during the inactive phase to investigate how mistimed feeding affects muscle mitochondrial metabolism. Rats on an ad libitum (AL) diet were compared to those that could eat only during the light (inactive) or dark (active) phase. Mitochondrial respiration, metabolic gene expressions, and metabolite concentrations were determined in the soleus muscle. Rats on AL feeding or dark-fed TRF showed a clear daily rhythm in muscle mitochondrial respiration. This rhythm in mitochondrial oxidative phosphorylation capacity was abolished in light-fed TRF animals and overall 24h respiration was lower. The expression of several genes involved in mitochondrial biogenesis and the fission/fusion machinery was altered in light-fed animals. Metabolomics analysis indicated that light-fed animals had lost rhythmic levels of α-ketoglutarate and citric acid. Contrastingly, lipidomics showed that light-fed animals abundantly gained rhythmicity in levels of triglycerides. Furthermore, while the RER shifted entirely with the food intake in the light-fed animals, many measured metabolic parameters (e.g., activity and mitochondrial respiration) did not strictly align with the shifted timing of food intake, resulting in a mismatch between expected metabolic supply/demand (as dictated by the circadian timing system and light/dark-cycle) and the actual metabolic supply/demand (as dictated by the timing of food intake). These data suggest that shift-work impairs mitochondrial metabolism and causes metabolic inflexibility, which can predispose to T2DM.
    Keywords:  lipidomics; metabolomics; mitochondrial respiration; soleus muscle; time-restricted feeding
  2. Proc Natl Acad Sci U S A. 2022 Jan 25. pii: e2113845119. [Epub ahead of print]119(4):
      The ∼20,000 cells of the suprachiasmatic nucleus (SCN), the master circadian clock of the mammalian brain, coordinate subordinate cellular clocks across the organism, driving adaptive daily rhythms of physiology and behavior. The canonical model for SCN timekeeping pivots around transcriptional/translational feedback loops (TTFL) whereby PERIOD (PER) and CRYPTOCHROME (CRY) clock proteins associate and translocate to the nucleus to inhibit their own expression. The fundamental individual and interactive behaviors of PER and CRY in the SCN cellular environment and the mechanisms that regulate them are poorly understood. We therefore used confocal imaging to explore the behavior of endogenous PER2 in the SCN of PER2::Venus reporter mice, transduced with viral vectors expressing various forms of CRY1 and CRY2. In contrast to nuclear localization in wild-type SCN, in the absence of CRY proteins, PER2 was predominantly cytoplasmic and more mobile, as measured by fluorescence recovery after photobleaching. Virally expressed CRY1 or CRY2 relocalized PER2 to the nucleus, initiated SCN circadian rhythms, and determined their period. We used translational switching to control CRY1 cellular abundance and found that low levels of CRY1 resulted in minimal relocalization of PER2, but yet, remarkably, were sufficient to initiate and maintain circadian rhythmicity. Importantly, the C-terminal tail was necessary for CRY1 to localize PER2 to the nucleus and to initiate SCN rhythms. In CRY1-null SCN, CRY1Δtail opposed PER2 nuclear localization and correspondingly shortened SCN period. Through manipulation of CRY proteins, we have obtained insights into the spatiotemporal behaviors of PER and CRY sitting at the heart of the TTFL molecular mechanism.
    Keywords:  CRY1; FRAP; SCN; intracellular mobility; nuclear retention
  3. Neurosci Lett. 2022 Jan 17. pii: S0304-3940(22)00019-2. [Epub ahead of print] 136462
      In mammals, the suprachiasmatic nucleus (SCN) is a principal circadian pacemaker that optimizes the timing of behavioral rhythms and physiological events. Normally, circadian behavioral rhythms are entrained by the environmental light-dark (LD) cycle via the SCN. However, daily rhythms of other synchronizing signals, such as food availability, also emerge. When food availability is restricted to a single recurring daytime meal in nocturnal rodents, they exhibit increased activity during the hours immediately preceding feeding time; this is called food anticipatory activity (FAA). Many reports suggest that FAA is mediated by the food-entrainable oscillator (FEO) with circadian properties, but not the SCN. However, the neural locus and timekeeping mechanisms of the FEO, including its relationship with gastrointestinal hormone signaling, remain unclear. Herein, to examine whether secretin receptor signaling is necessary for the FEO, the effect of daily food restriction was studied in secretin receptor-deficient (Sctr-/-) mice. Adult wild-type (WT) and Sctr-/- mice were housed in separate cages containing a running wheel, with ad libitum food access and in a LD cycle (12 hours : 12 hours) for at least 2 weeks. After acclimation to the condition, food access times were gradually restricted and 4-hour restricted feeding lasted over 10 days. Subsequently, mice had ad libitum food access for 2 days and then fasted for 2 days. Thereafter, robust FAAs were observed in both WT and Sctr-/- mice during restricted feeding and subsequent fasting. These results indicate that secretin receptor signaling is not essential for the timekeeping mechanism of FEO.
    Keywords:  Circadian rhythm; Food anticipatory activity; Food-entrainable oscillator; Secretin
  4. Front Neuroendocrinol. 2022 Jan 13. pii: S0091-3022(22)00001-2. [Epub ahead of print] 100978
      Sleep and the circadian clock are intertwined and have persisted throughout history. The suprachiasmatic nucleus (SCN) orchestrates sleep by controlling circadian (Process C) and homeostatic (Process S) activities. As a "hand" on the endogenous circadian clock, melatonin is critical for sleep regulation. Light serves as a cue for sleep/wake control by activating retino-recipient cells in the SCN and subsequently suppressing melatonin. Clock genes are the molecular timekeepers that keep the 24 h cycle in place. Two main sleep and behavioural disorder diagnostic manuals have now officially recognised the importance of these processes for human health and well-being. The body's ability to respond to daily demands with the least amount of effort is maximised by carefully timing and integrating all components of sleep and waking. In the brain, the organization of timing is essential for optimal brain physiology.
    Keywords:  Circadian clock; Clock genes; Sleep; Sleep disorder; Sleep medicine
  5. Nat Cardiovasc Res. 2022 Jan;1(1): 45-58
      The heart is a highly metabolic organ that uses multiple energy sources to meet its demand for ATP production. Diurnal feeding-fasting cycles result in substrate availability fluctuations which, together with increased energetic demand during the active period, impose a need for rhythmic cardiac metabolism. The nuclear receptors REV-ERBα and β are essential repressive components of the molecular circadian clock and major regulators of metabolism. To investigate their role in the heart, here we generated mice with cardiomyocyte (CM)-specific deletion of both Rev-erbs, which died prematurely due to dilated cardiomyopathy. Loss of Rev-erbs markedly downregulated fatty acid oxidation genes prior to overt pathology, which was mediated by induction of the transcriptional repressor E4BP4, a direct target of cardiac REV-ERBs. E4BP4 directly controls circadian expression of Nampt and its biosynthetic product NAD+ via distal cis-regulatory elements. Thus, REV-ERB-mediated E4BP4 repression is required for Nampt expression and NAD+ production by the salvage pathway. Together, these results highlight the indispensable role of circadian REV-ERBs in cardiac gene expression, metabolic homeostasis and function.
  6. Front Cell Dev Biol. 2021 ;9 799971
      Circadian rhythms orchestrate organismal physiology and behavior in order to anticipate daily changes in the environment. Virtually all cells have an internal rhythm that is synchronized every day by Zeitgebers (environmental cues). The synchrony between clocks within the animal enables the fitness and the health of organisms. Conversely, disruption of rhythms is linked to a variety of disorders: aging, cancer, metabolic diseases, and psychological disorders among others. At the cellular level, mammalian circadian rhythms are built on several layers of complexity. The transcriptional-translational feedback loop (TTFL) was the first to be described in the 90s. Thereafter oscillations in epigenetic marks highlighted the role of chromatin state in organizing the TTFL. More recently, studies on the 3D organization of the genome suggest that genome topology could be yet another layer of control on cellular circadian rhythms. The dynamic nature of genome topology over a solar day implies that the 3D mammalian genome has to be considered in the fourth dimension-in time. Whether oscillations in genome topology are a consequence of 24 h gene-expression or a driver of transcriptional cycles remains an open question. All said and done, circadian clock-gated phenomena such as gene expression, DNA damage response, cell metabolism and animal behavior-go hand in hand with 24 h rhythms in genome topology.
    Keywords:  3D genome; DNA damage; chromatin; circadian rhythm; clock; genome topology
  7. Biology (Basel). 2021 Dec 24. pii: 20. [Epub ahead of print]11(1):
      Metabolic syndrome (MetS) is a combination of cardiovascular risk factors associated with type 2 diabetes, obesity, and cardiovascular diseases. The circadian clock gene polymorphisms are very likely to participate in metabolic syndrome genesis and development. However, research findings of the association between circadian rhythm gene polymorphisms and MetS and its comorbidities are not consistent. In this study, a review of the association of circadian clock gene polymorphisms with overall MetS risk was performed. In addition, a meta-analysis was performed to clarify the association between circadian clock gene polymorphisms and MetS susceptibility based on available data. The PubMed and Scopus databases were searched for studies reporting the association between circadian rhythm gene polymorphisms (ARNTL, BMAL1, CLOCK, CRY, PER, NPAS2, REV-ERBα, REV-ERBβ, and RORα) and MetS, and its comorbidities diabetes, obesity, and hypertension. Thirteen independent studies were analyzed with 17,381 subjects in total. The results revealed that the BMAL1 rs7950226 polymorphism was associated with an increased risk of MetS in the overall population. In contrast, the CLOCK rs1801260 and rs6850524 polymorphisms were not associated with MetS. This study suggests that some circadian rhythm gene polymorphisms might be associated with MetS in different populations and potentially used as predictive biomarkers for MetS.
    Keywords:  circadian clock genes; hypertension; metabolic syndrome; obesity; type 2 diabetes mellitus
  8. J Nutr. 2021 Nov 22. pii: nxab397. [Epub ahead of print]
      BACKGROUND: The maternal metabolic milieu is challenged during pregnancy and may result in unwarranted metabolic complications. A time-restricted eating (TRE) pattern may optimize the metabolic response to pregnancy by improving glucose metabolism and reducing circulating glucose concentrations, as it does in nonpregnant individuals.OBJECTIVES: The objectives of this study were to 1) assess eating timing in pregnant women; 2) understand the perceptions of adopting a TRE pattern; 3) determine the barriers and support mechanisms for incorporating a TRE pattern; and 4) identify those most willing to adopt a TRE pattern during pregnancy.
    METHODS: This was a cross-sectional quantitative and quasi-qualitative online survey study for women who were pregnant at the time of study completion or had given birth in the prior 2 years. Group analyses were performed based off willingness to try a TRE pattern using chi-squared analyses, independent samples t-tests, or an analysis of variance. Three separate reviewers reviewed qualitative responses.
    RESULTS: A total of 431 women (BMI, 27.5 ± 0.3 kg/m2) completed the study. Of the participating women, 23.7% reported willingness to try a TRE pattern during pregnancy. Top barriers to adopting a TRE pattern during pregnancy were concerns for 1) safety; 2) nausea; and 3) hunger. The highest ranked support mechanisms were: 1) the ability to choose the eating window; 2) more frequent prenatal visits to ensure the health of the baby; and 3) receiving feedback from a dietician/nutritionist. Women who did not identify as White/Caucasian expressed a higher willingness to try a TRE pattern during pregnancy (P = 0.01). Women who were nulliparous expressed a higher willingness to try a TRE pattern (P = 0.05).
    DISCUSSION: TRE, an alternative dietary strategy shown to optimize metabolic control, may be effective to prevent and manage pregnancy-related metabolic impairments. To create an effective TRE intervention during pregnancy, the input of pregnant mothers is necessary to increase adherence and acceptability.
    Keywords:  circadian rhythm; eating patterns; gestational diabetes; gestational weight gain; intermittent fasting; obesity