bims-ciryme Biomed News
on Circadian rhythms and metabolism
Issue of 2025–11–30
eight papers selected by
Gabriela Da Silva Xavier, University of Birmingham
  1. Somatostatin regulates the clock sensitivity to evening light.
  2. Time-Series RNA Sequencing Reveals Temperature-Specific and Temperature-Compensated Circadian Genes in Drosophila.
  3. Time-Restricted Feeding Extends Healthspan in Female and Lifespan in Male C57BL/6J Mice.
  4. The sleep-wake history contributes to rhythmic BMAL1 chromatin binding in the cerebral cortex but not in the liver.
  5. Remimazolam-induced anesthesia does not affect circadian rhythms significantly in mice.
  6. Fasting hijacks proximal tubule circadian control mechanisms to regulate glucose reabsorption via the Nrf1/Sglt2 pathway in mice.
  7. Aberrant DNA methylation within circadian entrainment and clock genes two years after pediatric critical illness is associated with impaired physical and neurocognitive development.
  8. NADH dehydrogenase reverses dietary and clock metabolic syndrome.
  1. Sci Rep. 2025 Nov 28. 15(1): 42664
    Somatostatin regulates the clock sensitivity to evening light.
    Yoshiaki Yamaguchi, Satoru Masubuchi, Emi Kiyokage, Kazunori Toida, Yasutaka Mizoro, Toru Suzuki, Miho Sato, Jean-Michel Fustin, Keiko Tominaga, Hitoshi Okamura.
      Entrainment of the internal clock to the light-dark cycle is a fundamental feature of biological rhythms. Here, we show that animals genetically deficient for somatostatin (SST) are unable to respond normally to long photoperiodic conditions, showing a significantly delayed phase of activity. The phase delay is also reproduced in the cognate SSTR1 receptor knockout mice and in mice in which SSTR1 is pharmacologically inhibited. We also provide histological evidence that SST inhibits light-induced activation of SSTR1 cells. Furthermore, chronic administration of CH-275, an SSTR1 agonist, normalizes the phase delay of the circadian clock in SST-deficient mice under long photoperiod. Together, these results provide insights into the inhibitory effect of the SST-SSTR1 system in the regulation of light sensitivity of the central clock in the SCN at dusk.
    DOI:  https://doi.org/10.1038/s41598-025-26904-2
  2. bioRxiv. 2025 Nov 04. pii: 2025.11.04.686609. [Epub ahead of print]
    Time-Series RNA Sequencing Reveals Temperature-Specific and Temperature-Compensated Circadian Genes in Drosophila.
    Fumihiro Ito, Fei Zhang, Wanhe Li.
      Circadian rhythms align the physiology and behavior of living organisms with the 24-hour day. As a defining property of circadian rhythms, temperature compensation preserves the 24-hour rhythmic periodicity despite environmental temperature changes. While the molecular clockwork that drives genome-wide oscillations in gene expression is well characterized, how circadian gene expression contributes to the maintenance of rhythmic outputs under thermal variation and to produce temperature compensation remains uninvestigated. We profiled circadian gene expression in the ectothermic animal Drosophila melanogaster using time-series RNA-seq of head tissues under constant darkness at 18°C, 25°C, and 29°C. Locomotion assays confirmed that behavioral rhythms were temperature compensated under these conditions. Analyses of the time-series RNA-seq samples revealed hundreds of oscillating genes at each temperature, yet the majority were temperature specific. Only 14 genes, including the core clock components period ( per ) and vrille ( vri ), oscillated across all three constant darkness conditions at different temperatures. Even among these, the phase, amplitude, and expression levels of these oscillating genes often shifted with temperature. Thus, temperature-compensated oscillating genes are rare and largely confined to core clock genes, while most oscillating genes are temperature-specific. Our results suggested a potential architecture: a robust, temperature-compensated core set of oscillating genes, and a flexible, temperature-responsive output layer. The latter likely establishes temperature-specific oscillating gene expression programs that enable the animal to achieve temperature compensation at behavioral and physiological levels.
    DOI:  https://doi.org/10.1101/2025.11.04.686609
  3. bioRxiv. 2025 Oct 23. pii: 2025.10.22.683527. [Epub ahead of print]
    Time-Restricted Feeding Extends Healthspan in Female and Lifespan in Male C57BL/6J Mice.
    Samantha E Iiams, Nathan J Skinner, Victoria A Acosta-Rodríguez, Mary Wight-Carter, Carla B Green, Joseph S Takahashi.
      Time-restricted feeding (TRF) aligned with an organism's circadian rhythm has been shown to improve health, but its long-term effects on healthspan and lifespan in mammals, especially under normal dietary conditions, remain unclear. In this study, we tested the impact of 12-hour (h) and 8h nightly TRF windows on aging in male and female mice fed regular chow. TRF improved several health measures, including the regularity of behavioral patterns, body weight and composition, frailty, and disease onset, with stronger effects observed in the 8h-TRF group, which self-imposed a caloric restriction. When integrated into a composite Healthspan Index, these improvements revealed that TRF prolonged healthspan in females more effectively than in males. Only 8h-TRF extended lifespan in males by 12%, suggesting that TRF exerts sex-specific effects on aging.
    DOI:  https://doi.org/10.1101/2025.10.22.683527
  4. Proc Natl Acad Sci U S A. 2025 Dec 02. 122(48): e2515047122
    The sleep-wake history contributes to rhythmic BMAL1 chromatin binding in the cerebral cortex but not in the liver.
    Carlos Neves, Charlotte N Hor, Sonia Jimenez, Paul Franken.
      The timing and quality of sleep is regulated by circadian- and sleep-wake-driven processes. The core clock gene Bmal1 not only affects the circadian timing of sleep, but also the response to sleep deprivation (SD), which, in turn, causes long-term changes in cortical Bmal1 expression. We aimed at separating the circadian- and sleep-wake-driven contributions to BMAL1 binding to its target genes in the cerebral cortex by scheduling 6 SDs at 4 h intervals across the daily 12 h light/12 h dark cycle. We show that BMAL1 rhythmically bound its tissue-specific targets with tissue-specific dynamics, reaching peak binding 2 to 4 h later in the cortex than in the liver, while trough times did not differ. The SDs affected BMAL1 binding most significantly in the cortex, causing 80% of rhythmically bound regions to lose rhythmicity, suggesting BMAL1 binding has a prominent sleep-wake-driven component in this tissue. Analyses of the promoters of other core clock-genes indicate that BMAL1 binding to Bhlhe41 and Nr2d1 have a strong sleep-wake-driven component, while for Per2 two binding regions were identified one with circadian- and the other with sleep-wake-driven binding dynamics. Our results attest to a nonadditive interaction of time-of-day and time-spent-awake affecting the core molecular circadian circuitry. It further highlights that rhythms in gene expression in peripheral tissues are an emergent property of molecular interactions beyond that of the core molecular clock circuitry.
    Keywords:  Bmal1; Circadian; Gene regulation; Mus musculus; Sleep
    DOI:  https://doi.org/10.1073/pnas.2515047122
  5. Sci Rep. 2025 Nov 26.
    Remimazolam-induced anesthesia does not affect circadian rhythms significantly in mice.
    Yasuhito Suzuki, Ryo Imai, Yoshitaka Aoki, Shingo Kawashima, Kazuya Hokamura, Tetsuro Kimura, Tadayoshi Kurita, Takasumi Katoh, Soichiro Mimuro, Hiroshi Makino, Kazuo Umemura, Yoshiki Nakajima.
      Although inhalational general anesthesia affects mammalian circadian rhythms, which are generated through oscillations in expression of clock genes in the suprachiasmatic nucleus (SCN), the impact of intravenous benzodiazepine (BDZ)-induced general anesthesia is not well understood. We investigated the effects of remimazolam (RMZ), an ultra-short-acting BDZ that has recently gained widespread use in clinical anesthesia, on circadian rhythms and clock gene expression in the SCN in male C57BL/6J mice. Phase shifts in behavioral rest-activity circadian rhythms were quantitatively measured under constant dark conditions. No significant differences were detected among the interventions tested: continuous RMZ injection, bolus RMZ injection, and saline injection at different circadian times. Analyses of day/night activity distribution and the percentage of mice in inactivity bouts showed no significant differences among these groups. To assess the effects of RMZ on clock gene expression, we used continuous RMZ injection, which better reflects clinical anesthesia conditions. Quantitative real-time polymerase chain reaction revealed that the mRNA expression levels of major clock genes Per2, Bmal1, Cry1, and Npas2 in the SCN were decreased, whereas the neuronal activity marker Egr1 was increased. The period of circadian oscillations in clock gene Per2 expression-analyzed by bioluminescence rhythms of cultured SCN tissue from PER2::LUC mice-did not change with any concentration of RMZ administration. Our findings show that RMZ has minimal effects on circadian rhythms under our experimental protocols, suggesting that RMZ has the potential to reduce complications related to circadian rhythm disruption by general anesthesia.
    Keywords:  Benzodiazepine; Circadian rhythm; Perioperative complications; Remimazolam
    DOI:  https://doi.org/10.1038/s41598-025-29999-9
  6. Nat Commun. 2025 Nov 25. 16(1): 10447
    Fasting hijacks proximal tubule circadian control mechanisms to regulate glucose reabsorption via the Nrf1/Sglt2 pathway in mice.
    Xiaoyue Pan, Cyrus Mowdawalla, Samantha Bagnato, Jeffrey Pessin, Volker Vallon, M Mahmood Hussain.
      The kidneys contribute to glucose homeostasis by gluconeogenesis and glucose reabsorption. Herein, we identified previously unknown fasting-induced, glucagon-mediated inhibitory effect of the circadian clock gene basic helix-loop-helix ARNT like 1 (Bmal1) on the expression of the main proximal tubule glucose transporter solute carrier family 5 member 2 (Sglt2) in mice. During fasting, glucagon induces Bmal1, which increases expression of nuclear receptor subfamily 1, group D, member 1 (Rev-erbα). Rev-erbα represses nuclear respiratory factor 1, a transcriptional activator of Sglt2, and diminishes Sglt2 expression and thereby kidney glucose reabsorption capacity. During refeeding (lower glucagon) this process is attenuated, thereby inducing glucose reabsorption. The physiological role of this mechanism appears to ensure optimal temporal retrieval of filtered glucose during fasting/refeeding. Thus, this study demonstrates that during fasting and refeeding, glucagon regulates renal glucose reabsorption by utilizing the local cellular circadian machinery.
    DOI:  https://doi.org/10.1038/s41467-025-65402-x
  7. Clin Epigenetics. 2025 Nov 23.
    Aberrant DNA methylation within circadian entrainment and clock genes two years after pediatric critical illness is associated with impaired physical and neurocognitive development.
    Grégoire Coppens, Arnout B G Cramer, Ilse Vanhorebeek, Fabian Güiza, Pieter J Wouters, Inês Chaves, Matthijs de Hoog, Karolijn Dulfer, Koen F M Joosten, Greet Van den Berghe, Sascha C A T Verbruggen.
       BACKGROUND: Pediatric critical illness can disrupt circadian rhythms, potentially leading to long-term deficits in growth, neurocognition, and behavior. Disturbances in circadian rhythms have been associated with altered gene expression and DNA methylation. We investigated long-term DNA methylation alterations in circadian entrainment and clock genes in children previously admitted to the pediatric intensive care unit (PICU), the influence of parenteral nutrition (PN) timing hereon and their associations with long-term health outcomes.
    METHODS: This study is a secondary analysis of the PEPaNIC randomized controlled trial (RCT) and its two-year follow-up. The PEPaNIC-RCT randomized critically ill children to early initiation of supplemental PN within the first 24 h or its omission in the first week of PICU admission. DNA methylation of 127 circadian entrainment and clock genes was studied in buccal mucosa DNA of former PICU patients (n = 818) and matched healthy children (n = 392) at the two-year follow-up using Infinium® HumanMethylation EPIC BeadChips. Multivariable linear models were used to identify differential methylation between former patients and controls and their association with randomization group and outcomes at two-year follow-up.
    RESULTS: Former PICU patients showed 61 differentially methylated CpG sites (DMPs) within 34 of the genes, with 60 (98.4%) showing hypomethylation as compared with healthy children. Omitting early PN during PICU stay did not affect CpG site methylation. 702 associations (34.9%) were observed between abnormal DNA methylation and adverse long-term health and developmental outcomes, most notably visual-motor integration (47 DMPs, 77%), height (46 DMPs, 75%) and total IQ (46 DMPs, 75%).
    CONCLUSION: Former PICU patients exhibited altered DNA methylation in circadian entrainment and clock genes compared to healthy children, and this was associated with impaired growth, neurocognition and behavioral problems at two-year follow-up. Disruptions in circadian entrainment and clock gene methylation may contribute to the adverse long-term health consequences that children experience after critical illness.
    Keywords:  Children; Circadian rhythm; Clock genes; Critical illness; DNA methylation; Epigenetics; PICU; Parenteral nutrition
    DOI:  https://doi.org/10.1186/s13148-025-02027-3
  8. bioRxiv. 2025 Oct 23. pii: 2025.10.22.684030. [Epub ahead of print]
    NADH dehydrogenase reverses dietary and clock metabolic syndrome.
    Chelsea Hepler, Nathan J Waldeck, Benjamin J Weidemann, Biliana Marcheva, You-Jia Chen, Jacqueline Hecker, Ziming Zhu, Rino Nozawa, Joseph V Mastroni, Anneke K Thorne, Colleen R Reczek, Jonathan Cedernaes, Kathryn M Ramsey, Clara B Peek, Grant D Barish, Navdeep S Chandel, Joseph Bass.
      Circadian clocks are internal timing systems that enable organisms to anticipate and adapt to daily environmental changes. These rhythms arise from a transcription-translation feedback loop in which CLOCK/BMAL1 regulate the expression of thousands of genes, including their repressors PER/CRY 1 . Disruption of circadian rhythms contributes to obesity, metabolic disease, and cancer 2-4 , yet how the clock maintains metabolic homeostasis remains limited. Here we report that the clock regulates oxidative metabolism through diurnal respiration of mitochondrial respiratory chain complex I. Genetic loss of the clock and high fat diet feeding in male mice led to reduced complex I respiration within adipocytes, leading to suppression of PPAR and insulin signaling pathways. In contrast, preserving complex I function maintained adipogenic and metabolic gene networks and protected against diet- and circadian-induced metabolic dysfunction independently of weight gain. These findings reveal that circadian disruption impairs metabolic health through mitochondrial complex I dysfunction, establishing clock control of complex I as a key regulator of transcriptional and metabolic homeostasis.
    DOI:  https://doi.org/10.1101/2025.10.22.684030
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