bims-ciryme 2025-05-18 papers

bims-ciryme

Biomed News

on Circadian rhythms and metabolism

Issue of 2025–05–18
nine papers selected by
Gabriela Da Silva Xavier, University of Birmingham

Circadian synchronization differentially modifies cytokine-mediated transcriptomic remodeling and cell death in INS-1 cells and mouse islets.
Evolutionary origins of self-sustained Kai protein circadian oscillators in cyanobacteria.
Anti-Müllerian hormone signalling sustains circadian homeostasis in zebrafish.
Upstream open reading frames dynamically modulate CLOCK protein translation to regulate circadian rhythms and sleep.
Early-Life Ventral Hippocampal Lesion and Circadian Disruption Result in Altered Behavior in Adult Mice in a Sex-Dependent Manner.
Cancer-induced FOXP1 disrupts and reprograms skeletal-muscle circadian transcription in cachexia.
Exercise as a Synchronizer: Effects on Circadian Re-Entrainment of Core Body Temperature and Metabolism Following Light-Dark Cycle Inversion in Mice.
Stat3 Silencing Affects Circadian Clock Gene Expression and Lipopolysaccharide Response in the Suprachiasmatic Nucleus, Cortex, and Glioblastoma Cell Cultures.
The NONO protein regulates nonclassical DNA structure: Effects on circadian genes and DNA damage.

iScience. 2025 May 16. 28(5): 112431

Circadian synchronization differentially modifies cytokine-mediated transcriptomic remodeling and cell death in INS-1 cells and mouse islets.

Phillip Alexander Keller Andersen, Rasmus H Reeh, Isabel Sanders, Emilie Bender Overlund, Georgia Katsioudi, Cecilia Jiménez-Sánchez, Emil Zeng Skovhøj, Anniek Frederike Lubberding, Charna Dibner, Thomas Mandrup-Poulsen.

  Perturbation of the β-cell circadian clock causes oxidative stress and secretory failure, and proinflammatory cytokines disrupt the β-cell core clock. We hypothesized that cytokine-mediated clock perturbation in β-cells depends on circadian synchronization status. Cytokine-mediated core clock mRNA expression in non-synchronized insulin-producing INS-1 cells were potentiated upon synchronization, which were differentially translated into alterations in protein levels. Synchronization sensitized INS-1 cells to cytokine-mediated cytotoxicity, associated with potentiation of NF-κB activity. Inhibition of NF-κB abrogated cytokine-mediated clock gene-expression independent of synchronization status and reversed cytokine-mediated period lengthening. In contrast, in murine islets, cytokines generally reduced core clock mRNA expression independently of synchronization status or NF-κB activity. Synchronization prevented cytokine-mediated cytotoxicity, but not NF-κB activity to a degree comparable to that of KINK-1, while alterations in islet rhythmicity were unaffected by NF-κB inhibition. In conclusion, circadian synchronization differentially modifies cytokine-mediated transcriptomic remodeling and cell death in INS-1 cells and murine islets, depending on NF-κB involvement.

Keywords:  Cell biology; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2025.112431
Nat Commun. 2025 May 15. 16(1): 4541

Evolutionary origins of self-sustained Kai protein circadian oscillators in cyanobacteria.

Atsushi Mukaiyama, Yoshihiko Furuike, Kumiko Ito-Miwa, Yasuhiro Onoue, Kota Horiuchi, Kanta Kondo, Eiki Yamashita, Shuji Akiyama.

Light-dark cycles affect photosynthetic efficiency in autotrophic cyanobacteria; therefore, determining whether ancient cyanobacteria possessed a self-sustained circadian clock when oxygenic photosynthetic systems were established is an important issue in chronobiology. Here we examine the oscillation of the clock protein KaiC in modern cyanobacteria, as well as the function and structure of ancestral Kai proteins, to determine the evolutionary origin of the self-sustained Kai-protein oscillators. The results show that the oldest double-domain KaiC in ancestral bacteria lacks the factors functionally and structurally essential for rhythmicity. The ancestral Kai proteins have acquired these factors through molecular evolution that occurred around Global Oxidation and Snowball Earth events, and are eventually inherited as a self-sustained circadian oscillator by the most recent common ancestor of cyanobacteria capable of oxygenic photosynthesis. This autonomous Kai protein oscillator is further inherited by most freshwater and marine cyanobacteria present today as an autotrophic basis for time-optimal acquisition and consumption of energy from oxygenic photosynthesis.

DOI: https://doi.org/10.1038/s41467-025-59908-7
Nat Commun. 2025 May 10. 16(1): 4359

Anti-Müllerian hormone signalling sustains circadian homeostasis in zebrafish.

Qiaohong Lin, Xian Du, Fan Ren, Ying Liu, Gaorui Gong, Si Ge, Weiwei Li, Zhi Li, Li Zhou, Ming Duan, Xi-Yin Li, Guang-Zhong Wang, Rui Xiao, Jian-Fang Gui, Jie Mei.

Circadian clocks temporally orchestrate the behavioural and physiological rhythms. The core molecules establishing the circadian clock are clear; however, the critical signalling pathways that cause or favour the homeostasis are poorly understood. Here, we report that anti-Müllerian hormone (Amh)-mediated signalling plays an important role in sustaining circadian homeostasis in zebrafish. Notably, amh knockout dampens molecular clock oscillations and disrupts both behavioural and hormonal circadian rhythms, which are recapitulated in bmpr2a null mutants. Somatotropes and gonadotropes are identified as Amh-targeted pituitary cell populations. Single-cell transcriptome analysis further reveals a lineage-specific regulation of pituitary clock by Amh. Moreover, Amh-induced effect on clock gene expression can be abolished by blocking Smad1/5/9 phosphorylation and bmpr2a knockout. Mechanistically, Amh binds to its receptors, Bmpr2a/Bmpr1bb, which in turn activate Smad1/5/9 by phosphorylation and promote circadian gene expression. Our findings reveal a key hormone signalling pathway for circadian homeostasis in zebrafish with implications for rhythmic organ functions and circadian health.

DOI: https://doi.org/10.1038/s41467-025-59528-1
PLoS Biol. 2025 May 12. 23(5): e3003173

Upstream open reading frames dynamically modulate CLOCK protein translation to regulate circadian rhythms and sleep.

Yuanqiang Sun, Ke Shui, Qinyu Li, Chenlu Liu, Wanting Jin, Jian-Quan Ni, Jian Lu, Luoying Zhang.

The circadian rhythm is an evolutionarily conserved mechanism with translational regulation increasingly recognized as pivotal in its modulation. In this study, we found that upstream open reading frames (uORFs) are enriched in Drosophila circadian rhythm genes, with particularly conserved uORFs present in core circadian clock genes. We demonstrate evidence that the uORFs of the core clock gene, Clock (Clk), rhythmically and substantially attenuate CLK protein translation in Drosophila, with pronounced suppression occurring during daylight hours. Eliminating Clk uORFs leads to increased CLK protein levels during the day and results in a shortened circadian cycle, along with a broad shift in clock gene expression rhythms. Notably, Clk uORF deletion also augments morning sleep by reducing dopaminergic activity. Beyond daily circadian adjustments, Clk uORFs play a role in modulating sleep patterns in response to seasonal daylight variations. Furthermore, the Clk uORFs act as an important regulator to shape the rhythmic expression of a vast array of genes and influence multifaceted physiological outcomes. Collectively, our research sheds light on the intricate ways uORFs dynamically adjust downstream coding sequences to acclimate to environmental shifts.

DOI: https://doi.org/10.1371/journal.pbio.3003173
Eur J Neurosci. 2025 May;61(9): e70134

Early-Life Ventral Hippocampal Lesion and Circadian Disruption Result in Altered Behavior in Adult Mice in a Sex-Dependent Manner.

Ahmed A Bouteldja, Lianne A Marceau, Lalit K Srivastava, Nicolas Cermakian.

  Schizophrenia is believed to arise because of the interaction of early abnormal neurodevelopment with environmental insults during key developmental stages later in life. Furthermore, disrupted circadian rhythms are reported in patients, and circadian disruption is associated with increased symptom severity, hinting at its role as a risk factor. Using the neonatal ventral hippocampal lesion mouse model, we aimed to assess the interaction between disrupted ventral hippocampal development with circadian disruption during adolescence in affecting behavior in male and female C57BL/6N mice. After conducting a series of behavioral tests, we found that the neonatal ventral hippocampal lesion and chronic jet lag during adolescence synergistically led to increased anxiety-like behavior in males. In females, the lesion prevented increased social preference caused by chronic jet lag and led to increased anxiety-like behavior. Mice were then moved to running wheel cages to measure their locomotor activity rhythms. We found that the lesioned male mice exposed to chronic jet lag exhibited fragmented rhythms under constant darkness. Moreover, lesioned male and female mice, especially those exposed to chronic jet lag, had reduced activity counts under constant light. These findings highlight that the interaction of abnormal neurodevelopment in areas relevant to schizophrenia with circadian disruption during adolescence results in lasting behavioral changes in a sex-dependent manner in mice.

Keywords:  chronic jet lag; circadian rhythms; locomotor activity rhythms; neonatal ventral hippocampal lesion model; schizophrenia

DOI:  https://doi.org/10.1111/ejn.70134
Cell Rep. 2025 May 10. pii: S2211-1247(25)00460-7. [Epub ahead of print]44(5): 115689

Cancer-induced FOXP1 disrupts and reprograms skeletal-muscle circadian transcription in cachexia.

Jeremy B Ducharme, Daria Neyroud, Martin M Schonk, Miguel A Gutierrez-Monreal, Zhiguang Huo, Haley O Tucker, Karyn A Esser, Sarah M Judge, Andrew R Judge.

  Cancer cachexia is a debilitating metabolic disorder characterized by involuntary loss of body and muscle mass, leading to increased morbidity and mortality. We previously found that forkhead box P1 (FoxP1) upregulation in skeletal muscle causes muscle wasting and is required for muscle wasting in response to cancer. However, transcriptional networks targeted by FoxP1 in skeletal muscles undergoing cancer-induced wasting remain largely unknown. Here, we identify FoxP1 as a key disruptor of the skeletal-muscle clock in response to cancer that reprograms circadian patterns of gene expression at cachexia onset. Specifically, we show that cancer-induced FoxP1 rewires the skeletal-muscle circadian transcriptome toward pathways associated with muscle wasting and disrupts the temporal patterning of pathways governing glucose, lipid, and oxidative metabolism. These findings thus implicate cancer/disease-specific functions of FOXP1 in the disruption and reprograming of the skeletal-muscle circadian transcriptome, which may contribute to muscle wasting and the development of cachexia.

Keywords:  CP: Cancer; ChIP-seq; RNA-seq; cancer cachexia; circadian rhythm; inflammation; metabolism; muscle atrophy; muscle clock; pancreatic cancer; skeletal muscle

DOI:  https://doi.org/10.1016/j.celrep.2025.115689
J Pineal Res. 2025 Apr;77(3): e70057

Exercise as a Synchronizer: Effects on Circadian Re-Entrainment of Core Body Temperature and Metabolism Following Light-Dark Cycle Inversion in Mice.

Andrea Michele Ciorciari, Emanuel Irizarry, Angela Montaruli, Katja A Lamia.

  Core body temperature (CBT) is a crucial marker of circadian synchrony, reflecting behavioral, metabolic, and environmental adaptations. Disruptions to CBT rhythms, as seen in shift workers or jetlag, indicate desynchronization and can lead to significant health consequences. Exercise is a potent non-photic zeitgeber that may help align circadian rhythms with external cues, but its role in re-entrainment following abrupt phase shifts remains unclear. This study investigated whether voluntary exercise accelerates the re-entrainment of CBT and metabolic rhythms in mice subjected to a 12-h light-dark cycle inversion (LDI). Fifteen C57BL/6 J mice underwent LDI and were divided into two groups. Mice in the control (CTRL) group remained sedentary throughout the experiment while mice in the other group were provided running wheels for 2 weeks after LDI. CBT was continuously monitored using implanted telemetric capsules and metabolic parameters were assessed before and 2 weeks after LDI. Mice that had access to running wheels (RW mice) initially displayed a greater disruption of CBT rhythmicity following LDI, suggesting unstructured physical activity may temporarily exacerbate misalignment, acting as a conflicting signal. Despite this, exercise accelerated recovery, as the phase of the CBT rhythm in RW mice re-aligned to the new light-dark cycle faster than that of the CTRL mice did. The phase of VO₂ rhythms in RW mice also showed trends toward faster realignment. These findings highlight the dual role of exercise as a zeitgeber, capable of both disrupting and accelerating circadian realignment depending on timing. Voluntary exercise may thus serve as an effective intervention to restore circadian synchrony and metabolic homeostasis in individuals experiencing circadian disruptions.

Keywords:  biological clock; body temperature; circadian rhythm; exercise; light; metabolism; mice

DOI:  https://doi.org/10.1111/jpi.70057
FASEB J. 2025 May 31. 39(10): e70577

Stat3 Silencing Affects Circadian Clock Gene Expression and Lipopolysaccharide Response in the Suprachiasmatic Nucleus, Cortex, and Glioblastoma Cell Cultures.

Eva Filipovská, Kateřina Skálová, Veronika Spišská, Jorge Mendoza, Zdeňka Bendová.

  In mammals, the suprachiasmatic nucleus (SCN) serves as the central circadian pacemaker, regulating rhythms essential for physiological processes. STAT3, a transcription factor primarily involved in immune signaling, exhibits circadian rhythmicity in SCN astrocytes. This study examined the role of STAT3 in circadian regulation across several cell types, including primary cultures of rat SCN and cortex, SCN cells and organotypic SCN slices from PER2::LUC mice, and C6 glioblastoma cells. Furthermore, the involvement of STAT3 in inflammatory responses was investigated in SCN and cortical primary cultures. STAT3 silencing enhanced Bmal1 expression across all tested cell types, disrupted Bmal1 rhythmicity in C6 cells, and reduced the amplitude of the PER2-driven rhythm in bioluminescence in SCN primary cells and organotypic cultures. In SCN cells, STAT3 silencing also attenuated its own expression and Gfap, whereas in cortical cells, it exhibited broader effects. Under LPS stimulation, STAT3 silencing in SCN cells reduced most LPS-induced genes, including inflammatory and oxidative stress markers, while showing variable effects in cortical cells. These findings indicate that while the role of STAT3 in the circadian clockwork appears consistent across cell types, its involvement in functional gene expression and immune responses may vary depending on the tissue and differ between SCN and cortical primary cells.

Keywords:  Stat3; clock genes; glioblastoma cells; lipopolysaccharide; suprachiasmatic nucleus

DOI:  https://doi.org/10.1096/fj.202403177RR
iScience. 2025 May 16. 28(5): 112408

The NONO protein regulates nonclassical DNA structure: Effects on circadian genes and DNA damage.

Ermanno Moriggi, Melissa Pisteljic, Alex Rosi-Andersen, Lennart Opitz, Abdelhalim Azzi, Steven A Brown.

  The DBHS protein family of Nono, PSPC1, and SFPQ regulates diverse aspects of RNA metabolism. Whether these proteins share similar functions is currently unknown. In mouse embryonic fibroblasts (MEFs), we observed around 2000 circadian and non-circadian genes regulated by Nono and PSPC1, with only 35% in common. Considering specifically circadian genes, up- or downregulation by Nono and PSPC1 depends mainly on the gene phase. We postulated a regulatory role of Nono on R-loops, the class of non-B DNA structures that form during transcription. We confirmed this by showing a broad effect of Nono on genome-wide R-loop homeostasis. Interestingly, the R-loop regulation by Nono occurs in a time-of-day dependent manner among the circadian genes. Moreover, we showed a protective role of Nono in a DNA damage cellular model that involves R-loop accumulation. Further studies are required to understand the circadian regulation of R-loops and their implications on gene regulation and disease.

Keywords:  Molecular interaction; Molecular mechanism of gene regulation; Nucleic acids; Properties of biomolecules; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2025.112408