bims-ciryme Biomed News
on Circadian rhythms and metabolism
Issue of 2025–03–30
eight papers selected by
Gabriela Da Silva Xavier, University of Birmingham
  1. Multiple oscillators underlie circadian food anticipation in mice.
  2. Control of circadian muscle glucose metabolism through the BMAL1-HIF axis in obesity.
  3. Dopaminergic neurons in the paraventricular hypothalamus extend the food consumption phase.
  4. RORα fine-tunes the circadian control of hepatic triglyceride synthesis and gluconeogenesis.
  5. Food insecurity promotes adiposity in mice.
  6. The P-loop NTPase RUVBL2 is a conserved clock component across eukaryotes.
  7. A combined mathematical and experimental approach reveals the drivers of time-of-day drug sensitivity in human cells.
  8. Understanding sleep health challenges of defence shift workers to design a digital, sleep and circadian management tool.
  1. Neurobiol Sleep Circadian Rhythms. 2025 May;18 100116
    Multiple oscillators underlie circadian food anticipation in mice.
    David E Ehichioya, Ishrat Masud, S K Tahajjul Taufique, Melody Shen, Sofia Farah, Shin Yamazaki.
      Circadian pacemakers orchestrate behavioral and physiological rhythms, enabling organisms to anticipate daily reoccurring environmental events such as light and dark, temperature changes, and food availability. When nocturnal rodents are subjected to time-restricted feeding during the day, they typically display food anticipatory activity several hours before mealtime. Upon releasing mice to ad libitum feeding, this anticipatory activity is abolished immediately but, following food deprivation, reappears at approximately the same time. However, the mechanism by which rodents retain this time memory of food availability during ad libitum feeding has remained elusive. We utilized the open-source Feeding Experimentation Device 3 (FED3) to measure food-seeking nose-poking behavior. We programmed the FED3 to dispense a pellet by a single left nose-poke, but not by right poke. During daytime restricted feeding, mice exhibited strong anticipatory nose-poking a few hours prior to the daytime meal in both rewarded left and unrewarded right pokes. In addition, mice also exhibited elevation of both rewarded and unrewarded pokes at night, coinciding with mice's previous habitual feeding time. Following ad libitum feeding, rewarded daytime nose-poking gradually moved back to habitual nighttime. However, following food deprivation, anticipatory poking immediately reappeared during the day and night, coinciding with the times of previous daytime restricted feeding and nighttime habitual feeding. Under ad libitum feeding, db/db mice didn't exhibit a clear daily rhythm in food intake. However, these mice exhibited robust food anticipation in both nose-pokes and activity during daytime restricted feeding. Following release back to ad libitum feeding, db/db mice poked sporadically during the day and night, and following food deprivation, anticipation promptly reappeared. These data suggest that there are at least two oscillators underlying food anticipation: one oscillator with a phase that changes according to food availability, and another oscillator with a phase unaffected by feeding conditions. In db/db mice, the first oscillator is likely impaired, and the second oscillator is unaffected.
    Keywords:  Entrainment; Extra-SCN circadian pacemaker; Metabolism; Motivation; Operant chamber; Time memory; Type 2 diabetes; db/db mice
    DOI:  https://doi.org/10.1016/j.nbscr.2025.100116
  2. Proc Natl Acad Sci U S A. 2025 Apr;122(13): e2424046122
    Control of circadian muscle glucose metabolism through the BMAL1-HIF axis in obesity.
    Claire A Chaikin, Abhishek V Thakkar, Adam W T Steffeck, Eric M Pfrender, Kaitlyn Hung, Pei Zhu, Nathan J Waldeck, Rino Nozawa, Weimin Song, Christopher R Futtner, Mattia Quattrocelli, Joseph Bass, Issam Ben-Sahra, Clara B Peek.
      Disruptions of circadian rhythms are widespread in modern society and lead to accelerated and worsened symptoms of metabolic syndrome. In healthy mice, the circadian clock factor BMAL1 is required for skeletal muscle function and metabolism. However, the importance of muscle BMAL1 in the development of metabolic diseases, such as diet-induced obesity (DIO), remains unclear. Here, we demonstrate that skeletal muscle-specific BMAL1-deficient mice exhibit worsened glucose tolerance upon high-fat diet feeding, despite no evidence of increased weight gain. Metabolite profiling from Bmal1-deficient muscles revealed impaired glucose utilization specifically at early steps in glycolysis that dictate the switch between anabolic and catabolic glucose fate. We provide evidence that this is due to abnormal control of the nutrient stress-responsive hypoxia-inducible factor (HIF) pathway. Genetic HIF1α stabilization in muscle Bmal1-deficient mice restores glucose tolerance and expression of 217/736 dysregulated genes during DIO, including glycolytic enzymes. Together, these data indicate that during DIO, skeletal muscle BMAL1 is an important regulator of HIF-driven glycolysis and metabolic flexibility, which influences the development of high-fat-diet-induced glucose intolerance.
    Keywords:  circadian rhythm; diet-induced obesity; hypoxia; skeletal muscle
    DOI:  https://doi.org/10.1073/pnas.2424046122
  3. Proc Natl Acad Sci U S A. 2025 Apr;122(13): e2411069122
    Dopaminergic neurons in the paraventricular hypothalamus extend the food consumption phase.
    Winda Ariyani, Chiharu Yoshikawa, Haruka Tsuneoka, Izuki Amano, Itaru Imayoshi, Hiroshi Ichinose, Chiho Sumi-Ichinose, Noriyuki Koibuchi, Tadahiro Kitamura, Daisuke Kohno.
      Feeding behavior is controlled by various neural networks in the brain that are involved in different feeding phases: Food procurement, consumption, and termination. However, the specific neural circuits controlling the food consumption phase remain poorly understood. Here, we investigated the roles of dopaminergic neurons in the paraventricular nucleus of the hypothalamus (PVH) in the feeding behavior in mice. Our results indicated that the PVH dopaminergic neurons were critical for extending the food consumption phase and involved in the development of obesity through epigenetic mechanisms. These neurons synchronized with proopiomelanocortin neurons during consumption, were stimulated by proopiomelanocortin activation, and projected to the lateral habenula (LHb), where dopamine receptor D2 was involved in the increase in food consumption. In addition, upregulated tyrosine hydroxylase (TH) expression in PVH was associated with obesity and indispensable for obesity induction in mice lacking Dnmt3a. Taken together, our results highlight the roles of PVH dopaminergic neurons in promoting food consumption and obesity induction.
    Keywords:  DNA methylation; dopamine; food intake; hypothalamus
    DOI:  https://doi.org/10.1073/pnas.2411069122
  4. Sci Rep. 2025 Mar 26. 15(1): 10464
    RORα fine-tunes the circadian control of hepatic triglyceride synthesis and gluconeogenesis.
    Chloé Monnier, Munkhzul Ganbold, Martine Auclair, Natacha Roblot, Andréas Barnabé Boutin, Paul Ketil Boutin, Bruno Fève, Bénédicte Antoine.
      Circadian rhythms play a fundamental role in hepatic metabolism, orchestrating lipid synthesis and glucose homeostasis. RORα, a nuclear receptor involved in circadian regulation, has been implicated in fine-tuning these metabolic processes. We previously showed a therapeutic potential of antagonizing RORα to reduce body fat in mice. Our current aim is to investigate the impact of the whole-body RORα deletion on hepatic lipid metabolism over a complete circadian cycle. Using RORα-knockout (staggerer) mice, this study reveals a time-dependent disruption in hepatic triglyceride synthesis, with reduced lipogenesis during the light-phase and altered transcriptional regulation of key metabolic genes, including Srebp1c and Insigs. Despite increased Srebp1c transcription at night, the anticipated rise in lipid synthesis was prevented by phase-shifted Insig expression, modulating precursor maturation. Moreover, core clock genes rhythmic expression was attenuated and phase-shifted for Reverbα. Pharmacological inhibition of RORα using an inverse agonist (SR3335) mirrored the metabolic effects observed in staggerer mice, further supporting the role of RORα as a crucial regulator of lipid and glucose homeostasis in mice fed a chow diet. These findings highlight the intricate interaction between the circadian clock and hepatic metabolism, situating RORα as a promising target to prevent metabolic disorders such as obesity and dyslipidemia.
    Keywords:  Circadian rhythms; Gluconeogenesis; Lipid synthesis; Liver; RORα; Staggerer
    DOI:  https://doi.org/10.1038/s41598-025-95228-y
  5. Obesity (Silver Spring). 2025 Mar 23.
    Food insecurity promotes adiposity in mice.
    Cláudia R E Gil, Jens Lund, Jan J Żylicz, Pablo Ranea-Robles, Thorkild I A Sørensen, Christoffer Clemmensen.
       OBJECTIVE: The obesity epidemic, driven by a complex interplay of environmental and biological factors, remains a significant global health challenge. Herein, we investigate the impact of food insecurity, characterized by unpredictable food access, on the regulation of body weight and body composition in mice.
    METHODS: Male and female C57BL/6J mice were subjected to a combination of intermittent fasting and calorie restriction to simulate food insecurity.
    RESULTS: Our new model demonstrates that food insecurity increases fat mass and decreases lean mass in both sexes on a standard chow diet. Additionally, high-fat diet-fed male mice exposed to the food insecurity paradigm show decreased lean mass despite being in positive energy balance. Transcriptomic analysis of white adipose tissue from food-insecure male mice revealed upregulation of metabolic pathways associated with fat mass expansion and downregulation of immune response-related transcripts.
    CONCLUSIONS: These findings underscore the role of food insecurity in driving metabolic adaptations that favor fat storage. Understanding this paradoxical link between food insecurity and adiposity is crucial for developing targeted interventions to address the disproportionate incidence of obesity in socioeconomically disadvantaged populations.
    DOI:  https://doi.org/10.1002/oby.24259
  6. Nature. 2025 Mar 26.
    The P-loop NTPase RUVBL2 is a conserved clock component across eukaryotes.
    Meimei Liao, Yanqin Liu, Zhancong Xu, Mingxu Fang, Ziqing Yu, Yufan Cui, Zhengda Sun, Ran Huo, Jieyu Yang, Fusheng Huang, Mingming Liu, Qin Zhou, Xiaocui Song, Hui Han, She Chen, Xiaodong Xu, Ximing Qin, Qun He, Dapeng Ju, Tao Wang, Nirav Thakkar, Paul E Hardin, Susan S Golden, Eric Erquan Zhang.
      The eukaryotic circadian clock keeps time by using a transcription-translation feedback loop, which exhibits an architecture that is conserved across a diverse range of organisms, including fungi, plants and animals1. Despite their mechanistic similarity, the molecular components of these clocks indicate a lack of common ancestry2. Our study reveals that RUVBL2, which is a P-loop NTPase enzyme previously shown to affect circadian phase and amplitude as part of mammalian clock super-complexes, influences the circadian period through its remarkably slow ATPase activity, resembling the well-characterized KaiC-based clock in cyanobacteria. A screen of RUVBL2 variants identified arrhythmic, short-period and long-period mutants that altered circadian locomotor activity rhythms following delivery by adeno-associated virus to the murine suprachiasmatic nucleus. Enzymatic assays showed that wild-type RUVBL2 hydrolyses only around 13 ATP molecules a day, a vastly reduced turnover compared with typical ATPases. Notably, physical interactions between RUVBL2 orthologues and core clock proteins in humans, Drosophila and the fungus Neurospora, along with consistent circadian phenotypes of RUVBL2-mutant orthologues across species, reinforce their clock-related function in eukaryotes. Thus, as well as establishing RUVBL2 as a common core component in eukaryotic clocks, our study supports the idea that slow ATPase activity, initially discovered in cyanobacteria, is a shared feature of eukaryotic clocks.
    DOI:  https://doi.org/10.1038/s41586-025-08797-3
  7. Commun Biol. 2025 Mar 25. 8(1): 491
    A combined mathematical and experimental approach reveals the drivers of time-of-day drug sensitivity in human cells.
    Nica Gutu, Hitoshi Ishikuma, Carolin Ector, Ulrich Keilholz, Hanspeter Herzel, Adrián E Granada.
      The circadian clock plays a pivotal role in regulating various aspects of cancer, influencing tumor growth and treatment responses. There are significant changes in drug efficacy and adverse effects when drugs are administered at different times of the day, underscoring the importance of considering the time of day in treatments. Despite these well-established findings, chronotherapy approaches in drug treatment have yet to fully integrate into clinical practice, largely due to the stringent clinical requirements for proving efficacy and safety, alongside the need for deeper mechanistic insights. In this study, we employ a combined mathematical and experimental approach to systematically investigate the factors influencing time-of-day drug sensitivity in human cells. Here we show how circadian and drug properties independently shape time-of-day profiles, providing valuable insights into the temporal dynamics of treatment responses. Understanding how drug efficacy fluctuates throughout the day holds immense potential for the development of personalized treatment strategies aligned with an individual's internal biological clock, revolutionizing cancer treatment by maximizing therapeutic benefits. Moreover, our framework offers a promising avenue for refining future drug screening efforts, paving the way for more effective and targeted therapies across diverse tissue types.
    DOI:  https://doi.org/10.1038/s42003-025-07931-1
  8. Sci Rep. 2025 Mar 26. 15(1): 10483
    Understanding sleep health challenges of defence shift workers to design a digital, sleep and circadian management tool.
    Prerna Varma, Lin Shen, Svetlana Postnova, Kylie King, Mark E Howard, Eugene Aidman, Shantha W M Rajaratnam, Tracey L Sletten.
      Defence personnel need to be agile and responsive in their assessment of strategic and tactical tasks. Sleep and circadian disruptions, however, can compromise personnel's readiness. Digital health technologies have the potential to provide sleep and circadian health management advice but need to be designed with active involvement from stakeholders and communities. This study explored challenges with shift work in a cohort of defence personnel to identify end-user expectations for a sleep health smartphone application. Eight shift working Air Traffic Control personnel from the Australian Defence Force participated in 60-70-minute semi-structured online interviews. Informal discussions were also held with various defence stakeholders to determine requirements for an app. Defence personnel reported disruptions to their sleep, family, and social life due to environmental and operational circumstances, such as shift work, mental load, and unplanned schedules. They were highly receptive to a digital intervention and emphasised need for personalised support. Gamification, availability of the app via the defence forces, and high data security were recognised as key enablers. These insights should serve as theoretical foundation for further development, co-design, and testing of digital health tools in other shift worker cohorts, and to better examine and address the impacts of operational demands on their health and performance.
    Keywords:  Behaviour change; Intervention development; Military health; Participatory approaches; Shift work; Sleep health support
    DOI:  https://doi.org/10.1038/s41598-025-93597-y
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