bims-ciryme Biomed News
on Circadian rhythms and metabolism
Issue of 2025–07–06
seven papers selected by
Gabriela Da Silva Xavier, University of Birmingham
  1. Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms.
  2. Clock-dependent regulation of a homeostatic sleep center maintains daytime sleep and evening activity.
  3. Muscle Rev-erb controls time-dependent adaptations to chronic exercise in mice.
  4. Human CLOCK enhances neocortical function.
  5. Temperature and CO2 concentration in honey bee hives exhibit circadian rhythms.
  6. TRPV1 Desensitization Abolishes Metabolic Effects of Time-Restricted Feeding in Rats.
  7. BMAL1 and ARNT enable circadian HIF2α responses in clear cell renal cell carcinoma.
  1. J Clin Invest. 2025 Jul 01. pii: e185000. [Epub ahead of print]135(13):
    Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms.
    Milan Stoiljkovic, Jae Eun Song, Hee-Kyung Hong, Heiko Endle, Luis Varela, Jonatas Catarino, Xiao-Bing Gao, Zong-Wu Liu, Peter Sotonyi, Sabrina Diano, Jonathan Cedernaes, Joseph T Bass, Tamas L Horvath.
      Sustaining the strong rhythmic interactions between cellular adaptations and environmental cues has been posited as essential for preserving the physiological and behavioral alignment of an organism to the proper phase of the daily light/dark (LD) cycle. Here, we demonstrate that mitochondria and synaptic input organization of suprachiasmatic (SCN) vasoactive intestinal peptide-expressing (VIP-expressing) neurons showed circadian rhythmicity. Perturbed mitochondrial dynamics achieved by conditional ablation of the fusogenic protein mitofusin 2 (Mfn2) in VIP neurons caused disrupted circadian oscillation in mitochondria and synapses in SCN VIP neurons, leading to desynchronization of entrainment to the LD cycle in Mfn2-deficient mice that resulted in an advanced phase angle of their locomotor activity onset, alterations in core body temperature, and sleep-wake amount and architecture. Our data provide direct evidence of circadian SCN clock machinery dependence on high-performance, Mfn2-regulated mitochondrial dynamics in VIP neurons for maintaining the coherence in daily biological rhythms of the mammalian organism.
    Keywords:  Behavior; Cell biology; Metabolism; Mitochondria; Neuroscience; Synapses
    DOI:  https://doi.org/10.1172/JCI185000
  2. Curr Biol. 2025 Jun 21. pii: S0960-9822(25)00691-8. [Epub ahead of print]
    Clock-dependent regulation of a homeostatic sleep center maintains daytime sleep and evening activity.
    Cynthia T Hsu, Camilo Guevara, Samantha L Killiany, Joy Shon, Stephane Dissel, Amita Sehgal.
      Homeostatic sleep centers promote sleep in response to prolonged wakefulness, but their contribution to circadian-regulated daily sleep is still unclear. Do neuronal circuits driving rebound sleep after extended wakefulness also drive circadian-gated sleep, or does rebound sleep differ on a neurophysiological level from daily baseline sleep? We observed in Drosophila that 23E10+ neurons, which include a homeostatic sleep center, the dorsal fan-shaped body (dFSB),1,2,3,4,5 promote sleep in a time-of-day-dependent manner-the neurons play the strongest role in the maintenance of daytime sleep, and this effect on the siesta maps to cholinergic neurons within the dFSB. We asked whether 23E10+ neurons interact with the circadian clock to regulate daily sleep and find their role in maintaining the daytime siesta is at least partially dependent on the period gene. Through in vivo imaging, we show that calcium levels in the dFSB display a circadian rhythm, with a peak coinciding with the daytime siesta. In the absence of a period, the 24-h rhythm is lost, but a daytime increase in calcium activity is maintained. Loss of pigment dispersing factor (PDF) signaling causes premature downregulation of calcium activity in the dFSB, coinciding with the earlier truncation of the siesta in pdfr mutants and resulting in an earlier onset of night sleep. Silencing the dFSB is sufficient to rescue the timing of night sleep onset in pdfr mutants. These results indicate that the dFSB, a homeostatic sleep center, relies on the circadian clock to restrict sleep drive to specific times of day.
    Keywords:  Drosophila; circadian clock; fan-shaped body; pigment dispersing factor; sleep
    DOI:  https://doi.org/10.1016/j.cub.2025.06.003
  3. Nat Commun. 2025 Jul 01. 16(1): 5708
    Muscle Rev-erb controls time-dependent adaptations to chronic exercise in mice.
    Jidong Liu, Fang Xiao, Abhinav Choubey, Udhaya Kumar S, Yanxiang Wang, Sungguan Hong, Tingting Yang, Husniye Gul Otlu, Ege Sanem Oturmaz, Emanuele Loro, Yuxiang Sun, Pradip Saha, Tejvir S Khurana, Li Chen, Xinguo Hou, Zheng Sun.
      The best time of the day for chronic exercise training and the mechanism underlying the timing effects is unclear. Here, we show that low-intensity, low-volume treadmill training in mice before sleep yields greater benefits than after waking for muscle contractile performance and systemic glucose tolerance. Baseline muscle performance also exhibits diurnal variations, with higher strength but lower endurance before sleep than after waking. Muscle-specific knockout of circadian clock genes Rev-erbα/β (Rev-MKO) in male mice eradicates the diurnal variations in both training and baseline conditions without affecting muscle mass, mitochondrial content, food intake, or spontaneous activities. Multi-omics and metabolic measurements reveal that Rev-erb suppresses fatty acid oxidation and promotes carbohydrate metabolism before sleep. Thus, the muscle-autonomous clock, not feeding or locomotor behaviors, dictates diurnal variations of muscle functions and time-dependent adaptations to training, which has broad implications in metabolic disorders and sports medicine as Rev-erb agonists are exercise mimetics or enhancers.
    DOI:  https://doi.org/10.1038/s41467-025-60520-y
  4. Nat Neurosci. 2025 Jun 30.
    Human CLOCK enhances neocortical function.
    Yuxiang Liu, Miles R Fontenot, Ashwinikumar Kulkarni, Nitin Khandelwal, Seon Hye E Voth Park, Connor Criswell, Matthew Harper, Pin Xu, Nisha Gupta, Jay R Gibson, Joseph S Takahashi, Genevieve Konopka.
      The transcription factor CLOCK is ubiquitously expressed and important for circadian rhythms, while its human-specific expression in neocortex suggests additional functions. Here, we generated a mouse model (HU) that recapitulates human cortical expression of CLOCK. The HU mice show enhanced cognitive flexibility, which might be associated with alteration in spatiotemporal expression of CLOCK. Cell-type-specific genomic profiling identified upregulated genes related to dendritic growth and spine formation in excitatory neurons of HU mice. We also found that excitatory neurons in HU mice have increased dendritic complexity and spine density, and a greater frequency of excitatory postsynaptic currents, suggesting a greater abundance of neural connectivity. In contrast, CLOCK knockout in human induced pluripotent stem cell-derived neurons showed reduced complexity of dendrites and lower density of presynaptic puncta. Together, our data demonstrate that CLOCK might have evolved brain-relevant gains of function via altered spatiotemporal gene expression and that these functions may underlie human brain specializations.
    DOI:  https://doi.org/10.1038/s41593-025-01993-4
  5. Sci Rep. 2025 Jul 01. 15(1): 22042
    Temperature and CO2 concentration in honey bee hives exhibit circadian rhythms.
    W G Meikle, M Weiss.
      Worker honey bees exhibit circadian rhythms with respect to locomotor activity but circadian analyses have seldom been applied to colony-level behavior. Circadian rhythms have been defined as having three main characteristics: a period of approximately 24 h maintained in the absence of external cues; a period maintained over a range of temperatures; and a phase fixed by external cues from the environment. In this study honey bee colonies were subjected to two kinds of light regimes at 5 °C in a cold storage unit (CSU): (1) constant darkness; and (2) after 6-12 d constant darkness, 12 h light exposure from 6PM to 6AM (i.e. a phase approximately 12 h offset from ambient conditions). Periodogram analyses of data from the 1st light regime showed that temperature and CO2 concentration had stable 24 h periods after 20 d, as was observed for colonies in warmer temperatures in outside conditions. Period strength of temperature decreased over time in the CSU but not CO2. Cosinor analyses of data from the 2nd light regime showed a temperature phase change of about 9 h 37 min between the end of the CSU period, after 28-33 d in light regime, and after 7-12 d in outdoor conditions in the post-CSU period. The same comparison for CO2 concentration showed a phase change of about 11 h 55 min. These data indicated honey bee colonies produced circadian rhythms in hive temperature and CO2 concentration with periods both present in the absence of external cues, and with phases that can be driven by light. Rhythms associated with CO2 concentration changed with respect to light treatment more than rhythms associated with hive temperature. Based on data from longer-term (60 d) experiments, daily rhythm phases and day lengths differed significantly between hive temperature and CO2 after 15 d in the 12 l:12D light regime, and remained so in outdoor conditions.
    Keywords:  Cold storage; Colony-level behavior; Continuous monitoring; Cosinor analysis; Honey bee colonies; Periodogram analysis; Superorganism
    DOI:  https://doi.org/10.1038/s41598-025-03614-3
  6. J Biol Rhythms. 2025 Jun 28. 7487304251346606
    TRPV1 Desensitization Abolishes Metabolic Effects of Time-Restricted Feeding in Rats.
    Nayara A C Horta, Thais S R Cardoso, Paola Fernandes, Flávia M Araújo, Pedro Lucas Caillaux Luciano, Lucas R Drummond, Cândido C Coimbra, Maristela O Poletini.
      Time-restricted feeding (TRF) can improve metabolic outcomes. Rodents experiencing TRF exhibit an increase in spontaneous locomotor activity before mealtime and show a phase shift in the rhythm of clock gene expression in peripheral organs, particularly in the liver. Because activation of the transient receptor potential vanilloid-1 (TRPV1) channel produces similar beneficial effects on metabolism as TRF, we hypothesized that this channel mediates the metabolic changes induced by TRF. To assess the role of TRPV1 in metabolism and circadian responses, we utilized the agonist resiniferatoxin (RTX), which at a dosage of 20 µg/kg desensitizes TRPV1. After treatment with RTX or its vehicle, adult male rats were exposed to 21 days of TRF during the light phase. RTX-treated rats show some effects of TRF similar to vehicle-treated controls, with increased locomotor activity and body temperature at the beginning of the light phase, decreased body weight gain and food intake relative to ad-libitum-fed controls. However, RTX-treated rats did not show a decrease in VO2 consumption or an improvement in glucose tolerance induced by TRF. In addition, RTX treatment eliminated the temporal changes in the expression of clock genes Per1 and Rev-Erba in the liver as well as leptin blood levels. In addition, RTX abolished the temporal alterations of the Trb3 gene in the liver, which encodes a protein that negatively modulates insulin signaling without affecting the expression of insulin, Pparα, Pck1, G6pc, or other clock genes in the liver. In conclusion, TRPV1 may participate in the TRF-induced alterations in metabolism, most likely through its regulation of the temporal changes in Per1, Rev-Erba, and Trb3 expressions in the liver, along with leptin secretion.
    Keywords:  circadian clocks; glucose tolerance; insulin; leptin; mealtime
    DOI:  https://doi.org/10.1177/07487304251346606
  7. Nat Commun. 2025 Jul 01. 16(1): 5834
    BMAL1 and ARNT enable circadian HIF2α responses in clear cell renal cell carcinoma.
    Rebecca M Mello, Diego Gomez Ceballos, Colby R Sandate, Sicong Wang, Celine Jouffe, Daniel Agudelo, Nina Henriette Uhlenhaut, Nicolas H Thomä, M Celeste Simon, Katja A Lamia.
      Circadian disruption enhances cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). The core circadian transcription factor BMAL1 is closely related to ARNT, and we show that BMAL1-HIF2α regulates a subset of HIF2α target genes in ccRCC cells. Depletion of BMAL1 selectively reduces HIF2α chromatin association and target gene expression and reduces ccRCC growth in culture and in xenografts. Analysis of pre-existing data reveals higher BMAL1 in patient-derived xenografts that are sensitive to growth suppression by a HIF2α antagonist (PT2399). BMAL1-HIF2α is more sensitive than ARNT-HIF2α is to suppression by PT2399, and the effectiveness of PT2399 for suppressing xenograft tumor growth in vivo depends on the time of day at which it is delivered. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 influences HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells.
    DOI:  https://doi.org/10.1038/s41467-025-60904-0
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