bims-ciryme 2025-10-05 papers

Cell Rep. 2025 Sep 30. pii: S2211-1247(25)01125-8. [Epub ahead of print]44(10): 116354

The central clock drives metabolic rhythms in muscle stem cells.

Valentina Sica, Jacob G Smith, Oleg Deryagin, Eva Andrés, Vera Lukesova, Mirijam Egg, Nina Cabezas-Wallscheid, Salvador Aznar Benitah, Antonio L Serrano, Eusebio Perdiguero, Pura Muñoz-Cánoves.

Satellite cells (SCs), the skeletal muscle resident stem cells, maintain a state of quiescence yet exhibit robust circadian oscillations at the transcriptional level. How SC circadian rhythms are controlled is not well understood. Here, we use SC-specific reconstitution of the essential clock gene Bmal1 in mice to elucidate the role of the local SC clock and its interplay with the central clock in the brain. We find that 24-h rhythmicity of metabolic genes in SCs depends on central clock inputs, independent of the SC clock, and identify rhythmic feeding-fasting cycles as the key brain clock-dependent output controlling their oscillation. Functionally, central signals regulate SC metabolic state and SC-mediated muscle repair, and we identify intact autophagic function as a prerequisite for correct oscillation of metabolic transcripts. Overall, we show that the central clock acts dominantly via feeding-fasting cycles to control rhythmic gene expression and metabolic state in quiescent SCs.

Keywords: CP: Metabolism; CP: Stem cell research; autophagy; circadian clocks; circadian rhythms; inter-organ crosstalk; metabolism; muscle; quiescence; satellite cells; stem cells; time-restricted feeding

DOI: https://doi.org/10.1016/j.celrep.2025.116354

Sci Rep. 2025 Sep 30. 15(1): 33843

Sinusoidal regulation reduces circadian period variability.

Hotaka Kaji, Fumito Mori, Osamu Maruyama, Hiroshi Ito.

The rhythms transmitted from the circadian clock inevitably fluctuate because of molecular noise. The level of period fluctuations, observed not in the circadian clock, but in the output system that receives the transmitted rhythm, varies according to the organism and cell type, ranging from 0.5% to 10%. However, it remains unclear how the signal transduction involved in this transmission affects the fluctuations in the oscillation period of the output system. To address this, we investigated a coupled system consisting of a circadian clock and its output. We numerically and analytically demonstrated that the rhythmic regulation through which the clock controls downstream gene expression affects the level of fluctuations in the output system. Moreover, Gibbs sampling based on the analytically obtained fluctuation formula confirmed that the sine-wave-like regulatory functions effectively minimized the fluctuation of the output system. These theoretical insights provide new perspectives on signal transduction as a denoising mechanism embodied in the circadian system.

Keywords: Circadian rhythms; Fluctuations; Phase model; Waveform

DOI: https://doi.org/10.1038/s41598-025-04614-z

J Dev Orig Health Dis. 2025 Sep 29. 16 e36

Intrauterine growth restriction promotes hypothalamic circadian dysregulation in adult mouse offspring.

Alexandra E O'Brien, Peter J Mark, Jeremy T Smith, Kimberley C W Wang.

Adverse prenatal conditions can induce intrauterine growth restriction (IUGR) and increase the risk of adulthood metabolic disease. Mechanisms underlying developmentally programmed metabolic disease remain unclear but may involve disrupted postnatal circadian rhythms and kisspeptin signalling. We investigated the impact of maternal hypoxia-induced IUGR on hypothalamic and hepatic expression of clock genes (Bmal1, Per2 and Reverbα), metabolic genes (Pparα, Pparγ and Pgc1α) and kisspeptin genes (Kiss1 and Kiss1r) in adult offspring. Pregnant BALB/c mice were housed in hypoxic conditions (10.5% oxygen) from gestational day 11 to 17.5 and then returned to normoxic conditions until term (gestational day ∼ 21). Control animals were housed in normoxic conditions throughout pregnancy. Offspring were weighed at birth. At 8 weeks of age, body, liver and brain tissues were collected and weighed. Relative clock gene, metabolic gene and kisspeptin signalling gene expression were measured using qPCR. The IUGR offspring were lighter at birth and remained lighter at 8 weeks but with higher brain relative to body weight. The IUGR offspring had decreased hypothalamic Bmal1 and Reverbα expression, but unchanged hepatic clock gene expression and no change in hypothalamic or hepatic Per2 expression, compared with Control offspring. This tissue-specific change in clock gene expression suggests circadian dysregulation. There were no IUGR-related changes to metabolic gene expression in the hypothalamus or liver, but IUGR offspring had increased hypothalamic Kiss1r expression. These results demonstrate IUGR offspring from hypoxia pregnancies show central circadian misalignment and potentially disrupted hypothalamic Kiss1/Kiss1r signalling, which may contribute to developmentally programmed metabolic disease.

Keywords: Intrauterine growth restriction; circadian dysregulation; hypothalamus; liver; sex differences

DOI: https://doi.org/10.1017/S2040174425100214

Sci Rep. 2025 Sep 30. 15(1): 33729

Adiponectin receptor agonist, AdipoRon, restores hepatic clock gene expression in PCOS-associated NAFLD.

Shivam Sharma, Shaheen Wasil Kabeer, Vinod Kumar, Kulbhushan Tikoo.

Persistent lower levels of adiponectin are associated with hyperandrogenism, predisposing PCOS women to NAFLD. This study elucidated the therapeutic potential of a small molecule adiponectin receptor agonist-AdipoRon, utilizing an in-vivo PCOS rat model mimicking the manifestation of PCOS along with hepatosteatosis. Our study demonstrated that Adiporon reduced lipid accumulation in PCOS-associated NAFLD by alleviating insulin resistance & lipogenesis. AdipoRon also reversed hyperandrogenism and adiponectin deficiency in PCOS animals. In addition, AdipoRon was found to restore altered PCOS-induced hepatic circadian gene expression (Bmal1, Clock, Per3, Cry2, Reverba, and Rora). Interestingly, at the epigenetic level, global transcription activation marks, i.e., H3K4me3, H3K9/14ac, and H3K36me2, were upregulated in disease conditions. Furthermore, our ChIP data confirmed that circadian genes Bmal1, Reverba, And Rora are epigenetically regulated. ChIP assay data showed an increased H3K36 dimethylation at the Bmal1 and Rora promoter, whereas a significant decrease was observed at the Reverbα promoter in PCOS-associated NAFLD. AdipoRon ameliorated these PCOS-induced epigenetic alterations, modulating the hepatic circadian gene expression. We present the preliminary evidence illustrating the epigenetic modulation of AdipoRon, thereby regulating hepatic circadian gene expression. This study provides insights regarding the therapeutic potential of AdipoRon in PCOS-associated NAFLD, which can be of profound clinical significance.

Keywords: AdipoRon; Epigenetics; histone modifications; Hepatic circadian system; lipid metabolism; PCOS-associated NAFLD

DOI: https://doi.org/10.1038/s41598-025-93126-x