bims-ciryme 2025-10-19 papers

Cell Rep. 2025 Oct 14. pii: S2211-1247(25)01208-2. [Epub ahead of print]44(10): 116437

Normal circadian period length requires repression of Npas2 by REV-ERB nuclear receptors.

Michael C Tackenberg, Kristina M Heliodoro, Lily C Melink, Yifan Liu, Kun Zhu, Mitchell A Lazar.

REV-ERB nuclear receptors are integrated into the molecular circadian clock present in most mammalian cells. Loss of REV-ERBs (REV-ERB DKO) within the suprachiasmatic nucleus (SCN) in vivo leads to a marked shortening of the circadian period, but it remains unclear whether REV-ERB regulation of circadian period is tissue autonomous, if it is conserved across tissues, and how it is established. Here, we show that period shortening in the absence of REV-ERBs is tissue autonomous, is consistent between brain and liver, and is brought about through derepression of clock transcription factors NPAS2 and CLOCK. Thus, in addition to disruption of synchrony with the external environment, our results demonstrate that the circadian impacts of REV-ERB loss also include the alteration of core circadian properties with tissue-specific consequences.

Keywords: CP: Metabolism; CP: Neuroscience

DOI: https://doi.org/10.1016/j.celrep.2025.116437

Mol Metab. 2025 Oct 15. pii: S2212-8778(25)00177-2. [Epub ahead of print] 102270

Dimorphic regulation of time-restricted feeding effects by hepatocyte Period 1.

Jiameng Sun, Cassandra B Higgins, Joshua A Adams, Yiming Zhang, Shannon C Kelly, Hyo-Jin Kim, Brian J DeBosch.

OBJECTIVE: Obesity is linked to metabolic disorders including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease. Lifestyle interventions, such as time-restricted feeding (TRF), have proven to be effective for long-term weight management. The metabolic effects of TRF are closely associated with circadian clock function in the liver. We previously demonstrated that the circadian gene Period 1 (Per1) mediates responses to acute fasting in both sexes. We therefore hypothesized that hepatocyte Per1 contributes to the long-term adaptations to repeated fasting exposure in the form of TRF, and investigated its role in diet-induced obesity in both sexes.
METHODS: Male and female mice with or without hepatocyte Per1 (Per1fl/fl and Per1LKO) were subjected to either ad libitum feeding (ALF) or TRF restricted to the active phase (8 h/day).
RESULTS: TRF attenuated Western diet-induced weight gain and peripheral and hepatic lipid accumulation, and improved heat production, metabolic substrate flexibility, and glucose homeostasis in Per1fl/fl and Per1LKO males. In contrast, hepatocyte Per1 was required for TRF-induced improvements in energy expenditure and peripheral and hepatic lipid accumulation in females. Surprisingly, TRF failed to significantly attenuate diet-induced weight gain or glucose and insulin tolerance in females independent of genotype. Transcriptomic data revealed sex-specific transcriptional responses to TRF and to hepatocyte-specific Per1 deletion. Specifically, genes involved in lipid metabolism were differentially regulated when comparing TRF-treated Per1fl/fl and Per1LKO female mice.
CONCLUSIONS: Hepatocyte Per1 mediates the energy, lipid, and glucose homeostatic effects of TRF, and this regulation is almost completely sex-dependent.

Keywords: Circadian clock; Metabolism; Obesity; Period; Time-restricted feeding

DOI: https://doi.org/10.1016/j.molmet.2025.102270

J Clin Endocrinol Metab. 2025 Oct 15. pii: dgaf564. [Epub ahead of print]

Effects of prednisolone administration on clock gene expression and indices of circadian rhythms in healthy human males.

Simon Bøggild Hansen, Jelena Skaaning Stankovic Frederiksen, Andreas Lodberg, Mathias Flensted Poulsen, Christian Brix Folsted Andersen, Henrik Oster, Niels Jessen, Jens Otto Lunde Jørgensen.

PURPOSE: To investigate the impact of glucocorticoid (GC) exposure on clock gene expression in human skeletal muscle and fat, circadian variations in peripheral interstitial glucose levels, blood pressure, total and bioactive GC levels, and sleep quality.
METHODS: Randomized double-blind crossover trial with ten healthy males aged 18-34 years. Prednisolone (12.5 mg)/placebo given in random order twice daily at 07:00h and 19:00h for five days with a 6-week washout.
MAIN FINDINGS: Prednisolone suppressed endogenous circadian cortisol levels while mean±SD AUC serum free GC activity (µmol/l*min) increased 4.5-fold [121.9±30.8 (prednisolone) vs 27.2±8.3 (placebo), p < 0.001]. Prednisolone significantly abrogated the normal ≈ threefold morning:evening variation in mRNA expression of four clock genes - BMAL1, NPAS2, PER3 and REV-ERB-β - in both adipose tissue and skeletal muscle. Prednisolone also increased nocturnal levels of interstitial glucose 67% [95% CI 36 to 97, p < 0.001] more than diurnal levels. Prednisolone increased mean±SD nocturnal systolic blood pressure (mmHg) [123±14 (prednisolone) vs 116±7 (placebo), p = 0.05] and reduced mean±SD sleep efficiency (%) [84±4 (prednisolone) vs 87±5 (placebo), p = 0.04].
CONCLUSIONS AND PERSPECTIVES: Prednisolone abrogates the temporal pattern of clock gene expression in human skeletal muscle and adipose tissue This is accompanied by perturbations of circadian variations in interstitial glucose levels, blood pressure as well as sleep quality We hypothesize that adverse effects of high-dose prednisolone treatment are partly mediated by disrupted clocks in metabolic tissues.

Keywords: Circadian rhythms; Clock genes; Glucocorticoids; Glucose; Metabolism

DOI: https://doi.org/10.1210/clinem/dgaf564

J Dent Res. 2025 Oct 18. 220345251372506

Effects of Circadian Misalignment on Young and Aging Salivary Glands.

H Mortazavi, R Said, G S Katselis, P Chumala, G Pannone, S Papagerakis, P Papagerakis.

Several empirical observations strongly suggest that salivary function is regulated by the circadian clock. Salivary volume, electrolytes levels, and saliva protein composition all show 24-h cycle fluctuations. The exact effects of circadian disruption on salivary gland (SG) physiology and its potential role in salivary pathologies have not been elucidated. Here, we examined the effects of circadian disruption on SG structure, functional gene and protein expression, and immune status using several circadian knockout (KO) mice models where we targeted the following canonical clock genes: brain and muscle ARNT-like 1 protein (Bmal1) KO, Period2 (Per2) KO, Cryptochrome1 (Cry1) KO, Cryptochrome2 (Cry2) KO, and Cryptochrome 1 and 2 double KO (DKOCry). All mice were females of young and old age, and data were compared with wild type (control) mice. Our results showed that circadian dysregulation had limited effects on stimulated salivary secretion and SG structure. Yet, circadian disruption significantly affected the expression of several key salivary markers, including mucins, amylase, and aquaporins, in young and aged SGs with increased amylase and acidic mucin production observed in several KO models. In addition, targeting of clock genes has resulted in subtle alterations of the salivary immune microenvironment with increased lymphocyte infiltration and upregulated levels of proinflammatory cytokines. These immune shifts were more pronounced in aged glands with the most proinflammatory phenotypes observed in DKOCry and Bmal1KO mice. Collectively, our results implicate the circadian clock in the intricate temporal regulation governing SG function. Our data also suggest that circadian dysregulation may predispose to increased tissue stress and inflammation. Exploration of salivary system chronobiology represents a new avenue for salivary disease prevention and treatment.

Keywords: Sjögren’s disease; autoimmunity; circadian rhythms; cytokines; saliva; salivary physiology

DOI: https://doi.org/10.1177/00220345251372506