Editorial: Circadian desynchrony: Consequences, mechanisms, and Open Issues

**Background:** Most biological processes exhibit sustained circadian rhythms generated by endogenous clocks with approximately 24-hour periods. In mammals, these rhythms are driven by a transcriptional-translational feedback loop, while in cyanobacteria, phosphorylation cycles generate endogenous 24-hour rhythms. Proper entrainment of endogenous rhythms to environmental cycles (zeitgebers) allows organisms to anticipate predictable environmental changes and is associated with longevity, reproductive success, and fitness. Circadian desynchrony can be experimentally imposed by altering molecular timekeeping mechanisms or zeitgebers, or it can result from human activities such as light pollution, global warming, shift work, and mistimed eating. This editorial summarizes articles in a Research Topic addressing the consequences of various models of circadian desynchrony.

**Methods:** The editorial reviews multiple original research articles and reviews included in the Research Topic. Rumanova et al. exposed nocturnal rats to dim artificial light at night for 2 weeks and measured plasma metabolites and cholesterol. Bilu et al. reviewed studies on artificial light at night and photoperiod changes in the diurnal fat sand rat (Psammomys obesus), examining effects on type 2 diabetes, obesity, adipocyte dysfunction, cataracts, depression, and anxiety. Hollis et al. used RNA-seq datasets from the Genotype-Tissue Expression (GTEx) project to compare gene expression between intensive care patients and those who died acutely. Oneda et al. tested whether wheel running exercise in mice improved resynchronization of body clocks under conditions mimicking social jetlag. Zhao et al. developed a luminescence reporter for Synechocystis cyanobacteria and studied kai cluster mutants (kaiAB1C1-ko) with disrupted rhythms in mixed cultures. Peng et al. developed Vip^tTA^ knock-in mice expressing tetracycline transactivator specifically in VIP neurons to study multi-oscillator circadian systems.

**Key Results:** Rumanova et al. found that rats exposed to dim artificial light at night for only 2 weeks had increased cholesterol and disrupted daily rhythms of plasma metabolites. Bilu et al. reported that artificial light at night and photoperiod changes exacerbated type 2 diabetes, obesity, adipocyte dysfunction, cataracts, depression, and anxiety in the fat sand rat; interventions such as morning bright light exposure or access to running wheels improved or prevented these health issues. Hollis et al. found that hundreds of genes from multiple tissues were differentially expressed between intensive care patients and those who died acutely; clock output genes, but not core clock genes, were overrepresented among dysregulated genes in intensive care patients, and the gene expression profile resembled that seen in previous clinical studies of sleep deprivation and fasting. Oneda et al. demonstrated that wheel running exercise in mice improved resynchronization of body clocks under social jetlag-mimicking conditions. Zhao et al. showed that kai cluster mutants (kaiAB1C1-ko) with severely disrupted rhythms were outcompeted by wild-type strains in mixed cultures. Peng et al. developed Vip^tTA^ knock-in mice as a tool for validating a multi-oscillator circadian system that allows optimal entrainment.

**Clinical Implications:** The editorial highlights several potential clinical interventions. Increasing the salience of zeitgebers through morning bright light exposure or exercise may counteract circadian disruption. Bilu et al. suggest implementing these interventions in clinical trials to determine if they can positively impact human health. Hollis et al. propose that intensive care protocols restoring sleep/wake and nutritional rhythms may benefit patients, given that clock output mechanisms are affected in intensive care settings. Oneda et al. suggest exercise could be an approach to improve social jetlag in humans. The editorial emphasizes that understanding circadian desynchrony is important for developing interventions for human health and for minimizing the impact of human activities on animals in the wild.