bims-ciryme 2024-10-13 papers

bims-ciryme

Biomed News

on Circadian rhythms and metabolism

Issue of 2024–10–13
eight papers selected by
Gabriela Da Silva Xavier, University of Birmingham

Synergy between time-restricted feeding and time-restricted running is necessary to shift the muscle clock in male wistar rats.
Resilience to Chronic Stress Is Characterized by Circadian Brain-Liver Coordination.
A repeatedly evolved mutation in Cryptochrome-1 of subterranean animals alters behavioral and molecular circadian rhythms.
The role of circadian clock gene Arntl in the winter depression-like behavior in melatonin-proficient female CBA/N mice.
Sex-Related Variation in Circadian Rhythms in the Bumble Bee Bombus Terrestris.
The Reindeer Circadian Clock Is Rhythmic and Temperature-compensated But Shows Evidence of Weak Coupling Between the Secondary and Core Molecular Clock Loops.
Functional inversion of circadian regulator REV-ERBα leads to tumorigenic gene reprogramming.
Circadian clock dysregulation: a potential mechanism of depression in obstructive sleep apnea patients.

Neurobiol Sleep Circadian Rhythms. 2024 Nov;17 100106

Synergy between time-restricted feeding and time-restricted running is necessary to shift the muscle clock in male wistar rats.

Ayano Shiba, Paul de Goede, Roberta Tandari, Ewout Foppen, Nikita L Korpel, Tom V Coopmans, Tom P Hellings, Merel W Jansen, Annelou Ruitenberg, Wayne I G R Ritsema, Chun-Xia Yi, Joram D Mul, Dirk Jan Stenvers, Andries Kalsbeek.

  Circadian disruption is an important factor driving the current-day high prevalence of obesity and type-2 diabetes. While the impact of incorrect timing of caloric intake on circadian disruption is widely acknowlegded, the contribution of incorrect timing of physical activity remains relatively understudied. Here, we modeled the incorrect timing of physical activity in nightshift workers in male Wistar rats, by restricting running wheel access to the innate inactive (light) phase (LR). Controls included no wheel access (NR); access only during the innate active (dark) period (DR); or unrestricted (ad libitum) access (ALR). LR did not shift the phase of the muscle or liver clock, but dampened the muscle clock amplitude. As our previous study demonstrated that light-phase restricted feeding did shift the liver clock, but made the muscle clock arrhythmic, we next combined the time restriction of wheel and food access to either the light phase (LRLF) or dark phase (DRDF). LRLF produced a ∼12 h shift in the majority of clock gene rhythms in both skeletal muscle and liver. On the other hand, DRDF was most effective in reducing body weight and the accumulation of fat mass. Therefore, in order to shift the muscle clock in male Wistar rats, synergy between the timing of feeding and physical activity is necessary. These findings may contribute to further improve the design of lifestyle strategies that try to limit metabolic misalignment caused by circadian disruption.

Keywords:  Circadian misalignment; Energy metabolism; Liver; Muscle; Time restriction; Wheel running

DOI:  https://doi.org/10.1016/j.nbscr.2024.100106
Biol Psychiatry Glob Open Sci. 2024 Nov;4(6): 100385

Resilience to Chronic Stress Is Characterized by Circadian Brain-Liver Coordination.

Christina Savva, Ivan Vlassakev, Blynn G Bunney, William E Bunney, Lucas Massier, Marcus Seldin, Paolo Sassone-Corsi, Paul Petrus, Shogo Sato.

   Background: Chronic stress has a profound impact on circadian regulation of physiology. In turn, disruption of circadian rhythms increases the risk of developing both psychiatric and metabolic disorders. To explore the role of chronic stress in modulating the links between neural and metabolic rhythms, we characterized the circadian transcriptional regulation across different brain regions and the liver as well as serum metabolomics in mice exposed to chronic social defeat stress, a validated model for studying depressive-like behaviors.
Methods: Male C57BL/6J mice underwent chronic social defeat stress, and subsequent social interaction screening identified distinct behavioral phenotypes associated with stress resilience and susceptibility. Stressed mice and their control littermates were sacrificed every 4 hours over the circadian cycle for comprehensive analyses of the circadian transcriptome in the hypothalamus, hippocampus, prefrontal cortex, and liver together with assessments of the circadian circulatory metabolome.
Results: Our data demonstrate that stress adaptation was characterized by reprogramming of the brain as well as the hepatic circadian transcriptome. Stress resiliency was associated with an increase in cyclic transcription in the hypothalamus, hippocampus, and liver. Furthermore, cross-tissue analyses revealed that resilient mice had enhanced transcriptional coordination of circadian pathways between the brain and liver. Conversely, susceptibility to social stress resulted in a loss of cross-tissue coordination. Circadian serum metabolomic profiles corroborated the transcriptome data, highlighting that stress-resilient mice gained circadian rhythmicity of circulating metabolites, including bile acids and sphingomyelins.
Conclusions: This study reveals that resilience to stress is characterized by enhanced metabolic rhythms and circadian brain-liver transcriptional coordination.

Keywords:  Chronic social stress; Circadian rhythms; Gene expression; Metabolism; Mouse model for depressive-like behaviors; Multitissue omics analysis

DOI:  https://doi.org/10.1016/j.bpsgos.2024.100385
bioRxiv. 2024 Sep 23. pii: 2024.09.19.613894. [Epub ahead of print]

A repeatedly evolved mutation in Cryptochrome-1 of subterranean animals alters behavioral and molecular circadian rhythms.

Amruta Swaminathan, Alexander Kenzior, Colin McCoin, Andrew Price, Kyle Weaver, Aurélie Hintermann, NatiCia Morris, Alex C Keene, Nicolas Rohner.

The repeated evolution of similar phenotypes in independent lineages often occurs in response to similar environmental pressures, through similar or different molecular pathways. Recently, a repeatedly occurring mutation R263Q in a conserved domain of the protein Cryptochrome-1 (CRY1) was reported in multiple species inhabiting subterranean environments. Cryptochromes regulate circadian rhythms, and glucose and lipid metabolism. Subterranean species show changes to their circadian rhythm and metabolic pathways, making it likely that this mutation in CRY1 contributes to adaptive phenotypic changes. To identify the functional consequences of the CRY1 R263Q mutation, we generated a mouse model homozygous for this mutation. Indirect calorimetry experiments revealed delayed energy expenditure, locomotor activity and feeding patterns of mutant mice in the dark phase, but no further metabolic phenotypes - unlike a full loss of function of CRY1. Gene expression analyses showed altered expression of several canonical circadian genes in the livers of the mutant mice, fortifying the notion that CRY1 R263Q impacts metabolism. Our data provide the first characterization of a novel mutation that has repeatedly evolved in subterranean environments, supporting the idea that shared environmental constraints can drive the evolution of similar phenotypes through similar genetic changes.

DOI: https://doi.org/10.1101/2024.09.19.613894
Biochem Biophys Res Commun. 2024 Oct 02. pii: S0006-291X(24)01326-3. [Epub ahead of print]734 150790

The role of circadian clock gene Arntl in the winter depression-like behavior in melatonin-proficient female CBA/N mice.

Liang Ren, Kousuke Okimura, Akira Ishikawa, Naohiro Kon, Shigeki Shimba, Takashi Yoshimura.

  Seasonal affective disorder (SAD), also known as winter depression, is a subtype of depression typically manifesting in winter. Typical symptoms of SAD, such as an increased need for sleep and carbohydrate cravings associated with increased appetite and weight, are distinct from those of major depression, and the underlying mechanisms of SAD remain unclear. Although laboratory mice are generally considered non-seasonal animals, we observed depression-like behaviors in melatonin-proficient female CBA/N mice maintained under winter-mimicking conditions. Transcriptome analysis of the brains of CBA/N mice maintained under winter- and summer-mimicking conditions revealed changes in the expression of circadian clock genes, including Arntl (also known as Bmal1). We generated Arntl-deficient, melatonin-proficient CBA/N mice using the speed congenic method to examine the role of Arntl in depressive behavior. The tail suspension test in these mice revealed a depressive phenotype. These results suggested that the circadian clock gene Arntl may be involved in winter depression-like behavior.

Keywords:  Circadian rhythm; Melatonin; Photoperiodic response; Winter depression

DOI:  https://doi.org/10.1016/j.bbrc.2024.150790
J Biol Rhythms. 2024 Oct 06. 7487304241283863

Sex-Related Variation in Circadian Rhythms in the Bumble Bee Bombus Terrestris.

Ozlem Gonulkirmaz-Cancalar, Guy Bloch.

  Mating success depends on many factors, but first of all, a male and a female need to meet at the same place and time. The circadian clock is an endogenous system regulating activity and sex-related behaviors in animals. We studied bumble bees (Bombus terrestris) in which the influence of circadian rhythms on sexual behavior has been little explored. We characterized circadian rhythms in adult emergence and locomotor activity under different illumination regimes for males and gynes (unmated queens). We developed a method to monitor adult emergence from the pupal cocoon and found no circadian rhythms in this behavior for either males or gynes. These results are not consistent with the hypothesis that the circadian clock regulates emergence from the pupa in this species. Consistent with this premise, we found that both gynes and males do not show circadian rhythms in locomotor activity during the first 3 days after pupal emergence, but shortly after developed robust circadian rhythms that are readily shifted by a phase delay in illumination regime. We conclude that the bumble bees do not need strong rhythms in adult emergence and during early adult life in their protected and regulated nest environment, but do need strong activity rhythms for timing flights and mating-related behaviors. Next, we tested the hypothesis that the locomotor activity of males and gynes have a similar phase, which may improve mating success. We found that both males and gynes have strong endogenous circadian rhythms that are entrained by the illumination regime, but males show rhythms at an earlier age, their rhythms are stronger, and their phase is slightly advanced relative to that of gynes. An earlier phase may be advantageous to males competing to mate a receptive gyne. Our results are consistent with the hypothesis that sex-related variations in circadian rhythms is shaped by sexual selection.

Keywords:  bumble bees; circadian rhythms; eclosion rhythms; locomotor activity; mating synchronization

DOI:  https://doi.org/10.1177/07487304241283863
J Biol Rhythms. 2024 Oct 06. 7487304241283066

The Reindeer Circadian Clock Is Rhythmic and Temperature-compensated But Shows Evidence of Weak Coupling Between the Secondary and Core Molecular Clock Loops.

Daniel Appenroth, Chandra S Ravuri, Sara K Torppa, Shona H Wood, David G Hazlerigg, Alexander C West.

  Circadian rhythms synchronize the internal physiology of animals allowing them to anticipate daily changes in their environment. Arctic habitats may diminish the selective advantages of circadian rhythmicity by relaxing daily rhythmic environmental constraints, presenting a valuable opportunity to study the evolution of circadian rhythms. In reindeer, circadian control of locomotor activity and melatonin release is weak or absent, and the molecular clockwork is reportedly non-functional. Here we present new evidence that the circadian clock in cultured reindeer fibroblasts is rhythmic and temperature-compensated. Compared with mouse fibroblasts, however, reindeer fibroblasts have a short free-running period, and temperature cycles have an atypical impact on clock gene regulation. In reindeer cells, Per2 and Bmal1 reporters show rapid responses to temperature cycles, with a disintegration of their normal antiphasic relationship. The antiphasic Per2-Bmal1 relationship re-emerges immediately after release from temperature cycles, but without complete temperature entrainment and with a marked decline in circadian amplitude. Experiments using Bmal1 promoter reporters with mutated RORE sites showed that a reindeer-like response to temperature cycles can be mimicked in mouse or human cell lines by decoupling Bmal1 reporter activity from ROR/REV-ERB-dependent transcriptional regulation. We suggest that weak coupling between core and secondary circadian feedback loops accounts for the observed behavior of reindeer fibroblasts in vitro. Our findings highlight diversity in how the thermal environment affects the temporal organization of mammals living under different thermoenergetic constraints.

Keywords:  Rangifer tarandus; cell culture; circadian; entrainment; polar; reindeer; temperature compensation

DOI:  https://doi.org/10.1177/07487304241283066
Proc Natl Acad Sci U S A. 2024 Oct 15. 121(42): e2411321121

Functional inversion of circadian regulator REV-ERBα leads to tumorigenic gene reprogramming.

Yatian Yang, Xiong Zhang, Demin Cai, Xingling Zheng, Xuan Zhao, June X Zou, Jin Zhang, Alexander D Borowsky, Marc A Dall'Era, Eva Corey, Nicholas Mitsiades, Hsing-Jien Kung, Xinbin Chen, Jian Jian Li, Michael Downes, Ronald M Evans, Hong-Wu Chen.

  Profound functional switch of key regulatory factors may play a major role in homeostasis and disease. Dysregulation of circadian rhythm (CR) is strongly implicated in cancer with mechanisms poorly understood. We report here that the function of REV-ERBα, a major CR regulator of the orphan nuclear receptor subfamily, is dramatically altered in tumors in both its genome binding and functional mode. Loss of CR is linked to a functional inversion of REV-ERBα from a repressor in control of CR and metabolic gene programs in normal tissues to a strong activator in different cancers. Through changing its association from NCoR/HDAC3 corepressor complex to BRD4/p300 coactivators, REV-ERBα directly activates thousands of genes including tumorigenic programs such as MAPK and PI3K-Akt signaling. Functioning as a master transcriptional activator, REV-ERBα partners with pioneer factor FOXA1 and directly stimulates a large number of signaling genes, including multiple growth factors, receptor tyrosine kinases, RASs, AKTs, and MAPKs. Moreover, elevated REV-ERBα reprograms FOXA1 to bind new targets through a BRD4-mediated increase in local chromatin accessibility. Pharmacological targeting with SR8278 diminishes the function of both REV-ERBα and FOXA1 and synergizes with BRD4 inhibitor in effective suppression of tumorigenic programs and tumor growth. Thus, our study revealed a functional inversion by a CR regulator in driving gene reprogramming as an unexpected paradigm of tumorigenesis mechanism and demonstrated a high effectiveness of therapeutic targeting such switch.

Keywords:  CRPC; REV-ERBα; antagonist; liver; prostate

DOI:  https://doi.org/10.1073/pnas.2411321121
Transl Psychiatry. 2024 Oct 07. 14(1): 423

Circadian clock dysregulation: a potential mechanism of depression in obstructive sleep apnea patients.

Agata Gabryelska, Szymon Turkiewicz, Piotr Kaczmarski, Adrian Gajewski, Piotr Białasiewicz, Dominik Strzelecki, Maciej Chałubiński, Marcin Sochal.

Obstructive sleep apnea (OSA) is characterized by co-occurrence with affective disorders. Our study aims to investigate the association of circadian clock gene expressions, and the presence and severity of depressive symptoms in OSA patients. The study included 184 individuals, who underwent polysomnography (PSG) and had their peripheral blood collected in the evening before and the morning after the PSG. Patients were divided into two groups: the OSA (apnea-hypopnea index (AHI) > 5) and the control group (AHI < 5). RNA was extracted from peripheral blood leukocytes. Expression levels of the selected genes (BMAL1, CLOCK, PER1, CRY1, NPAS2, and NR1D1) were assessed by qRT-PCR. Questionnaire data was collected in the morning (including the Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), Chronotype Questionnaire (CQ), and Montgomery-Åsberg Depression Rating Scale (MADRS)). The expression of all examined circadian clock genes in OSA patients was upregulated in the morning compared to the evening (except NPAS2). No differences were observed between OSA and control groups at either time point. Additionally, there was a positive correlation between the severity of depressive symptoms (assessed with MADRS) and morning expression of circadian genes in the group of OSA patients. Finally, in multivariable linear regression, ISI score (B = 0.750, p < 0.001), AM score of CQ (B = 0.416, p = 0.007), and morning PER1 gene expression (B = 4.310, p = 0.042) were found to be predictive factors for greater severity of depression symptoms in OSA patients. Dysregulated circadian clock gene expression in OSA patients is linked to depressive symptom severity, suggesting circadian disruption may underlie affective symptoms in OSA.

DOI: https://doi.org/10.1038/s41398-024-03134-0