Anthony H. Tsang
José Cesar Rosa-Neto- 1Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom
- 2Department of Cell and Developmental Biology, Immunometabolism Research Group, Institute of Biomedical Sciences, University of Sao Paulo (USP), Sao Paulo, Brazil
Editorial on the Research Topic
Circadian rhythm in cellular endocrinology
The drastic fluctuations of environmental factors over the course of a day compelled organisms to evolve an intrinsic timekeeping mechanism – the so-called circadian clock – allowing for anticipation and adaptation to the daily predictable recurring changes.
The mammalian circadian clock is comprised of a distributed cellular timing system organized in a hierarchical manner. At the molecular level, cellular circadian rhythms are controlled by a genetically encoded machinery. This in turn is comprised of an interlocked transcriptional-translational feedback loop of a set of ubiquitously expressed clock genes which drive the rhythmic expression of a host of target genes, known as clock-controlled genes, in a tissue-specific manner. The suprachiasmatic nucleus (SCN) of the hypothalamus serves as the master clock that synchronizes the peripheral and other central nervous systems (CNS) clocks to each other and to the external light-dark cycle (1).
In mammals, endocrine systems are one of the major outlets of the circadian clock to regulate physiological processes. Emerging evidence shows that many hormonal systems are subject to circadian regulation – circulating levels of many endocrine factors as well as the responsiveness of target tissues to these factors oscillate over the 24-hr daily cycle (For a comprehensive review, see (1)). Among those, the glucocorticoids (GCs) and melatonin play a special role in circadian biology. Not only are their syntheses, releases, and target tissues’ sensitivity regulated by the circadian clock, GCs and melatonin also play a major role in synchronizing cellular clocks of a wide range of tissues in the CNS and the periphery (2, 3). More recently, other hormones such as adiponectin – an adipokine and oxyntomodulin – and incretin have also been found to reset cellular clocks, albeit in a tissue-specific manner (4, 5). Thus, not only do endocrine factors serve as mere outputs of the circadian systems, but they also feedback and contribute to the robustness of it at various levels.
Glucose homeostatic regulation by insulin illustrates one of the best characterized endocrine process regulated by the intricate interplays between central and peripheral clocks: the CNS clocks play a role in controlling energy balance and regulating whole-body insulin sensitivity (6), the pancreatic beta-cell clock has been shown to regulate insulin release (7), and circadian clocks in metabolic tissues fine-tune local insulin sensitivity (8). Misalignments of these clocks, such as those induced by mistimed food consumption of highly palatable energy-dense food, leads to a state of internal circadian desynchrony which has been established as a risk factor for obesity and related metabolic disorders (9). Several other hormonal systems have been found to be regulated by the circadian clock following similar principles.
In this Research Topic, we highlight recent progress in the understanding of the interaction between cellular circadian rhythms, endocrine functions, and physiological homeostasis. Various aspects of the cardiovascular system have long been shown to display diurnal and circadian rhythms. Notably, there are higher incidences of complications during the morning (10). Yu et al. summarized the current evidence of plasminogen-activator inhibitor 1 (PAI-1) – a secreted inhibitor of plasmin proteolytic activation (and hence a positive regulator for thrombosis) - as an important mediator for circadian influence of cardiovascular complications in a very interesting narrative review.
The stress response coordinates behavior and physiology to cope with imminent perceived dangers. Various components of the stress response have been shown to be subject to circadian regulation (11). Two original studies in this Research Topic provide new insights into this research area. Using a cell model of hypothalamic neurons, Alcántara-Alonso et al. have uncovered a molecular mechanism wherein a hypothalamic stress-induced neuropeptide urocortin 2 differentially regulates the expression of hypothalamic appetite-regulating neuropeptides and clock genes via engaging type 2 corticotropin releasing hormone receptor (CRH-R2), illustrating a potential mechanism via which the stress responses reset circadian behaviors. On the other hand, using a mouse model with selective deletion of a pleotropic protein deacetylase SIRT1 in cartilage as a model of growth impairment, Shtaif et al., reveal that cartilage SIRT1 plays an unexpected role in cognitive and anxiolytic function, providing a plausible link between body growth and cognitive development. Though this study does not observe circadian abnormities in these mutant mice under normal light-dark holding conditions, it remains interesting to explore the circadian behavior and cartilage biology under constant conditions, as SIRT1 has long been known to regulate clock gene oscillations in both the SCN master and peripheral clocks (12).
Furthermore, misaligned dietary timing has been extensively linked with several metabolic diseases. In this Research Topic, He et al., demonstrated in a mouse model of diet-induced cholesterol gallstone formation that improper timing of feeding exacerbates the disease progression, correlating with dysregulated cholesterol and hepatic bile acid metabolism as well as fluctuation in gut microbiota.
In summary, the circadian clock is extensively intertwined with endocrine functions, from the cellular to the interorgan levels. As a major output of the circadian clock, novel insights into elucidating the interaction between the circadian and the endocrine systems will help in developing therapeutic strategies to various forms of metabolic, endocrine, and circadian rhythm sleep disorders.
Author contributions
AT: Writing – original draft, Writing – review & editing. JR-N: Writing – original draft, Writing – review & editing.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Gamble KL, Berry R, Frank SJ, Young ME. Circadian clock control of endocrine factors. Nat Rev Endocrinol. (2014) 10:466–75. doi: 10.1038/nrendo.2014.78
2. Rao R, Androulakis IP. The physiological significance of the circadian dynamics of the HPA axis: Interplay between circadian rhythms, allostasis and stress resilience. Horm Behav. (2019) 110:77–89. doi: 10.1016/j.yhbeh.2019.02.018
3. Pevet P, Challet E, Felder-Schmittbuhl MP. Melatonin and the circadian system: Keys for health with a focus on sleep. Handb Clin Neurol. (2021) 179:331–43. doi: 10.1016/B978–0-12–819975–6.00021–2
4. Tsang AH, Koch CE, Kiehn JT, Schmidt CX, Oster H. An adipokine feedback regulating diurnal food intake rhythms in mice. Elife. (2020) 9. doi: 10.7554/eLife.55388
5. Landgraf D, Tsang AH, Leliavski A, Koch CE, Barclay JL, Drucker DJ, et al. Oxyntomodulin regulates resetting of the liver circadian clock by food. Elife. (2015) 4:e06253. doi: 10.7554/eLife.06253
6. Kolbe I, Brehm N, Oster H. Interplay of central and peripheral circadian clocks in energy metabolism regulation. J Neuroendocrinol. (2019) 31:e12659. doi: 10.1111/jne.12659
7. Chan K, Wong FS, Pearson JA. Circadian rhythms and pancreas physiology: A review. Front Endocrinol (Lausanne). (2022) 13:920261. doi: 10.3389/fendo.2022.920261
8. Brubaker PL, Martchenko A. Metabolic homeostasis: it’s all in the timing. Endocrinology. (2022) 163. doi: 10.1210/endocr/bqab199
9. Bass J. Interorgan rhythmicity as a feature of healthful metabolism. Cell Metab. (2024) 36:655–69. doi: 10.1016/j.cmet.2024.01.009
10. Belloir J, Makarem N, Shechter A. Sleep and circadian disturbance in cardiovascular risk. Curr Cardiol Rep. (2022) 24:2097–107. doi: 10.1007/s11886–022-01816-z
11. Koch CE, Leinweber B, Drengberg BC, Blaum C, Oster H. Interaction between circadian rhythms and stress. Neurobiol Stress. (2017) 6:57–67. doi: 10.1016/j.ynstr.2016.09.001
Keywords: circadian rhythm, endocrinology & metabolism, cardiovascular risk, stress responses, chronotherapy
Citation: Tsang AH and Rosa-Neto JC (2024) Editorial: Circadian rhythm in cellular endocrinology. Front. Endocrinol. 15:1429793. doi: 10.3389/fendo.2024.1429793
Received: 08 May 2024; Accepted: 17 May 2024;
Published: 28 May 2024.
Edited and Reviewed by:
Ralf Jockers, Université Paris Cité, FranceCopyright © 2024 Tsang and Rosa-Neto. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Anthony H. Tsang, YXQ3ODNAbWVkc2NobC5jYW0uYWMudWs=