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Metabolic Oscillations Controlled by the Biological Clock

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (15 January 2024) | Viewed by 12300

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Prof. Dr. Mario E. Guido

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Departamento de Química Biológica-CIQUIBIC, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre s/n Ciudad Universitaria, Córdoba 5000, Argentina
Interests: circadian rhythms; lipid metabolism; melatonin pathway

Special Issue Information

Dear Colleagues,

Biological clocks present in organs, tissues and even in individual cells and distributed all through different life domains, temporally regulate and organize crucial physiological and behavioral rhythms in a tight adaptation to environmental changes occurring over the light/dark cycles of a 24 h day/night extension or through seasonal variations. Rhythms may display periods in the circadian range, or even with shorter (ultradian) or longer (infradian) scales. It is known now that at the cellular level, the biological clock is composed of the canonical molecular clock driving the 24 h cycles of transcription–translation-based feedback loops and a metabolic oscillator also named cytooscillator, commanding daily variations at the level of cellular redox state (reactive oxygen species and peroxiredoxins), glycerolipid enzyme expression and metabolism and other parameters. Some of these metabolic oscillations still persist in the absence of transcription; they can be observed in normal cells and tissues and even in tumor cells after synchronization by extracellular signals involving light for retinal cells, nutrients in liver cells or synthetic glucocorticoids and serum in immortalized cell lines. Nevertheless, there is a very close cross-talk between the molecular clock and the metabolic oscillator in a cell, tissue or the whole organism which is perfectly visualized when the circadian timing system is disturbed as a consequence of modern life (continuous artificial illumination, nocturnal shift work, jet lag, hyper caloric diets, sedentary life, etc.). In fact, the circadian clock misalignment or disruption exerts severe effects on physiology and metabolism, causing a number of metabolic disorders such as type 2-diabetes, obesity, high blood pressure, hyperglycemia, hyperlipidemia, and others grouped as “the metabolic syndrome”, in addition to a higher risk of some cancer types. On the contrary, when the circadian clock is correctly aligned and synchronized, working in a tight harmony with the external environment or even under a restricted time and caloric feeding schedules, life span is prolonged and metabolic disorders and pathologies may decrease.

This special issue is addressed in the chronobiological field at elucidating the state of art regarding a recently characterized feature of the cellular clock related to the metabolic oscillator and its regulation by the circadian clock, as well as the interaction between both of these clocks, that in a cell may work together, or can be independently regulated in health or disease.

Original research and review articles are welcome to this special issue to shed light on novel observations regarding metabolic oscillations controlled by the biological clock that may impact on physiology, behavior and aging in health or even in disease progression, drug susceptibility and chronochemotherapy.

Prof. Dr. Mario E. Guido
Guest Editor

Manuscript Submission Information

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Published Papers (7 papers)

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Research

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17 pages, 1557 KiB

Open AccessArticle

Pharmacokinetic Model-Based Control across the Blood–Brain Barrier for Circadian Entrainment

by Síofra Ó. Murdoch, Eleonora M. Aiello and Francis J. Doyle III

Int. J. Mol. Sci. 2023, 24(19), 14830; https://doi.org/10.3390/ijms241914830 - 2 Oct 2023

Viewed by 828

Abstract

The ability to shift circadian phase in vivo has the potential to offer substantial health benefits. However, the blood–brain barrier prevents the absorption of the majority of large and many small molecules, posing a challenge to neurological pharmaceutical development. Motivated by the presence of the circadian molecule KL001, which is capable of causing phase shifts in a circadian oscillator, we investigated the pharmacokinetics of different neurological pharmaceuticals on the dynamics of circadian phase. Specifically, we developed and validated five different transport models that describe drug concentration profiles of a circadian pharmaceutical at the brain level under oral administration and designed a nonlinear model predictive control (MPC)-based framework for phase resetting. Performance of the novel control algorithm based on the identified pharmacokinetic models was demonstrated through simulations of real-world misalignment scenarios due to jet lag. The time to achieve a complete phase reset for 11-h phase delay ranged between 48 and 72 h, while a 5-h phase advance was compensated in 30 to 60 h. This approach provides mechanistic insight into the underlying structure of the circadian oscillatory system and thus leads to a better understanding of the feasibility of therapeutic manipulations of the system. Full article

(This article belongs to the Special Issue Metabolic Oscillations Controlled by the Biological Clock)

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15 pages, 3894 KiB

Open AccessArticle

FoxO3 Modulates Circadian Rhythms in Neural Stem Cells

by Swip Draijer, Raissa Timmerman, Jesse Pannekeet, Alexandra van Harten, Elham Aida Farshadi, Julius Kemmer, Demy van Gilst, Inês Chaves and Marco F. M. Hoekman

Int. J. Mol. Sci. 2023, 24(17), 13662; https://doi.org/10.3390/ijms241713662 - 4 Sep 2023

Cited by 1 | Viewed by 1189

Abstract

Both FoxO transcription factors and the circadian clock act on the interface of metabolism and cell cycle regulation and are important regulators of cellular stress and stem cell homeostasis. Importantly, FoxO3 preserves the adult neural stem cell population by regulating cell cycle and cellular metabolism and has been shown to regulate circadian rhythms in the liver. However, whether FoxO3 is a regulator of circadian rhythms in neural stem cells remains unknown. Here, we show that loss of FoxO3 disrupts circadian rhythmicity in cultures of neural stem cells, an effect that is mediated via regulation of Clock transcriptional levels. Using Rev-Erbα-VNP as a reporter, we then demonstrate that loss of FoxO3 does not disrupt circadian rhythmicity at the single cell level. A meta-analysis of published data revealed dynamic co-occupancy of multiple circadian clock components within FoxO3 regulatory regions, indicating that FoxO3 is a Clock-controlled gene. Finally, we examined proliferation in the hippocampus of FoxO3-deficient mice and found that loss of FoxO3 delayed the circadian phase of hippocampal proliferation, indicating that FoxO3 regulates correct timing of NSC proliferation. Taken together, our data suggest that FoxO3 is an integral part of circadian regulation of neural stem cell homeostasis. Full article

(This article belongs to the Special Issue Metabolic Oscillations Controlled by the Biological Clock)

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17 pages, 4895 KiB

Open AccessArticle

Inhibition of Expression of the Circadian Clock Gene Cryptochrome 1 Causes Abnormal Glucometabolic and Cell Growth in Bombyx mori Cells

by Jianfeng Qiu, Taiming Dai, Hui Tao, Xue Li, Cheng Luo, Yanghu Sima and Shiqing Xu

Int. J. Mol. Sci. 2023, 24(6), 5435; https://doi.org/10.3390/ijms24065435 - 12 Mar 2023

Viewed by 2442

Abstract

Cryptochrome is the earliest discovered photoreceptor protein in organisms. However, the effect of CRY (BmCRY), the clock protein in Bombyx mori, on the body or cell metabolism remains unclear. In this study, we continuously interfered with the expression of the BmCry1 gene (Cry1-KD) in the silkworm ovary cell line (BmN), and the BmN cells developed abnormally, with accelerated cell growth and a smaller nucleus. Metabolomics was used to identify the cause of the abnormal development of Cry1-KD cells based on gas chromatography/liquid chromatography-mass spectrometry. A total of 56 differential metabolites including sugars, acids, amino acids, and nucleotides were identified in wild-type and Cry1-KD cells. KEGG enrichment analysis showed that BmCry1 knockdown resulted in significantly upregulated glycometabolism in BmN cells, indicated by glucose-6-phosphate, fructose-6-phosphate, and pyruvic acid levels. The activities of key enzymes BmHK, BmPFK, and BmPK as well as their mRNA levels further confirmed that the glycometabolism level of Cry1-KD cells was significantly increased. Our results show that a possible mechanism of BmCry1 knockdown leading to abnormal cell development is the elevated level of glucose metabolism in cells. Full article

(This article belongs to the Special Issue Metabolic Oscillations Controlled by the Biological Clock)

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16 pages, 27496 KiB

Open AccessArticle

Role of Melatonin in Daily Variations of Plasma Insulin Level and Pancreatic Clock Gene Expression in Chick Exposed to Monochromatic Light

by Chao Song, Zixu Wang, Jing Cao, Yulan Dong and Yaoxing Chen

Int. J. Mol. Sci. 2023, 24(3), 2368; https://doi.org/10.3390/ijms24032368 - 25 Jan 2023

Cited by 3 | Viewed by 1910

Abstract

To clarify the effect of monochromatic light on circadian rhythms of plasma insulin level and pancreatic clock gene expression and its mechanism, 216 newly hatched chicks were divided into three groups (intact, sham operation and pinealectomy) and were raised under white (WL), red (RL), green (GL) or blue (BL) light for 21 days. Their plasma and pancreas were sampled at six four-hour intervals. For circadian rhythm analysis, measurements of plasma melatonin, insulin, and clock gene expression (cClock, cBmal1, cBmal2, cCry1, cCry2, cPer2, and cPer3) were made. Plasma melatonin, insulin, and the pancreatic clock gene all expressed rhythmically in the presence of monochromatic light. Red light reduced the mesor and amplitude of plasma melatonin in comparison to green light. The mesor and amplitude of the pancreatic clock gene in chickens exposed to red light were dramatically reduced, which is consistent with the drop in plasma melatonin levels. Red light, on the other hand, clearly raised the level of plasma insulin via raising the expression of cVamp2, but not cInsulin. After the pineal gland was removed, the circadian expressions of plasma melatonin and pancreatic clock gene were significantly reduced, but the plasma insulin level and the pancreatic cVamp2 expression were obviously increased, resulting in the disappearance of differences in insulin level and cVamp2 expression in the monochromatic light groups. Therefore, we hypothesize that melatonin may be crucial in the effect of monochromatic light on the circadian rhythm of plasma insulin level by influencing the expression of clock gene in chicken pancreas. Full article

(This article belongs to the Special Issue Metabolic Oscillations Controlled by the Biological Clock)

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Review

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42 pages, 3557 KiB

Open AccessReview

Studying the Human Microbiota: Advances in Understanding the Fundamentals, Origin, and Evolution of Biological Timekeeping

by Adam Siebieszuk, Monika Sejbuk and Anna Maria Witkowska

Int. J. Mol. Sci. 2023, 24(22), 16169; https://doi.org/10.3390/ijms242216169 - 10 Nov 2023

Cited by 2 | Viewed by 1158

Abstract

The recently observed circadian oscillations of the intestinal microbiota underscore the profound nature of the human–microbiome relationship and its importance for health. Together with the discovery of circadian clocks in non-photosynthetic gut bacteria and circadian rhythms in anucleated cells, these findings have indicated the possibility that virtually all microorganisms may possess functional biological clocks. However, they have also raised many essential questions concerning the fundamentals of biological timekeeping, its evolution, and its origin. This narrative review provides a comprehensive overview of the recent literature in molecular chronobiology, aiming to bring together the latest evidence on the structure and mechanisms driving microbial biological clocks while pointing to potential applications of this knowledge in medicine. Moreover, it discusses the latest hypotheses regarding the evolution of timing mechanisms and describes the functions of peroxiredoxins in cells and their contribution to the cellular clockwork. The diversity of biological clocks among various human-associated microorganisms and the role of transcriptional and post-translational timekeeping mechanisms are also addressed. Finally, recent evidence on metabolic oscillators and host–microbiome communication is presented. Full article

(This article belongs to the Special Issue Metabolic Oscillations Controlled by the Biological Clock)

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17 pages, 1087 KiB

Open AccessReview

The Case for the Target of Rapamycin Pathway as a Candidate Circadian Oscillator

by Patricia Lakin-Thomas

Int. J. Mol. Sci. 2023, 24(17), 13307; https://doi.org/10.3390/ijms241713307 - 27 Aug 2023

Viewed by 1181

Abstract

The molecular mechanisms that drive circadian (24 h) rhythmicity have been investigated for many decades, but we still do not have a complete picture of eukaryotic circadian systems. Although the transcription/translation feedback loop (TTFL) model has been the primary focus of research, there are many examples of circadian rhythms that persist when TTFLs are not functioning, and we lack any good candidates for the non-TTFL oscillators driving these rhythms. In this hypothesis-driven review, the author brings together several lines of evidence pointing towards the Target of Rapamycin (TOR) signalling pathway as a good candidate for a non-TTFL oscillator. TOR is a ubiquitous regulator of metabolism in eukaryotes and recent focus in circadian research on connections between metabolism and rhythms makes TOR an attractive candidate oscillator. In this paper, the evidence for a role for TOR in regulating rhythmicity is reviewed, and the advantages of TOR as a potential oscillator are discussed. Evidence for extensive feedback regulation of TOR provides potential mechanisms for a TOR-driven oscillator. Comparison with ultradian yeast metabolic cycles provides an example of a potential TOR-driven self-sustained oscillation. Unanswered questions and problems to be addressed by future research are discussed. Full article

(This article belongs to the Special Issue Metabolic Oscillations Controlled by the Biological Clock)

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13 pages, 10658 KiB

Open AccessReview

Perfecting the Life Clock: The Journey from PTO to TTFL

by Weitian Li, Zixu Wang, Jing Cao, Yulan Dong and Yaoxing Chen

Int. J. Mol. Sci. 2023, 24(3), 2402; https://doi.org/10.3390/ijms24032402 - 26 Jan 2023

Cited by 4 | Viewed by 2676

Abstract

The ubiquity of biological rhythms in life implies that it results from selection in the evolutionary process. The origin of the biological clock has two possible hypotheses: the selective pressure hypothesis of the oxidative stress cycle and the light evasion hypothesis. Moreover, the biological clock gives life higher adaptability. Two biological clock mechanisms have been discovered: the negative feedback loop of transcription–translation (TTFL) and the post-translational oscillation mechanism (PTO). The TTFL mechanism is the most classic and relatively conservative circadian clock oscillation mechanism, commonly found in eukaryotes. We have introduced the TTFL mechanism of the classical model organisms. However, the biological clock of prokaryotes is based on the PTO mechanism. The Peroxiredoxin (PRX or PRDX) protein-based PTO mechanism circadian clock widely existing in eukaryotic and prokaryotic life is considered a more conservative oscillation mechanism. The coexistence of the PTO and TTFL mechanisms in eukaryotes prompted us to explain the relationship between the two. Finally, we speculated that there might be a driving force for the evolution of the biological clock. The biological clock may have an evolutionary trend from the PTO mechanism to the TTFL mechanism, resulting from the evolution of organisms adapting to the environment. Full article

(This article belongs to the Special Issue Metabolic Oscillations Controlled by the Biological Clock)

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