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Molecular Advances in Circadian Rhythm and Metabolism

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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: 20 April 2025 | Viewed by 6061

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Special Issue Editors

Dr. Olga Cela

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Guest Editor

Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
Interests: cellular bioenergetics; mitochondria physiology; chronobiology

Dr. Rosella Scrima

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Guest Editor

Laboratory of Biochemistry, Department of Clinical and Experimental Medicine, Università degli Studi di Foggia, Foggia, Italy
Interests: cancer; mitochondria physiology

Special Issue Information

Dear Colleagues,

Most of the organisms on Earth are subjected to circadian rhythms, which last 24 h, due to external oscillations (such as light, darkness, or temperature fluctuations) and internal stimuli such as endocrine signals. During evolution, organisms developed an autonomous time-keeping mechanism, enabling them to anticipate geo-physical diurnal changes, thereby acquiring a competitive advantage.

In mammals, the synchronization of circadian rhythms is systemically controlled by the suprachiasmatic nucleus (SCN), located in the hypothalamus and regulated via photic inputs sent by the optic nerve. Other local circadian clocks, synchronized by the SCN, are in the peripheral tissue and regulate physiological, biochemical, and behavioral rhythms.

At the molecular level, circadian rhythmicity is established autonomously through a transcriptional–translational feedback loop involving a core clock gene system with the heterodimeric complex formed by CLOCK and BMAL1 proteins that bind E-box regulatory sequences driving the extensive gene expression of clock-controlled genes.

It has been estimated via transcriptomic analysis that in mammals, depending on the tissue, 30–70% of the entire genome is under clock gene control. In this regard, mounting evidence indicates the tight control of catabolic and anabolic cell metabolism. Consistently, circadian disruption has a negative impact on metabolism, with increased metabolic risks and development in humans with cardiovascular, cancer, neurological and psychiatric, and immunological diseases. Intriguingly, factors affecting metabolism such as physical exercise and diet have been reported to influence circadian rhythms. This suggests a complex reciprocal interplay between metabolism and biological rhythms that warrants the deepening of our understanding in terms of molecular mechanisms, which this Special Issue intends to contribute with the aim to provide mechanistic insights into circadian physiology and to advance new chronotherapy approaches and therapeutic targets for metabolic disorders.

Dr. Olga Cela
Dr. Rosella Scrima
Guest Editors

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Keywords

circadian rhythms
metabolism
clock genes
protein processing/post-translational modifications
chronomedicine

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Published Papers (7 papers)

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Research

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21 pages, 2785 KiB

Open AccessArticle

Impact of Circadian Clock PER2 Gene Overexpression on Rumen Epithelial Cell Dynamics and VFA Transport Protein Expression

by Rahmat Ali, Yongkang Zhen, Xi Zanna, Jiaqi Lin, Chong Zhang, Jianjun Ma, Yuhong Zhong, Hosameldeen Mohamed Husien, Ahmad A. Saleh and Mengzhi Wang

Int. J. Mol. Sci. 2024, 25(22), 12428; https://doi.org/10.3390/ijms252212428 - 19 Nov 2024

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Abstract

The circadian gene PER2 is recognized for its regulatory effects on cell proliferation and lipid metabolism across various non-ruminant cells. This study investigates the influence of PER2 gene overexpression on goat rumen epithelial cells using a constructed pcDNA3.1-PER2 plasmid, assessing its impact on circadian gene expression, cell proliferation, and mRNA levels of short-chain fatty acid (SCFA) transporters, alongside genes related to lipid metabolism, cell proliferation, and apoptosis. Rumen epithelial cells were obtained every four hours from healthy dairy goats (n = 3; aged 1.5 years; average weight 45.34 ± 4.28 kg), cultured for 48 h in vitro, and segregated into control (pcDNA3.1) and overexpressed (pcDNA3.1-PER2) groups, each with four biological replicates. The study examined the potential connection between circadian rhythms and nutrient assimilation in ruminant, including cell proliferation, apoptosis, cell cycle dynamics, and antioxidant activity and the expression of circadian-related genes, VFA transporter genes and regulatory factors. The introduction of the pcDNA3.1-PER2 plasmid drastically elevated PER2 expression levels by 3471.48-fold compared to controls (p < 0.01), confirming effective overexpression. PER2 overexpression resulted in a significant increase in apoptosis rates (p < 0.05) and a notable reduction in cell proliferation at 24 and 48 h post-transfection (p < 0.05), illustrating an inhibitory effect on rumen epithelial cell growth. PER2 elevation significantly boosted the expression of CCND1, WEE1, p21, and p16 (p < 0.05) while diminishing CDK4 expression (p < 0.05). While the general expression of intracellular inflammation genes remained stable, TNF-α expression notably increased. Antioxidant marker levels (SOD, MDA, GSH-Px, CAT, and T-AOC) exhibited no significant change, suggesting no oxidative damage due to PER2 overexpression. Furthermore, PER2 overexpression significantly downregulated AE2, NHE1, MCT1, and MCT4 mRNA expressions while upregulating PAT1 and VH+ ATPase. These results suggest that PER2 overexpression impairs cell proliferation, enhances apoptosis, and modulates VFA transporter-related factors in the rumen epithelium. This study implies that the PER2 gene may regulate VFA absorption through modulation of VFA transporters in rumen epithelial cells, necessitating further research into its specific regulatory mechanisms. Full article

(This article belongs to the Special Issue Molecular Advances in Circadian Rhythm and Metabolism)

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14 pages, 2037 KiB

Open AccessCommunication

Influence of Acute Inflammation on the Expression of Clock Genes in the Ovine Pars Tuberalis Under Different Photoperiodic Conditions

by Karolina Wojtulewicz, Monika Tomczyk, Maciej Wójcik, Hanna Antushevich, Joanna Bochenek and Andrzej Przemysław Herman

Int. J. Mol. Sci. 2024, 25(21), 11471; https://doi.org/10.3390/ijms252111471 - 25 Oct 2024

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The pars tuberalis (PT) plays an important role in the photoperiodic regulation of the secretory activity of the pituitary gland. Additionally, PT secretory activity may be influenced by the animal’s immune status. The melatonin signal processing in PT cells occurs through the presence of melatonin receptors and the expression of molecular clock genes. This study aimed to define the effects of acute inflammation induced by intravenous administration of lipopolysaccharide (LPS) on the expression of clock genes in the PT of ewes under different photoperiodic conditions. Two analogous experiments were conducted in different photoperiods: short-day and long-day. Both experiments included 24 sheep divided into two groups: day (n = 12) and night (n = 12), further subdivided into a control group (n = 6) and a group treated with LPS (n = 6) at a dose of 400 ng/kg. Under short-day conditions, the expression of clock circadian regulator, basic helix-loop-helix ARNT like 1, cryptochrome circadian regulator (CRY) 1, 2, and casein kinase 1 epsilon genes was lower during inflammation. LPS injection increased expression of the period circadian regulator 1 gene during the night. Under long-day conditions, CRY1 mRNA level was lower during the night, while diurnal CRY2 mRNA expression was decreased after LPS injection. Our results showed that inflammation disturbed the expression of molecular clock genes in the PT; however, this influence was partly dependent on photoperiod conditions. Full article

(This article belongs to the Special Issue Molecular Advances in Circadian Rhythm and Metabolism)

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18 pages, 2966 KiB

Open AccessArticle

Autonomous Oscillatory Mitochondrial Respiratory Activity: Results of a Systematic Analysis Show Heterogeneity in Different In Vitro-Synchronized Cancer Cells

by Olga Cela, Rosella Scrima, Consiglia Pacelli, Michela Rosiello, Claudia Piccoli and Nazzareno Capitanio

Int. J. Mol. Sci. 2024, 25(14), 7797; https://doi.org/10.3390/ijms25147797 - 16 Jul 2024

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Abstract

Circadian oscillations of several physiological and behavioral processes are an established process in all the organisms anticipating the geophysical changes recurring during the day. The time-keeping mechanism is controlled by a transcription translation feedback loop involving a set of well-characterized transcription factors. The synchronization of cells, controlled at the organismal level by a brain central clock, can be mimicked in vitro, pointing to the notion that all the cells are endowed with an autonomous time-keeping system. Metabolism undergoes circadian control, including the mitochondrial terminal catabolic pathways, culminating under aerobic conditions in the electron transfer to oxygen through the respiratory chain coupled to the ATP synthesis according to the oxidative phosphorylation chemiosmotic mechanism. In this study, we expanded upon previous isolated observations by utilizing multiple cell types, employing various synchronization protocols and different methodologies to measure mitochondrial oxygen consumption rates under conditions simulating various metabolic stressors. The results obtained clearly demonstrate that mitochondrial respiratory activity undergoes rhythmic oscillations in all tested cell types, regardless of their individual respiratory proficiency, indicating a phenomenon that can be generalized. However, notably, while primary cell types exhibited similar rhythmic respiratory profiles, cancer-derived cell lines displayed highly heterogeneous rhythmic changes. This observation confirms on the one hand the dysregulation of the circadian control of the oxidative metabolism observed in cancer, likely contributing to its development, and on the other hand underscores the necessity of personalized chronotherapy, which necessitates a detailed characterization of the cancer chronotype. Full article

(This article belongs to the Special Issue Molecular Advances in Circadian Rhythm and Metabolism)

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12 pages, 3431 KiB

Open AccessArticle

Circadian Synchronization of Feeding Attenuates Rats’ Food Restriction-Induced Anxiety and Amygdalar Thyrotropin-Releasing Hormone Downregulation

by Paulina Soberanes-Chávez, Jariz Trujillo-Barrera and Patricia de Gortari

Int. J. Mol. Sci. 2024, 25(11), 5857; https://doi.org/10.3390/ijms25115857 - 28 May 2024

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Abstract

Anxiety is a common comorbidity of obesity, resulting from prescribing long-term caloric restriction diets (CRDs); patients with a reduced food intake lose weight but present anxious behaviors, poor treatment adherence, and weight regain in the subsequent 5 years. Intermittent fasting (IF) restricts feeding time to 8 h during the activity phase, reducing patients’ weight even with no caloric restriction; it is unknown whether an IF regime with ad libitum feeding avoids stress and anxiety development. We compared the corticosterone blood concentration between male Wistar rats fed ad libitum or calorie-restricted with all-day or IF food access after 4 weeks, along with their anxiety parameters when performing the elevated plus maze (EPM). As the amygdalar thyrotropin-releasing hormone (TRH) is believed to have anxiolytic properties, we evaluated its expression changes in association with anxiety levels. The groups formed were the following: a control which was offered food ad libitum (C-adlib) or 30% of C-adlib’s energy requirements (C-CRD) all day, and IF groups provided food ad libitum (IF-adlib) or 30% of C-adlib’s requirements (IF-CRD) with access from 9:00 to 17:00 h. On day 28, the rats performed the EPM and, after 30 min, were decapitated to analyze their amygdalar TRH mRNA expression by in situ hybridization and corticosterone serum levels. Interestingly, circadian feeding synchronization reduced the body weight, food intake, and animal anxiety levels in both IF groups, with ad libitum (IF-adlib) or restricted (IF-CRD) food access. The anxiety levels of the experimental groups resulted to be negatively associated with TRH expression, which supported its anxiolytic role. Therefore, the low anxiety levels induced by synchronizing feeding with the activity phase would help patients who are dieting to improve their diet therapy adherence. Full article

(This article belongs to the Special Issue Molecular Advances in Circadian Rhythm and Metabolism)

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14 pages, 509 KiB

Open AccessArticle

Circadian Gene Variants: Effects in Overweight and Obese Pregnant Women

by Marica Franzago, Paola Borrelli, Pierluigi Cavallo, Luciano Di Tizio, Diego Gazzolo, Marta Di Nicola, Liborio Stuppia and Ester Vitacolonna

Int. J. Mol. Sci. 2024, 25(7), 3838; https://doi.org/10.3390/ijms25073838 - 29 Mar 2024

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Abstract

Obesity and overweight are common and complex conditions influenced by multiple genetic and environmental factors. Several genetic variants located in the genes involved in clock systems and fat taste perception can affect metabolic health. In particular, the polymorphisms in CLOCK and BMAL1 genes were reported to be significantly related to cardiovascular disease, metabolic syndrome, sleep reduction, and evening preference. Moreover, genetic variants in the CD36 gene have been shown to be involved in lipid metabolism, regulation of fat intake, and body weight regulation. The aim of this study is to evaluate, for the first time, the association between variants in some candidate genes (namely, BMAL1 rs7950226 (G>A), CLOCK rs1801260 (A>G), CLOCK rs4864548 (G>A), CLOCK rs3736544 (G>A), CD36 rs1984112 (A>G), CD36 rs1761667 (G>A)) and overweight/obesity (OB) in pregnant women. A total of 163 normal-weight (NW) and 128 OB participants were included. A significant correlation was observed between A-allele in CLOCK rs4864548 and an increased risk of obesity (OR: 1.97; 95% CI 1.22–3.10, p = 0.005). In addition, we found that subjects carrying the haplotype of rs1801260-A, rs4864548-A, and rs3736544-G are likely to be overweight or obese (OR 1.47, 95% CI 1.03–2.09, p = 0.030), compared with those with other haplotypes. Moreover, a significant relation was observed between third-trimester lipid parameters and genetic variants—namely, CD36 rs1984112, CD36 rs1761667, BMAL1 rs7950226, and CLOCK rs1801260. A multivariate logistic regression model revealed that CLOCK rs4864548 A-allele carriage was a strong risk factor for obesity (OR 2.05, 95% CI 1.07–3.93, p = 0.029); on the other hand, greater adherence to Mediterranean diet (OR 0.80, 95% CI 0.65–0.98, p = 0.038) and higher HDL levels (OR 0.96, 95% CI 0.94–0.99, p = 0.021) were related to a reduced risk of obesity. Interestingly, an association between maternal CLOCK rs4864548 and neonatal birthweight was detected (p = 0.025). These data suggest a potential role of the polymorphisms in clock systems and in fat taste perception in both susceptibility to overweight/obesity and influencing the related metabolic traits in pregnant women. Full article

(This article belongs to the Special Issue Molecular Advances in Circadian Rhythm and Metabolism)

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Review

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27 pages, 2414 KiB

Open AccessReview

Interaction Between Early Meals (Big-Breakfast Diet), Clock Gene mRNA Expression, and Gut Microbiome to Regulate Weight Loss and Glucose Metabolism in Obesity and Type 2 Diabetes

by Daniela Jakubowicz, Yael Matz, Zohar Landau, Rachel Chava Rosenblum, Orit Twito, Julio Wainstein and Shani Tsameret

Int. J. Mol. Sci. 2024, 25(22), 12355; https://doi.org/10.3390/ijms252212355 - 18 Nov 2024

Viewed by 432

Abstract

The circadian clock gene system plays a pivotal role in coordinating the daily rhythms of most metabolic processes. It is synchronized with the light–dark cycle and the eating–fasting schedule. Notably, the interaction between meal timing and circadian clock genes (CGs) allows for optimizing metabolic processes at specific times of the day. Breakfast has a powerful resetting effect on the CG network. A misaligned meal pattern, such as skipping breakfast, can lead to a discordance between meal timing and the endogenous CGs, and is associated with obesity and T2D. Conversely, concentrating most calories and carbohydrates (CH) in the early hours of the day upregulates metabolic CG expression, thus promoting improved weight loss and glycemic control. Recently, it was revealed that microorganisms in the gastrointestinal tract, known as the gut microbiome (GM), and its derived metabolites display daily oscillation, and play a critical role in energy and glucose metabolism. The timing of meal intake coordinates the oscillation of GM and GM-derived metabolites, which in turn influences CG expression, playing a crucial role in the metabolic response to food intake. An imbalance in the gut microbiota (dysbiosis) can also reciprocally disrupt CG rhythms. Evidence suggests that misaligned meal timing may cause such disruptions and can lead to obesity and hyperglycemia. This manuscript focuses on the reciprocal interaction between meal timing, GM oscillation, and circadian CG rhythms. It will also review studies demonstrating how aligning meal timing with the circadian clock can reset and synchronize CG rhythms and GM oscillations. This synchronization can facilitate weight loss and improve glycemic control in obesity and those with T2D. Full article

(This article belongs to the Special Issue Molecular Advances in Circadian Rhythm and Metabolism)

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13 pages, 1279 KiB

Open AccessReview

Melatonin as a Circadian Marker for Plasmodium Rhythms

by Bárbara K. M. Dias, Abhinab Mohanty and Célia R. S. Garcia

Int. J. Mol. Sci. 2024, 25(14), 7815; https://doi.org/10.3390/ijms25147815 - 17 Jul 2024

Viewed by 909

Abstract

Plasmodium, a digenetic parasite, requires a host and a vector for its life cycle completion. Most Plasmodium species display circadian rhythmicity during their intraerythrocytic cycle within the host, aiding in immune evasion. This rhythmicity, however, diminishes in in vitro cultures, highlighting the importance of host-derived signals for synchronizing the parasite’s asexual cycle. Studies indicate a species–specific internal clock in Plasmodium, dependent on these host signals. Melatonin, a hormone the pineal gland produces under circadian regulation, impacts various physiological functions and is extensively reviewed as the primary circadian marker affecting parasite rhythms. Research suggests that melatonin facilitates synchronization through the PLC-IP₃ signaling pathway, activating phospholipase C, which triggers intracellular calcium release and gene expression modulation. This evidence strongly supports the role of melatonin as a key circadian marker for parasite synchronization, presenting new possibilities for targeting the melatonin pathway when developing novel therapeutic approaches. Full article

(This article belongs to the Special Issue Molecular Advances in Circadian Rhythm and Metabolism)

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