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Molina-Montes E, Rodríguez-Barranco M, Alcalá-Santiago Á, Gálvez-Navas JM, Huerta JM, Amiano P, Lasheras C, Moreno-Iribas C, Jimenez-Zabala A, Chirlaque MD, Gasque A, Luján-Barroso L, Agudo A, Jakszyn P, Quirós JR, Sánchez MJ. Nutritional profile of the diet according to circadian clock genes in the European Prospective Investigation into Cancer and Nutrition (EPIC) chronodiet study. Clin Nutr 2025; 49:165-177. [PMID: 40328174 DOI: 10.1016/j.clnu.2025.04.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 02/23/2025] [Accepted: 04/21/2025] [Indexed: 05/08/2025]
Abstract
BACKGROUND & AIMS Circadian rhythms seem to impact both dietary intake and metabolism, depending on the individual's chronotype. We aimed to explore whether the nutritional composition of meals throughout the day is influenced by genetics linked to the circadian clock and chronotype within the "European Prospective Investigation into Cancer and Nutrition (EPIC) chronodiet" study. METHODS The study population comprised 3,183 subjects with information on diet and twelve genetic variants of six genes (PER1, PER2, PER3, CRY1, NR1D1, CLOCK). The associations between the variants with chrononutrition variables (macronutrients and serving sizes of each meal) were evaluated using linear regression, considering an additive genetic model, and adjusting for sex, age and center, among others. The β coefficients, 95 % confidence intervals (CI), and p-values corrected for multiple comparisons were estimated. A genetic risk score (GRS) that was associated to the evening/late chronotype as well as overweight/obesity in a previous study, the chronotype-GRS, was tested for its association with chrononutrition variables. RESULTS The nutritional profile of the diet differed according to the individual's chronotype, with evening/late chronotypes exhibiting an unbalanced intake during breakfast and dinner compared to the intermediate and early chronotypes (e.g., percentage of fats consumed at breakfast relative to the total fat intake: 13 % and 9 %, respectively). However, significant differences were not encountered by the chronotype-GRS. In multivariate analyses, individual associations between the genetic variants and the nutrients revealed some nominal associations (e.g., rs1801260 and rs2070062 with carbohydrates at breakfast: β = -0.06 to 0.08). Higher scorings of the chronotype-GRS were inversely associated with the intake of proteins and carbohydrates (β = -0.46 and -0.41; nominal p-value<0.006; corrected = 0.25) during breakfast. Also, there was an inverse association between the chronotype-GRS and the breakfast's portion size (β = -0.3; nominal p-value = 0.03; corrected = 0.1). CONCLUSIONS Genetic susceptibility to an evening-like chronotype prone to overweight/obesity seems to be associated with a smaller serving size during breakfast, with lower protein and carbohydrate content.
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Affiliation(s)
- Esther Molina-Montes
- Department of Nutrition and Food Science, University of Granada, Granada, Spain; Institute of Nutrition and Food Technology (INYTA) 'José Mataix', Biomedical Research Centre, University of Granada, Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain; CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Miguel Rodríguez-Barranco
- Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain; CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain; Andalusian School of Public Health (EASP), Granada, Spain
| | - Ángela Alcalá-Santiago
- Department of Nutrition and Food Science, University of Granada, Granada, Spain; Institute of Nutrition and Food Technology (INYTA) 'José Mataix', Biomedical Research Centre, University of Granada, Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain.
| | - José María Gálvez-Navas
- Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain; CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain; Andalusian School of Public Health (EASP), Granada, Spain
| | - José María Huerta
- CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain; Department of Epidemiology, Murcia Regional Health Council-IMIB, Murcia, Spain
| | - Pilar Amiano
- CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain; Ministry of Health of the Basque Government, Sub Directorate for Public Health and Addictions of Gipuzkoa, San Sebastian, Spain; Biodonostia Health Research Institute, Epidemiology of Chronic and Communicable Diseases Group, San Sebastián, Spain
| | - Cristina Lasheras
- Functional Biology Department, School of Medicine, University of Oviedo, Asturias, Spain
| | - Conchi Moreno-Iribas
- CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain; Navarra Public Health Institute, Pamplona, Spain; Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
| | - Ana Jimenez-Zabala
- Ministry of Health of the Basque Government, Sub Directorate for Public Health and Addictions of Gipuzkoa, San Sebastian, Spain; Biodonostia Health Research Institute, Epidemiology of Chronic and Communicable Diseases Group, San Sebastián, Spain
| | - María-Dolores Chirlaque
- CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain; Department of Epidemiology, Murcia Regional Health Council-IMIB, Murcia, Spain; University of Murcia, Murcia, Spain
| | - Alba Gasque
- Navarra Public Health Institute, Pamplona, Spain
| | - Leila Luján-Barroso
- Unit of Nutrition and Cancer, Catalan Institute of Oncology - ICO, Nutrition and Cancer Group, Epidemiology, Public Health, Cancer Prevention and Palliative Care Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet de Llobregat, Spain
| | - Antonio Agudo
- Unit of Nutrition and Cancer, Catalan Institute of Oncology - ICO, Nutrition and Cancer Group, Epidemiology, Public Health, Cancer Prevention and Palliative Care Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet de Llobregat, Spain
| | - Paula Jakszyn
- Unit of Nutrition and Cancer, Catalan Institute of Oncology - ICO, Nutrition and Cancer Group, Epidemiology, Public Health, Cancer Prevention and Palliative Care Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet de Llobregat, Spain; Blanquerna Health Sciences Faculty, Ramon Llull University, 08022 Barcelona, Spain
| | | | - María José Sánchez
- Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain; CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain; Andalusian School of Public Health (EASP), Granada, Spain
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Lin L, Huang Y, Li A, Cai Y, Yan Y, Huang Y, He L, Chen Y, Wang S. Circadian clock controlled glycolipid metabolism and its relevance to disease management. Biochem Pharmacol 2025; 238:116967. [PMID: 40312018 DOI: 10.1016/j.bcp.2025.116967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 04/14/2025] [Accepted: 04/29/2025] [Indexed: 05/03/2025]
Abstract
The circadian clock is a critical regulator of physiological rhythms, orchestrating metabolic processes to adapt to daily environmental changes. This review focuses on the intricate relationship between circadian regulation and glycolipid metabolism, with implications for metabolic diseases. Central and peripheral clocks coordinate the rhythmic expression of key enzymes and transporters, ensuring glycolipid homeostasis. Disruptions to these rhythms can result in metabolic disorders characterized by altered glucose utilization, insulin sensitivity, and lipid storage. The molecular mechanisms underlying these processes include transcriptional-translational feedback loops involving clock factors that regulate glycolipid metabolism. Emerging therapeutic strategies, such as pharmacological and dietary interventions, highlight the translational potential of circadian biology. This review underscores the importance of circadian rhythm maintenance for glycolipid metabolism and its role in preventing metabolic disorders. Further elucidation of the molecular mechanisms linking circadian regulation to glycolipid metabolism could pave the way for precision medicine approaches tailored to individual circadian profiles.
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Affiliation(s)
- Luomin Lin
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China; Chinese Medicine Guangdong Laboratory, Hengqin, China
| | - Yuwei Huang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Aijing Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research and Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou, China
| | - Yuting Cai
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ying Yan
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuanqi Huang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Liangliang He
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research and Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou, China.
| | - Yijun Chen
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China; Chinese Medicine Guangdong Laboratory, Hengqin, China.
| | - Shuai Wang
- Chinese Medicine Guangdong Laboratory, Hengqin, China.
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3
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Fiorin FDS, Godinho DB, Dos Santos EB, Aguiar AS, Schuch FB, de Mello MT, Radak Z, Fighera MR, Royes LFF. Relationship among depression, fatigue, and sleep after traumatic brain injury: The role of physical exercise as a non-pharmacological therapy. Exp Neurol 2025; 386:115156. [PMID: 39864790 DOI: 10.1016/j.expneurol.2025.115156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/15/2025] [Accepted: 01/21/2025] [Indexed: 01/28/2025]
Abstract
Traumatic brain injury (TBI) is a burdensome condition frequently associated with an increased risk of psychiatric disorders. Although the exact molecular signaling pathways have not yet been fully defined, the compromised integrity of functional brain networks in regions such as the prefrontal cortex and anterior cingulate cortex has been linked to persistent symptoms, including depression, fatigue, and sleep disorders. Understanding how TBI affects neural physiology enables the development of effective interventions. One such strategy may be physical exercise, which promotes neural repair and behavioral rehabilitation after TBI. However, there are caveats to consider when interpreting the effects of physical exercise on TBI-induced mental health issues. This review will highlight the main findings from the literature investigating how different physical exercise protocols affect the progression of TBI-induced depression, fatigue, and sleep disturbances. Furthermore, we aim to explore potential neurobiological pathways that explain how physical exercise influences depression, fatigue, and sleep following TBI.
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Affiliation(s)
- Fernando da Silva Fiorin
- Exercise Biochemistry Laboratory, Center of Physical Education and Sports, Federal University of Santa Maria, Santa Maria, Brazil
| | - Douglas Buchmann Godinho
- Exercise Biochemistry Laboratory, Center of Physical Education and Sports, Federal University of Santa Maria, Santa Maria, Brazil
| | | | - Aderbal S Aguiar
- Biology of Exercise Laboratory, Department of Health Sciences, Federal University of Santa Catarina, Araranguá, Brazil
| | - Felipe Barreto Schuch
- Department of Sports Methods and Techniques, Federal University of Santa Maria, Santa Maria, Brazil; Faculty of Health Sciences, Universidad Autónoma de Chile, Providencia, Chile; Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marco Túlio de Mello
- Sports Training Centre, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Zsolt Radak
- Research Institute of Sport Science, University of Physical Education, Budapest, Hungary
| | - Michele Rechia Fighera
- Exercise Biochemistry Laboratory, Center of Physical Education and Sports, Federal University of Santa Maria, Santa Maria, Brazil
| | - Luiz Fernando Freire Royes
- Exercise Biochemistry Laboratory, Center of Physical Education and Sports, Federal University of Santa Maria, Santa Maria, Brazil; Department of Sports Methods and Techniques, Federal University of Santa Maria, Santa Maria, Brazil.
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Hunter AL, Bechtold DA. The metabolic significance of peripheral tissue clocks. Commun Biol 2025; 8:497. [PMID: 40140664 PMCID: PMC11947457 DOI: 10.1038/s42003-025-07932-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 03/12/2025] [Indexed: 03/28/2025] Open
Abstract
The circadian clock is a transcriptional-translational feedback loop which oscillates in virtually all nucleated cells of the body. In the decades since its discovery, it has become evident that the molecular clockwork is inextricably linked to energy metabolism. Given the frequency with which metabolic dysfunction and clock disruption co-occur, understanding why and how clock and metabolic processes are reciprocally coupled will have important implications for supporting human health and wellbeing. Here, we discuss the relevance of molecular clock function in metabolic tissues and explore its role not only as a driver of day-night variation in gene expression, but as a key mechanism for maintaining metabolic homeostasis in the face of fluctuating energy supply and demand.
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Affiliation(s)
- A Louise Hunter
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK.
- Diabetes, Endocrinology & Metabolism Centre, Oxford Road Campus, Manchester University NHS Foundation Trust, Manchester, M13 9WL, UK.
| | - David A Bechtold
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK.
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Chen Y, Hosono T, Ono M, Daikoku T, Toyoda N, Nomura S, Kagami K, Orisaka S, Horike SI, Shi Y, Xu P, Morishige JI, Fujiwara T, Fujiwara H, Ando H. Comparison of the Effects of Inappropriate Meal Timing-Induced and Genetic Models of Circadian Clock Disruption on Uterine mRNA Expression Profiles. J Nutr 2024; 154:3718-3725. [PMID: 39395574 DOI: 10.1016/j.tjnut.2024.10.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 09/05/2024] [Accepted: 10/04/2024] [Indexed: 10/14/2024] Open
Abstract
BACKGROUND Accumulating evidence reveals that inappropriate meal timing contributes to the development of lifestyle-related diseases. An underlying mechanism is thought to be the disruption of the intracellular circadian clock in various tissues based on observations in both systemic and tissue-specific clock gene-deficient mice. However, whether the effects of conditional clock gene knockout are comparable to those of inappropriate meal timing remains unclear. OBJECTIVES This study aimed to compare the effects of a recently developed 28-h feeding cycle model with those of a core clock gene Bmal1 uterine conditional knockout (Bmal1 cKO) model on uterine mRNA expression profiles. METHODS The models were generated by subjecting C57BL/6J mice to an 8-h/20-h feeding/fasting cycle for 2 wk and crossing Bmal1-floxed mice with PR-Cre mice. Microarray analyses were conducted using uterine samples obtained at the beginning of the dark and light periods. RESULTS The analyses identified 516 and 346, significantly 4-fold and 2-fold, up- or downregulated genes in the 28-h feeding cycle and Bmal1 cKO groups, respectively, compared with each control group. Among these genes, only 7 (1.4%) and 63 (18.2%) were significantly up- or downregulated in the other model. Moreover, most (n = 44, 62.9%) of these genes were oppositely regulated. These findings were confirmed by gene set enrichment analyses. CONCLUSIONS This study reveals that a 28-h feeding cycle and Bmal1 cKO differently affect gene expression profiles and highlights the need for considering this difference to assess the pathophysiology of diseases associated with inappropriate meal timing.
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Affiliation(s)
- Yuchen Chen
- Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Takashi Hosono
- Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Masanori Ono
- Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo, Japan
| | - Takiko Daikoku
- Division of Animal Disease Model, Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Japan
| | - Natsumi Toyoda
- Division of Animal Disease Model, Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Japan
| | - Satoshi Nomura
- Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Kyosuke Kagami
- Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Shunsuke Orisaka
- Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Shin-Ichi Horike
- Division of Integrated Omics Research, Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Japan
| | - Yifan Shi
- Department of Cellular and Molecular Function Analysis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Pingping Xu
- Department of Cellular and Molecular Function Analysis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Jun-Ichi Morishige
- Department of Cellular and Molecular Function Analysis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Tomoko Fujiwara
- Department of Human Life Environments, Kyoto Notre Dame University, Kyoto, Japan
| | - Hiroshi Fujiwara
- Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan; Ochi Yume Clinic Nagoya, Nagoya, Japan.
| | - Hitoshi Ando
- Department of Cellular and Molecular Function Analysis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
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Fatima G, Parvez S, Tuomainen P, Fedacko J, Kazmi DH, Elkilany GEN. Amalgamation of Circadian Clock Gene with Incidence of Myocardial Infarction. INDIAN JOURNAL OF CARDIOVASCULAR DISEASE IN WOMEN 2024; 9:155-161. [DOI: 10.25259/ijcdw_69_2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Objectives:
The present study included 40 participants to investigate the association of circadian locomotor output cycles kaput (CLOCK) rs4580704 polymorphism with myocardial infarction (MI) cases.
Materials and Methods:
In this study, we enrolled 20 male and 20 female cases with MI. Genomic DNA extraction was done from lymphocytes using conventional techniques, employing the QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany) from lymphocytes. Genotyping was conducted through TaqMan single-nucleotide polymorphism genotyping assays, employing real-time polymerase chain reaction (PCR) on a 7500 Real-Time PCR System (Applied Biosystems, Foster City, CA, USA). This streamlined approach ensures accurate and efficient analysis of genetic markers associated with MI across gender groups.
Results:
The study revealed significant associations between body mass index (BMI), hypertension, obesity, current smoking, and type 2 diabetes among both male and female MI patients. However, age, systolic blood pressure (SBP), and diastolic blood pressure (DBP) did not exhibit significant differences between genders. Analysis of CLOCK rs4580704 polymorphism indicated no variance in genotype and allele frequencies between male and female MI patients. When considering both genders, CLOCK rs4580704 polymorphism was significantly associated with BMI, hypertension, obesity, current smoking, and type 2 diabetes (P = 0.02, P = 0.02, P = 0.04, and P = 0.02, respectively). Nevertheless, logistic regression analysis showed no significant differences among MI cases across the various models of CLOCK rs4580704 polymorphism.
Conclusion:
No significant association was found between CLOCK rs4580704 polymorphism and MI in both genders. However, significant links were identified between this polymorphism and various cardiovascular risk factors including BMI, SBP, DBP, hypertension, obesity, current smoking, and type 2 diabetes in MI cases. These findings underscore the potential influence of CLOCK rs4580704 polymorphism on cardiovascular risk profiles among individuals with MI.
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Affiliation(s)
- Ghizal Fatima
- Department of Biotechnology, Era’s Lucknow Medical College and Hospital, Uttar Pradesh, India
| | - Sidrah Parvez
- Department of Biotechnology, Era’s Lucknow Medical College and Hospital, Uttar Pradesh, India
| | - Petri Tuomainen
- Department of Cardiology, University of Eastern Finland, Centre for Medicine and Clinical Research, Kuopio, Finland
| | - Jan Fedacko
- Department of Gerontology and Geriatric, Medipark, University Research Park, PJ Safarik University, Kosice, Slovakia
| | - Danish Hasan Kazmi
- Department of Cardiology, Medanta Heart Institute, Amar Shaheed Path, Lucknow, Uttar Pradesh, India
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Vatier C, Christin-Maitre S. Epigenetic/circadian clocks and PCOS. Hum Reprod 2024; 39:1167-1175. [PMID: 38600622 DOI: 10.1093/humrep/deae066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 03/04/2024] [Indexed: 04/12/2024] Open
Abstract
Polycystic ovary syndrome (PCOS) affects 6-20% of reproductive-aged women. It is associated with increased risks of metabolic syndrome, Type 2 diabetes, cardiovascular diseases, mood disorders, endometrial cancer and non-alcoholic fatty liver disease. Although various susceptibility loci have been identified through genetic studies, they account for ∼10% of PCOS heritability. Therefore, the etiology of PCOS remains unclear. This review explores the role of epigenetic changes and modifications in circadian clock genes as potential contributors to PCOS pathogenesis. Epigenetic alterations, such as DNA methylation, histone modifications, and non-coding RNA changes, have been described in diseases related to PCOS, such as diabetes, cardiovascular diseases, and obesity. Furthermore, several animal models have illustrated a link between prenatal exposure to androgens or anti-Müllerian hormone and PCOS-like phenotypes in subsequent generations, illustrating an epigenetic programming in PCOS. In humans, epigenetic changes have been reported in peripheral blood mononuclear cells (PBMC), adipose tissue, granulosa cells (GC), and liver from women with PCOS. The genome of women with PCOS is globally hypomethylated compared to healthy controls. However, specific hypomethylated or hypermethylated genes have been reported in the different tissues of these women. They are mainly involved in hormonal regulation and inflammatory pathways, as well as lipid and glucose metabolism. Additionally, sleep disorders are present in women with PCOS and disruptions in clock genes' expression patterns have been observed in their PBMC or GCs. While epigenetic changes hold promise as diagnostic biomarkers, the current challenge lies in distinguishing whether these changes are causes or consequences of PCOS. Targeting epigenetic modifications potentially opens avenues for precision medicine in PCOS, including lifestyle interventions and drug therapies. However, data are still lacking in large cohorts of well-characterized PCOS phenotypes. In conclusion, understanding the interplay between genetics, epigenetics, and circadian rhythms may provide valuable insights for early diagnosis and therapeutic strategies in PCOS in the future.
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Affiliation(s)
- Camille Vatier
- Department of Endocrine and Reproductive Medicine, Center of Endocrine Rare Diseases of Growth and Development (CRESCENDO), FIRENDO, Endo-ERN, Hôpital Saint-Antoine, Assistance-Publique-Hôpitaux de Paris, Sorbonne University, Paris, France
- Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 938, Centre de Recherche Saint-Antoine et Institut de Cardio-Métabolisme et Nutrition (ICAN), Paris, France
| | - Sophie Christin-Maitre
- Department of Endocrine and Reproductive Medicine, Center of Endocrine Rare Diseases of Growth and Development (CRESCENDO), FIRENDO, Endo-ERN, Hôpital Saint-Antoine, Assistance-Publique-Hôpitaux de Paris, Sorbonne University, Paris, France
- INSERM UMR U933, Paris, France
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Franzago M, Borrelli P, Cavallo P, Di Tizio L, Gazzolo D, Di Nicola M, Stuppia L, Vitacolonna E. Circadian Gene Variants: Effects in Overweight and Obese Pregnant Women. Int J Mol Sci 2024; 25:3838. [PMID: 38612648 PMCID: PMC11011577 DOI: 10.3390/ijms25073838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 03/19/2024] [Accepted: 03/26/2024] [Indexed: 04/14/2024] Open
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.
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Affiliation(s)
- Marica Franzago
- Department of Medicine and Aging, School of Medicine, and Health Sciences, “G. D’Annunzio” University, Via dei Vestini, Chieti-Pescara, 66100 Chieti, Italy; (M.F.); (P.C.); (D.G.)
- Center for Advanced Studies and Technology (CAST), “G. D’Annunzio” University, Chieti-Pescara, 66100 Chieti, Italy;
| | - Paola Borrelli
- Laboratory of Biostatistics, Department of Medical, Oral and Biotechnological Sciences, “G. D’Annunzio” University, Chieti-Pescara, 66100 Chieti, Italy; (P.B.); (M.D.N.)
| | - Pierluigi Cavallo
- Department of Medicine and Aging, School of Medicine, and Health Sciences, “G. D’Annunzio” University, Via dei Vestini, Chieti-Pescara, 66100 Chieti, Italy; (M.F.); (P.C.); (D.G.)
| | - Luciano Di Tizio
- Department of Obstetrics and Gynaecology, SS. Annunziata Hospital, “G. D’Annunzio” University, 66100 Chieti, Italy;
| | - Diego Gazzolo
- Department of Medicine and Aging, School of Medicine, and Health Sciences, “G. D’Annunzio” University, Via dei Vestini, Chieti-Pescara, 66100 Chieti, Italy; (M.F.); (P.C.); (D.G.)
- Neonatal Intensive Care Unit, “G. D’Annunzio” University, 66100 Chieti, Italy
| | - Marta Di Nicola
- Laboratory of Biostatistics, Department of Medical, Oral and Biotechnological Sciences, “G. D’Annunzio” University, Chieti-Pescara, 66100 Chieti, Italy; (P.B.); (M.D.N.)
| | - Liborio Stuppia
- Center for Advanced Studies and Technology (CAST), “G. D’Annunzio” University, Chieti-Pescara, 66100 Chieti, Italy;
- Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, “G. D’Annunzio” University, Chieti-Pescara, 66100 Chieti, Italy
| | - Ester Vitacolonna
- Department of Medicine and Aging, School of Medicine, and Health Sciences, “G. D’Annunzio” University, Via dei Vestini, Chieti-Pescara, 66100 Chieti, Italy; (M.F.); (P.C.); (D.G.)
- Center for Advanced Studies and Technology (CAST), “G. D’Annunzio” University, Chieti-Pescara, 66100 Chieti, Italy;
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9
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Jesse TG, Becer E, Kalkan R. Identification of the Relationship Between DNA Methylation of Circadian Rhythm Genes and Obesity. Biochem Genet 2024; 62:281-293. [PMID: 37329425 DOI: 10.1007/s10528-023-10415-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 06/06/2023] [Indexed: 06/19/2023]
Abstract
In children, teenagers, and young adults, environmental factors and genetic modifications have contributed to the development of obesity. There is a close relationship between obesity and circadian rhythm. To understand the role of CLOCK and BMAL1 in obesity, we analyzed the methylation status of CLOCK and BMAL1 in obese and control subjects. In this paper, we analyzed the methylation status of the CLOCK and BMAL1 genes by using MS-HRM in a total of 55 obese and 54 control subjects. In our study, we demonstrated that the level of fasting glucose and the level of HDL-cholesterol were associated with CLOCK methylation in obesity. We also showed a significant association between BMAL1 gene methylation and waist and hip circumference in obese subjects. This is the first study that shows the methylation of BMAL1 is associated with the obese phenotype. However, we could not show a direct association between CLOCK methylation and the obese phenotype. In this paper, a novel epigenetic interaction between circadian clock genes and obesity was demonstrated.
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Affiliation(s)
- Tirah Galaya Jesse
- Department of Medical Genetics, Faculty of Medicine, Near East University, Mersin 10, Nicosia, 99138, Turkey
| | - Eda Becer
- Faculty of Pharmacy, Eastern Mediterranean University, Mersin 10, Famagusta, 99628, Turkey
| | - Rasime Kalkan
- Department of Medical Genetics, Faculty of Medicine, Near East University, Mersin 10, Nicosia, 99138, Turkey.
- Department of Medical Genetics, Faculty of Medicine, Cyprus Health and Social Sciences University, Mersin 10, Guzelyurt, 99138, Turkey.
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10
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Engin A. Misalignment of Circadian Rhythms in Diet-Induced Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:27-71. [PMID: 39287848 DOI: 10.1007/978-3-031-63657-8_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
The biological clocks of the circadian timing system coordinate cellular and physiological processes and synchronize them with daily cycles. While the central clock in the suprachiasmatic nucleus (SCN) is mainly synchronized by the light/dark cycles, the peripheral clocks react to other stimuli, including the feeding/fasting state, nutrients, sleep-wake cycles, and physical activity. During the disruption of circadian rhythms due to genetic mutations or social and occupational obligations, incorrect arrangement between the internal clock system and environmental rhythms leads to the development of obesity. Desynchronization between the central and peripheral clocks by altered timing of food intake and diet composition leads to uncoupling of the peripheral clocks from the central pacemaker and to the development of metabolic disorders. The strong coupling of the SCN to the light-dark cycle creates a situation of misalignment when food is ingested during the "wrong" time of day. Food-anticipatory activity is mediated by a self-sustained circadian timing, and its principal component is a food-entrainable oscillator. Modifying the time of feeding alone greatly affects body weight, whereas ketogenic diet (KD) influences circadian biology, through the modulation of clock gene expression. Night-eating behavior is one of the causes of circadian disruption, and night eaters have compulsive and uncontrolled eating with severe obesity. By contrast, time-restricted eating (TRE) restores circadian rhythms through maintaining an appropriate daily rhythm of the eating-fasting cycle. The hypothalamus has a crucial role in the regulation of energy balance rather than food intake. While circadian locomotor output cycles kaput (CLOCK) expression levels increase with high-fat diet-induced obesity, peroxisome proliferator-activated receptor-alpha (PPARα) increases the transcriptional level of brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1 (BMAL1) in obese subjects. In this context, effective timing of chronotherapies aiming to correct SCN-driven rhythms depends on an accurate assessment of the SCN phase. In fact, in a multi-oscillator system, local rhythmicity and its disruption reflects the disruption of either local clocks or central clocks, thus imposing rhythmicity on those local tissues, whereas misalignment of peripheral oscillators is due to exosome-based intercellular communication.Consequently, disruption of clock genes results in dyslipidemia, insulin resistance, and obesity, while light exposure during the daytime, food intake during the daytime, and sleeping during the biological night promote circadian alignment between the central and peripheral clocks. Thus, shift work is associated with an increased risk of obesity, diabetes, and cardiovascular diseases because of unusual eating times as well as unusual light exposure and disruption of the circadian rhythm.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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11
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Vales-Villamarín C, de Dios O, Mahíllo-Fernández I, Perales M, Pérez-Nadador I, Gavela-Pérez T, Soriano-Guillén L, Garcés C. Sex-dependent relationship of polymorphisms in CLOCK and REV-ERBα genes with body mass index and lipid levels in children. Sci Rep 2023; 13:22127. [PMID: 38092833 PMCID: PMC10719338 DOI: 10.1038/s41598-023-49506-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 12/08/2023] [Indexed: 12/17/2023] Open
Abstract
Circadian rhythms, which are governed by a circadian clock, regulate important biological processes associated with obesity. SNPs in circadian clock genes have been linked to energy and lipid homeostasis. The aim of our study was to evaluate the associations of CLOCK and REV-ERBα SNPs with BMI and plasma lipid levels in pre-pubertal boys and girls. The study sample population comprised 1268 children aged 6-8 years. Information regarding anthropometric parameters and plasma lipid concentrations was available. Genotyping of CLOCK SNPs rs1801260, rs4580704, rs3749474, rs3736544 and rs4864548 and REV-ERBα SNPs rs2017427, rs20711570 and rs2314339 was performed by RT-PCR. The CLOCK SNPs rs3749474 and rs4864548 were significantly associated with BMI in girls but no in boys. Female carriers of the minor alleles for these SNPs presented lower BMI compared to non-carriers. A significant association of the REV-ERBα SNP rs2071570 with plasma total cholesterol, LDL-cholesterol and Apo B in males was also observed. Male AA carriers showed lower plasma levels of total cholesterol, LDL-cholesterol and Apo B levels as compared with carriers of the C allele. No significant associations between any of the studied REV-ERBα SNPs and plasma lipid levels were observed in females. In summary, CLOCK and REV-ERBα SNPs were associated with BMI and plasma lipid levels respectively in a sex-dependent manner. Our findings suggest that sex-related factors may interact with Clock genes SNPs conditioning the effects of these polymorphisms on circadian alterations.
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Affiliation(s)
| | - Olaya de Dios
- Lipid Research Laboratory, IIS-Fundación Jiménez Díaz, 28040, Madrid, Spain
| | | | - Macarena Perales
- Lipid Research Laboratory, IIS-Fundación Jiménez Díaz, 28040, Madrid, Spain
| | - Iris Pérez-Nadador
- Lipid Research Laboratory, IIS-Fundación Jiménez Díaz, 28040, Madrid, Spain
| | | | | | - Carmen Garcés
- Lipid Research Laboratory, IIS-Fundación Jiménez Díaz, 28040, Madrid, Spain.
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12
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Franzago M, Borrelli P, Di Nicola M, Stuppia L, Vitacolonna E. Genetic Variants in CD36 Involved in Fat Taste Perception: Association with Anthropometric and Clinical Parameters in Overweight and Obese Subjects Affected by Type 2 Diabetes or Dysglycemia-A Pilot Study. Nutrients 2023; 15:4656. [PMID: 37960309 PMCID: PMC10647499 DOI: 10.3390/nu15214656] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 10/24/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
Obesity and overweight represent a growing health problem worldwide. Genes regulating the intake and metabolism of different nutrients can positively or negatively influence the efficacy of nutritional interventions against obesity and its complications. The aim of this study was to assess changes in anthropometric and clinical parameters and the adherence to a Mediterranean diet (MedDiet) over time in relation to nutrigenetic variants in overweight or obese subjects affected by Type 2 Diabetes (T2D) or dysglycemia, who were included in a nutritional program. A total of 23 subjects were included in this study. Clinical parameters, physical activity levels, and the adherence to a MedDiet were evaluated at baseline, at 6 (T6), and at 12 months (T12) during and after a diet/lifestyle intervention. In a single blood sample from each subject, rs1984112 (A>G) and rs1761667 (G>A) in CD36; rs7950226 (G>A) in BMAL1; and rs1801260 (A>G), rs4864548 (A>G), and rs3736544 (G>A) in CLOCK were genotyped with Real-Time PCR. Significant associations were observed between CD36 rs1761667 and weight (p = 0.025), hip circumference (p = 0.042), triglycerides (p = 0.047), and HbA1c (p = 0.012) at baseline. Moreover, the genotype AA in CD36 rs1761667 was significantly associated with a lower BMI when compared to G carriers at baseline, at T6, and also at T12. In addition, subjects with the AA genotype at CD36 rs1984112 had significantly lower levels of HbA1c (p = 0.027) than the GG and AG genotypes at baseline. These results show that variants in CD36 can have an impact on anthropometric and clinical parameters in overweight or obese subjects affected by T2D or dysglycemia, and that it might influence the success of the diet/lifestyle intervention.
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Affiliation(s)
- Marica Franzago
- Department of Medicine and Aging, School of Medicine and Health Sciences, “G. D’Annunzio” University, Via dei Vestini, Chieti-Pescara, 66100 Chieti, Italy;
- Center for Advanced Studies and Technology (CAST), “G. D’Annunzio” University, Chieti-Pescara, 66100 Chieti, Italy;
| | - Paola Borrelli
- Laboratory of Biostatistics, Department of Medical, Oral and Biotechnological Sciences, “G. D’Annunzio” University, Chieti-Pescara, 66100 Chieti, Italy; (P.B.); (M.D.N.)
| | - Marta Di Nicola
- Laboratory of Biostatistics, Department of Medical, Oral and Biotechnological Sciences, “G. D’Annunzio” University, Chieti-Pescara, 66100 Chieti, Italy; (P.B.); (M.D.N.)
| | - Liborio Stuppia
- Center for Advanced Studies and Technology (CAST), “G. D’Annunzio” University, Chieti-Pescara, 66100 Chieti, Italy;
- Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, “G. D’Annunzio” University, Chieti-Pescara, 66100 Chieti, Italy
| | - Ester Vitacolonna
- Department of Medicine and Aging, School of Medicine and Health Sciences, “G. D’Annunzio” University, Via dei Vestini, Chieti-Pescara, 66100 Chieti, Italy;
- Center for Advanced Studies and Technology (CAST), “G. D’Annunzio” University, Chieti-Pescara, 66100 Chieti, Italy;
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13
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Bolshette N, Ibrahim H, Reinke H, Asher G. Circadian regulation of liver function: from molecular mechanisms to disease pathophysiology. Nat Rev Gastroenterol Hepatol 2023; 20:695-707. [PMID: 37291279 DOI: 10.1038/s41575-023-00792-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/27/2023] [Indexed: 06/10/2023]
Abstract
A wide variety of liver functions are regulated daily by the liver circadian clock and via systemic circadian control by other organs and cells within the gastrointestinal tract as well as the microbiome and immune cells. Disruption of the circadian system, as occurs during jetlag, shift work or an unhealthy lifestyle, is implicated in several liver-related pathologies, ranging from metabolic diseases such as obesity, type 2 diabetes mellitus and nonalcoholic fatty liver disease to liver malignancies such as hepatocellular carcinoma. In this Review, we cover the molecular, cellular and organismal aspects of various liver pathologies from a circadian viewpoint, and in particular how circadian dysregulation has a role in the development and progression of these diseases. Finally, we discuss therapeutic and lifestyle interventions that carry health benefits through support of a functional circadian clock that acts in synchrony with the environment.
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Affiliation(s)
- Nityanand Bolshette
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Hussam Ibrahim
- University of Düsseldorf, Medical Faculty, Institute of Clinical Chemistry and Laboratory Diagnostics, Düsseldorf, Germany
| | - Hans Reinke
- University of Düsseldorf, Medical Faculty, Institute of Clinical Chemistry and Laboratory Diagnostics, Düsseldorf, Germany.
| | - Gad Asher
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
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14
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Gršković P, Korać P. Circadian Gene Variants in Diseases. Genes (Basel) 2023; 14:1703. [PMID: 37761843 PMCID: PMC10531145 DOI: 10.3390/genes14091703] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 08/19/2023] [Accepted: 08/25/2023] [Indexed: 09/29/2023] Open
Abstract
The circadian rhythm is a self-sustaining 24 h cycle that regulates physiological processes within the body, including cycles of alertness and sleepiness. Cells have their own intrinsic clock, which consists of several proteins that regulate the circadian rhythm of each individual cell. The core of the molecular clock in human cells consists of four main circadian proteins that work in pairs. The CLOCK-BMAL1 heterodimer and the PER-CRY heterodimer each regulate the other pair's expression, forming a negative feedback loop. Several other proteins are involved in regulating the expression of the main circadian genes, and can therefore also influence the circadian rhythm of cells. This review focuses on the existing knowledge regarding circadian gene variants in both the main and secondary circadian genes, and their association with various diseases, such as tumors, metabolic diseases, cardiovascular diseases, and sleep disorders.
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Affiliation(s)
| | - Petra Korać
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10 000 Zagreb, Croatia;
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15
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Malik MZ, Dashti M, Fatima Y, Channanath A, John SE, Singh RKB, Al-Mulla F, Thanaraj TA. Disruption in the regulation of casein kinase 2 in circadian rhythm leads to pathological states: cancer, diabetes and neurodegenerative disorders. Front Mol Neurosci 2023; 16:1217992. [PMID: 37475884 PMCID: PMC10354274 DOI: 10.3389/fnmol.2023.1217992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 06/12/2023] [Indexed: 07/22/2023] Open
Abstract
Introduction Circadian rhythm maintains the sleep-wake cycle in biological systems. Various biological activities are regulated and modulated by the circadian rhythm, disruption of which can result in onset of diseases. Robust rhythms of phosphorylation profiles and abundances of PERIOD (PER) proteins are thought to be the master keys that drive circadian clock functions. The role of casein kinase 2 (CK2) in circadian rhythm via its direct interactions with the PER protein has been extensively studied; however, the exact mechanism by which it affects circadian rhythms at the molecular level is not known. Methods Here, we propose an extended circadian rhythm model in Drosophila that incorporates the crosstalk between the PER protein and CK2. We studied the regulatory role of CK2 in the dynamics of PER proteins involved in circadian rhythm using the stochastic simulation algorithm. Results We observed that variations in the concentration of CK2 in the circadian rhythm model modulates the PER protein dynamics at different cellular states, namely, active, weakly active, and rhythmic death. These oscillatory states may correspond to distinct pathological cellular states of the living system. We find molecular noise at the expression level of CK2 to switch normal circadian rhythm to any of the three above-mentioned circadian oscillatory states. Our results suggest that the concentration levels of CK2 in the system has a strong impact on its dynamics, which is reflected in the time evolution of PER protein. Discussion We believe that our findings can contribute towards understanding the molecular mechanisms of circadian dysregulation in pathways driven by the PER mutant genes and their pathological states, including cancer, obesity, diabetes, neurodegenerative disorders, and socio-psychological disease.
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Affiliation(s)
- Md. Zubbair Malik
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Mohammed Dashti
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Yasmin Fatima
- Department of Computational Biology and Bioinformatics, Sam Higginbottom Institute of Agriculture, Technology and Sciences (Formerly Allahabad Agricultural Institute-Deemed University), Allahabad, India
| | - Arshad Channanath
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Sumi Elsa John
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - R. K. Brojen Singh
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Fahd Al-Mulla
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait
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16
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Hariri A, Mirian M, Zarrabi A, Kohandel M, Amini-Pozveh M, Aref AR, Tabatabaee A, Prabhakar PK, Sivakumar PM. The circadian rhythm: an influential soundtrack in the diabetes story. Front Endocrinol (Lausanne) 2023; 14:1156757. [PMID: 37441501 PMCID: PMC10333930 DOI: 10.3389/fendo.2023.1156757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 05/03/2023] [Indexed: 07/15/2023] Open
Abstract
Type 2 Diabetes Mellitus (T2DM) has been the main category of metabolic diseases in recent years due to changes in lifestyle and environmental conditions such as diet and physical activity. On the other hand, the circadian rhythm is one of the most significant biological pathways in humans and other mammals, which is affected by light, sleep, and human activity. However, this cycle is controlled via complicated cellular pathways with feedback loops. It is widely known that changes in the circadian rhythm can alter some metabolic pathways of body cells and could affect the treatment process, particularly for metabolic diseases like T2DM. The aim of this study is to explore the importance of the circadian rhythm in the occurrence of T2DM via reviewing the metabolic pathways involved, their relationship with the circadian rhythm from two perspectives, lifestyle and molecular pathways, and their effect on T2DM pathophysiology. These impacts have been demonstrated in a variety of studies and led to the development of approaches such as time-restricted feeding, chronotherapy (time-specific therapies), and circadian molecule stabilizers.
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Affiliation(s)
- Amirali Hariri
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mina Mirian
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, Türkiye
| | - Mohammad Kohandel
- Department of Applied Mathematics, Faculty of Mathematics, University of Waterloo, Waterloo, ON, Canada
| | - Maryam Amini-Pozveh
- Department of Prosthodontics Dentistry, Dental Materials Research Center, Dental Research Institute, School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana Farber Cancer Institute, Boston, MA, United States
- Translational Sciences, Xsphera Biosciences Inc., Boston, MA, United States
| | - Aliye Tabatabaee
- School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Pranav Kumar Prabhakar
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Lovely Professional University, Phagwara, Punjab, India
- Division of Research and Development, Lovely Professional University, Phagwara Punjab, India
| | - Ponnurengam Malliappan Sivakumar
- Institute of Research and Development, Duy Tan University, Da Nang, Vietnam
- School of Medicine and Pharmacy, Duy Tan University, Da Nang, Vietnam
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17
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Lee S. Association between CLOCK Gene Polymorphisms and Insomnia Risk According to Food Groups: A KoGES Longitudinal Study. Nutrients 2023; 15:2300. [PMID: 37242182 PMCID: PMC10222773 DOI: 10.3390/nu15102300] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/09/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
Food intake could mitigate or exacerbate the risk for insomnia associated with the CLOCK gene. This study investigated the associations between the clock circadian regulator (CLOCK) polymorphisms rs12649507 and rs4580704 and the risk of insomnia, as well as its interactions with food groups. Among 1430 adults, new insomnia cases were identified between 2005 and 2012. Single nucleotide polymorphisms were genotyped, and dietary intake was assessed. Next, Cox proportional hazard models were established. The fruit and meat groups significantly mitigated the risk of insomnia associated with rs12649507 among males (pinteraction = 0.006 in a recessive model; p = 0.010 in a dominant model). In contrast, among females the beverage group significantly increased the risk of insomnia (p = 0.041 in a dominant model). As for rs4580704, among males the fruit and meat groups modified the risk of insomnia (p = 0.006 in a recessive model; p = 0.001 in a dominant model). However, among females, the beverage group exacerbated the risk of insomnia associated with rs4580704 (p = 0.004 in a dominant model). In this longitudinal study, we observed a significantly modified insomnia risk associated with the CLOCK gene depending on food groups. Notably, in a general population the risks were modified according to both the fruit and meat intake among 775 males but exacerbated with beverage intake among 655 females.
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Affiliation(s)
- Sunghee Lee
- Department of Food and Nutrition, College of Health Science, Kangwon National University, Samcheok 25949, Republic of Korea
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18
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Schroor MM, Plat J, Mensink RP. Relation between single nucleotide polymorphisms in circadian clock relevant genes and cholesterol metabolism. Mol Genet Metab 2023; 138:107561. [PMID: 37023502 DOI: 10.1016/j.ymgme.2023.107561] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 02/21/2023] [Accepted: 03/24/2023] [Indexed: 03/29/2023]
Abstract
Single nucleotide polymorphisms (SNPs) in circadian clock relevant genes are associated with several metabolic health variables, but little is known about their associations with human cholesterol metabolism. Therefore, this study examined associations between SNPs in ARNTL, ARNTL2, CLOCK, CRY1, CRY2, PER2, and PER3 with the intestinal cholesterol absorption markers campesterol and sitosterol, the endogenous cholesterol synthesis marker lathosterol, and total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) concentrations in 456 healthy individuals from Western European descent. One SNP in ARNTL2 (rs1037924) showed a significant association with lathosterol. Several SNPs in ARNTL (rs4146388, rs58901760, rs6486121), ARNTL2 (rs73075788), CLOCK (rs13113518, rs35115774, rs6832769), and CRY1 (rs2078074) were significantly associated with intestinal cholesterol absorption. Genetic variants in CRY2, PER2, and PER3 were not significantly associated with intestinal cholesterol absorption or endogenous cholesterol synthesis. None of the SNPs were associated with TC or LDL-C, except for one SNP in PER2 (rs11894491) with serum LDL-C concentrations. The findings suggest that various SNPs in ARNTL, ARNTL2, CLOCK and CRY1 play a role in intestinal cholesterol absorption and endogenous cholesterol synthesis, which was not reflected in TC and LDL-C concentrations. The significant associations between SNPs and intestinal cholesterol absorption and endogenous cholesterol synthesis should be validated in other cohorts.
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Affiliation(s)
- Maite M Schroor
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6200 MD Maastricht, the Netherlands.
| | - Jogchum Plat
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6200 MD Maastricht, the Netherlands
| | - Ronald P Mensink
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6200 MD Maastricht, the Netherlands
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19
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[Prevalence of the GA risk haplotype of the rs1554483 and rs4864548 polymorphisms of the CLOCK gene associated with obesity and overweight in 26 populations]. NUTR HOSP 2023. [PMID: 36789957 DOI: 10.20960/nh.04256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023] Open
Abstract
INTRODUCTION the GA haplotype of polymorphisms rs1554483 and rs4864548 has been associated with components of the metabolic syndrome such as high blood pressure and triglyceride levels; its carriers have a risk of obesity, 1.5 times higher than the rest of the population. METHODOLOGY SNP rs1554483 and rs4864548 were obtained from 2504 individuals from the "1000genomes phase 3" database. Data were grouped into five macro populations (Africa, East Asia, South Asia, Europe and Latin America) covering a total of 26 populations. Differences in haplotype frequency between macro populations and populations were analyzed, for which Fisher's F statistic was used. RESULTS the macro population of Africa presented the lowest frequency (17.9 %) and that of East Asia the highest (57.4 %). Within the populations there is a relative homogeneity in the frequencies, except in the case of those that make up the macro population of Latin America where the Peruvian population of Lima and the Puerto Rican population present much higher frequencies than the rest. CONCLUSIONS the GA haplotype presents heterogeneity between macro populations, which suggests highly differentiated micro evolutionary processes between continents. We propose to study the association of the GA haplotype with other polymorphisms such as rs3749474, rs11932595 and rs6859524 that have also been associated with risk of obesity and factors associated with metabolic syndrome.
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20
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Timing of Meals and Sleep in the Mediterranean Population: The Effect of Taste, Genetics, Environmental Determinants, and Interactions on Obesity Phenotypes. Nutrients 2023; 15:nu15030708. [PMID: 36771415 PMCID: PMC9921798 DOI: 10.3390/nu15030708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/20/2023] [Accepted: 01/26/2023] [Indexed: 01/31/2023] Open
Abstract
Circadian rhythms regulate the sleep-wake and feeding-fasting cycles. Sleep and feeding constitute a complex cycle that is determined by several factors. Despite the importance of sleep duration and mealtimes for many obesity phenotypes, most studies on dietary patterns have not investigated the contribution of these variables to the phenotypes analyzed. Likewise, they have not investigated the factors related to sleep or mealtimes. Thus, our aims were to investigate the link between taste perception and eating/sleep patterns and to analyze the effect of the interactions between sleep/meal patterns and genetic factors on obesity phenotypes. We conducted a cross-sectional analysis on 412 adults from the Mediterranean population. We measured taste perception (bitter, sweet, salty, sour, and umami) and assessed sleep duration and waketime. The midpoint of sleep and social jetlag was computed. From the self-reported timing of meals, we estimated the eating window, eating midpoint, and eating jetlag. Adherence to the Mediterranean diet was measured with a validated score. Selected polymorphisms in the TAS2R38, CLOCK, and FTO genes were determined, and their associations and interactions with relevant phenotypes were analyzed. We found various associations between temporal eating, sleep patterns, and taste perception. A higher bitter taste perception was associated with an earlier eating midpoint (p = 0.001), breakfast time (p = 0.043), dinner time (p = 0.009), waketime (p < 0.001), and midpoint of sleep (p = 0.009). Similar results were observed for the bitter taste polymorphism TAS2R38-rs713598, a genetic instrumental variable for bitter perception, increasing the causality of the associations. Moreover, significant gene-sleep interactions were detected between the midpoint of sleep and the TAS2R38-rs713598 (p = 0.032), FTO-rs9939609 (p = 0.037), and CLOCK-rs4580704 (p = 0.004) polymorphisms which played a role in determining obesity phenotypes. In conclusion, our study provided more information on the sleep and mealtime patterns of the general Spanish Mediterranean population than on their main relationships. Moreover, we were able to show significant associations between taste perception, specifically bitter taste; sleep time; and mealtimes as well as an interaction between sleep time and several genetic variants linked to obesity phenotypes. However, additional research is needed to better characterize the causality and mechanisms behind these associations.
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Chrono-Nutrition: Circadian Rhythm and Personalized Nutrition. Int J Mol Sci 2023; 24:ijms24032571. [PMID: 36768893 PMCID: PMC9916946 DOI: 10.3390/ijms24032571] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
The human circadian system has a period of approximately 24 h and studies on the consequences of "chornodisruption" have greatly expanded. Lifestyle and environmental factors of modern societies (i.e., artificial lighting, jetlag, shift work, and around-the-clock access to energy-dense food) can induce disruptions of the circadian system and thereby adversely affect individual health. Growing evidence demonstrates a complex reciprocal relationship between metabolism and the circadian system, in which perturbations in one system affect the other one. From a nutritional genomics perspective, genetic variants in clock genes can both influence metabolic health and modify the individual response to diet. Moreover, an interplay between the circadian rhythm, gut microbiome, and epigenome has been demonstrated, with the diet in turn able to modulate this complex link suggesting a remarkable plasticity of the underlying mechanisms. In this view, the study of the impact of the timing of eating by matching elements from nutritional research with chrono-biology, that is, chrono-nutrition, could have significant implications for personalized nutrition in terms of reducing the prevalence and burden of chronic diseases. This review provides an overview of the current evidence on the interactions between the circadian system and nutrition, highlighting how this link could in turn influence the epigenome and microbiome. In addition, possible nutritional strategies to manage circadian-aligned feeding are suggested.
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Obstructive Sleep Apnea, Circadian Clock Disruption, and Metabolic Consequences. Metabolites 2022; 13:metabo13010060. [PMID: 36676985 PMCID: PMC9863434 DOI: 10.3390/metabo13010060] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 12/26/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
Obstructive sleep apnea (OSA) is a chronic disorder characterized by recurrent episodes of apnea and hypopnea during sleep. It is associated with various cardiovascular and metabolic complications, including type 2 diabetes mellitus (T2DM) and obesity. Many pathways can be responsible for T2DM development in OSA patients, e.g., those related to HIF-1 and SIRT1 expression. Moreover, epigenetic mechanisms, such as miRNA181a or miRNA199, are postulated to play a pivotal role in this link. It has been proven that OSA increases the occurrence of circadian clock disruption, which is also a risk factor for metabolic disease development. Circadian clock disruption impairs the metabolism of glucose, lipids, and the secretion of bile acids. Therefore, OSA-induced circadian clock disruption may be a potential, complex, underlying pathway involved in developing and exacerbating metabolic diseases among OSA patients. The current paper summarizes the available information pertaining to the relationship between OSA and circadian clock disruption in the context of potential mechanisms leading to metabolic disorders.
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Chrononutrition-When We Eat Is of the Essence in Tackling Obesity. Nutrients 2022; 14:nu14235080. [PMID: 36501110 PMCID: PMC9739590 DOI: 10.3390/nu14235080] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/24/2022] [Accepted: 11/25/2022] [Indexed: 12/03/2022] Open
Abstract
Obesity is a chronic and relapsing public health problem with an extensive list of associated comorbidities. The worldwide prevalence of obesity has nearly tripled over the last five decades and continues to pose a serious threat to wider society and the wellbeing of future generations. The pathogenesis of obesity is complex but diet plays a key role in the onset and progression of the disease. The human diet has changed drastically across the globe, with an estimate that approximately 72% of the calories consumed today come from foods that were not part of our ancestral diets and are not compatible with our metabolism. Additionally, multiple nutrient-independent factors, e.g., cost, accessibility, behaviours, culture, education, work commitments, knowledge and societal set-up, influence our food choices and eating patterns. Much research has been focused on 'what to eat' or 'how much to eat' to reduce the obesity burden, but increasingly evidence indicates that 'when to eat' is fundamental to human metabolism. Aligning feeding patterns to the 24-h circadian clock that regulates a wide range of physiological and behavioural processes has multiple health-promoting effects with anti-obesity being a major part. This article explores the current understanding of the interactions between the body clocks, bioactive dietary components and the less appreciated role of meal timings in energy homeostasis and obesity.
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Molina-Giraldo P, Murillo S, Meis L, Sans O, Amat-Bou M, Llobet M, Jimenez-Chillaron JC, Ramon-Krauel M, Lerin C. A time-restricted feeding intervention in children and adolescents with obesity: The TRansForm study protocol. Front Nutr 2022; 9:1026694. [DOI: 10.3389/fnut.2022.1026694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 10/04/2022] [Indexed: 11/17/2022] Open
Abstract
Obesity during childhood is of special concern as adiposity is typically tracked into adult life and it constitutes a major risk factor for future obesity and associated metabolic disorders. Recent studies indicate that time-restricted feeding (TRF) interventions may provide a promising strategy for obesity treatment. However, TRF interventions have only been tested in adult subjects. This study aims to determine both short- and long-term effects of a TRF intervention in children and adolescents with obesity. We will also investigate potential mechanisms mediating the response to the intervention, including the circadian rhythm and the gut microbiota composition. We have designed a randomized-controlled parallel-group clinical study in which children and adolescents (age range 8–18 year-old) with obesity will be subjected to time-restricted eating or no time restrictions for 2 months. Follow-up visits will allow for long-term effect assessments. We will measure anthropometric (BMI, body composition) and metabolic parameters (glucose and lipid metabolism), indicators of the circadian rhythm, and gut microbiota composition will be analyzed. This study will (1) determine safety and effectiveness of the TRF intervention in children and adolescents; (2) assess its long-term effects; and (3) evaluate potential mechanisms involved in the response to the intervention.Clinical trial registration[www.ClinicalTrials.gov], identifier [NCT05174871].
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Wang X, Rao J, Tan Z, Xun T, Zhao J, Yang X. Inflammatory signaling on cytochrome P450-mediated drug metabolism in hepatocytes. Front Pharmacol 2022; 13:1043836. [PMID: 36353494 PMCID: PMC9637984 DOI: 10.3389/fphar.2022.1043836] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 10/11/2022] [Indexed: 12/11/2023] Open
Abstract
Cytochrome P450 (CYP450) enzymes are membrane-bound blood proteins that are vital to drug detoxification, cell metabolism, and homeostasis. CYP450s belonging to CYP families 1-3 are responsible for nearly 80% of oxidative metabolism and complete elimination of approximately 50% of all common clinical drugs in humans liver hepatocytes. CYP450s can affect the body's response to drugs by altering the reaction, safety, bioavailability, and toxicity. They can also regulate metabolic organs and the body's local action sites to produce drug resistance through altered drug metabolism. Genetic polymorphisms in the CYP gene alone do not explain ethnic and individual differences in drug efficacy in the context of complex diseases. The purpose of this review is to summarize the impact of new inflammatory-response signaling pathways on the activity and expression of CYP drug-metabolizing enzymes. Included is a summary of recent studies that have identified drugs with the potential to regulate drug-metabolizing enzyme activity. Our goal is to inspire the development of clinical drug treatment processes that consider the impact of the inflammatory environment on drug treatment, as well as provide research targets for those studying drug metabolism.
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Affiliation(s)
- Xiaokang Wang
- Department of Pharmacy, Shenzhen Longhua District Central Hospital, Shenzhen, China
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Jiaoyu Rao
- Department of Pharmacy, Shenzhen Longhua District Central Hospital, Shenzhen, China
| | - Zhiyi Tan
- Guangzhou Customs Technology Center, Guangzhou, China
| | - Tianrong Xun
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Jingqian Zhao
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Xixiao Yang
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
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Monjes NM, Wagner PM, Guido ME. “Disruption of the molecular clock severely affects lipid metabolism in a Hepatocellular Carcinoma Cell model”. J Biol Chem 2022; 298:102551. [DOI: 10.1016/j.jbc.2022.102551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 09/23/2022] [Accepted: 09/25/2022] [Indexed: 11/26/2022] Open
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Influence of CLOCK Gene Variants on Weight Response after Bariatric Surgery. Nutrients 2022; 14:nu14173472. [PMID: 36079729 PMCID: PMC9460349 DOI: 10.3390/nu14173472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 08/18/2022] [Accepted: 08/19/2022] [Indexed: 12/02/2022] Open
Abstract
The Circadian Locomotor Output Cycles Kaput (CLOCK) gene has been linked to metabolic dysfunction and obesity. The purpose of this study was to analyze the association between single nucleotide polymorphisms (SNPs) of CLOCK gene with obesity and with long-term weight response after different bariatric surgery (BS) techniques. The cohort includes 375 patients with morbid obesity (MO) and 230 controls. In the association study of SNPs with weight response we combined several variables as phenotype at 6 years after surgery. The study protocol was registered in ISRCTN (ID80961259). The analysis of the selected SNPs was performed by allelic discrimination using Taqman® probes. The genotype association study was performed using the SNPStats program, with comparisons adjusted for sex, age, initial Body Mass Index, type 2 diabetes and hypertension diagnosis, and type of surgery. In the case-control study two of three SNPs were significantly associated with MO. The variant rs1801260 had a protective effect for MO whereas the TT genotype of rs3749474 variant had the strongest association with MO (OR = 2.25 (1.39–3.66); p = 0.0006). In the linear regression analysis both variants showed significant association with long-term weight loss and weight regain after BS, independently of the pre-surgery patient profile.
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Chan K, Wong FS, Pearson JA. Circadian rhythms and pancreas physiology: A review. Front Endocrinol (Lausanne) 2022; 13:920261. [PMID: 36034454 PMCID: PMC9399605 DOI: 10.3389/fendo.2022.920261] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 07/21/2022] [Indexed: 11/29/2022] Open
Abstract
Type 2 diabetes mellitus, obesity and metabolic syndrome are becoming more prevalent worldwide and will present an increasingly challenging burden on healthcare systems. These interlinked metabolic abnormalities predispose affected individuals to a plethora of complications and comorbidities. Furthermore, diabetes is estimated by the World Health Organization to have caused 1.5 million deaths in 2019, with this figure projected to rise in coming years. This highlights the need for further research into the management of metabolic diseases and their complications. Studies on circadian rhythms, referring to physiological and behavioral changes which repeat approximately every 24 hours, may provide important insight into managing metabolic disease. Epidemiological studies show that populations who are at risk of circadian disruption such as night shift workers and regular long-haul flyers are also at an elevated risk of metabolic abnormalities such as insulin resistance and obesity. Aberrant expression of circadian genes appears to contribute to the dysregulation of metabolic functions such as insulin secretion, glucose homeostasis and energy expenditure. The potential clinical implications of these findings have been highlighted in animal studies and pilot studies in humans giving rise to the development of circadian interventions strategies including chronotherapy (time-specific therapy), time-restricted feeding, and circadian molecule stabilizers/analogues. Research into these areas will provide insights into the future of circadian medicine in metabolic diseases. In this review, we discuss the physiology of metabolism and the role of circadian timing in regulating these metabolic functions. Also, we review the clinical aspects of circadian physiology and the impact that ongoing and future research may have on the management of metabolic disease.
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Affiliation(s)
- Karl Chan
- Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - F. Susan Wong
- Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
- Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - James Alexander Pearson
- Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
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Molina-Montes E, Rodríguez-Barranco M, Ching-López A, Artacho R, Huerta JM, Amiano P, Lasheras C, Moreno-Iribas C, Jimenez-Zabala A, Chirlaque MD, Barricarte A, Luján-Barroslo L, Agudo A, Jakszyn P, Quirós JR, Sánchez MJ. Circadian clock gene variants and their link with chronotype, chrononutrition, sleeping patterns and obesity in the European prospective investigation into cancer and nutrition (EPIC) study. Clin Nutr 2022; 41:1977-1990. [DOI: 10.1016/j.clnu.2022.07.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 07/15/2022] [Accepted: 07/16/2022] [Indexed: 11/03/2022]
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Johnson BS, Krishna MB, Padmanabhan RA, Pillai SM, Jayakrishnan K, Laloraya M. Derailed peripheral circadian genes in polycystic ovary syndrome patients alters peripheral conversion of androgens synthesis. Hum Reprod 2022; 37:1835-1855. [PMID: 35728080 DOI: 10.1093/humrep/deac139] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 05/26/2022] [Indexed: 11/13/2022] Open
Abstract
STUDY QUESTION Do circadian genes exhibit an altered profile in peripheral blood mononuclear cells (PBMCs) of polycystic ovary syndrome (PCOS) patients and do they have a potential role in androgen excess? SUMMARY ANSWER Our findings revealed that an impaired circadian clock could hamper the regulation of peripheral steroid metabolism in PCOS women. WHAT IS KNOWN ALREADY PCOS patients exhibit features of metabolic syndrome. Circadian rhythm disruption is involved in the development of metabolic diseases and subfertility. An association between shift work and the incidence of PCOS in females was recently reported. STUDY DESIGN, SIZE, DURATION This is a retrospective case-referent study in which peripheral blood samples were obtained from 101 control and 101 PCOS subjects. PCOS diagnoses were based on Rotterdam Consensus criteria. PARTICIPANTS/MATERIALS, SETTING, METHODS This study comprised 101 women with PCOS and 101 control volunteers, as well as Swiss albino mice treated with dehydroepiandrosterone (DHEA) to induce PCOS development. Gene expression analyses of circadian and steroidogenesis genes in human PBMC and mice ovaries and blood were executed by quantitative real-time PCR. MAIN RESULTS AND THE ROLE OF CHANCE We observed aberrant expression of peripheral circadian clock genes in PCOS, with a significant reduction in the core clock genes, circadian locomotor output cycles kaput (CLOCK) (P ≤ 0.00001), brain and muscle ARNT-like 1 (BMAL1) (P ≤ 0.00001) and NPAS2 (P ≤ 0.001), and upregulation of their negative feedback loop genes, CRY1 (P ≤ 0.00003), CRY2 (P ≤ 0.00006), PER1 (P ≤ 0.003), PER2 (P ≤ 0.002), DEC1 (P ≤ 0.0001) and DEC2 (P ≤ 0.00005). Transcript levels of an additional feedback loop regulating BMAL1 showed varied expression, with reduced RORA (P ≤ 0.008) and increased NR1D1 (P ≤ 0.02) in PCOS patients in comparison with the control group. We also demonstrated the expression pattern of clock genes in PBMCs of PCOS women at three different time points. PCOS patients also exhibited increased mRNA levels of steroidogenic enzymes like StAR (P ≤ 0.0005), CYP17A1 (P ≤ 0.005), SRD5A1 (P ≤ 0.00006) and SRD5A2 (P ≤ 0.009). Knockdown of CLOCK/BMAL1 in PBMCs resulted in a significant reduction in estradiol production, by reducing CYP19A1 and a significant increase in dihydrotestosterone production, by upregulating SRD5A1 and SRD5A2 in PBMCs. Our data also showed that CYP17A1 as a direct CLOCK-BMAL1 target in PBMCs. Phenotypic classification of PCOS subgroups showed a higher variation in expression of clock genes and steroidogenesis genes with phenotype A of PCOS. In alignment with the above results, altered expression of ovarian core clock genes (Clock, Bmal1 and Per2) was found in DHEA-treated PCOS mice. The expression of peripheral blood core clock genes in DHEA-induced PCOS mice was less robust and showed a loss of periodicity in comparison with that of control mice. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION We could not evaluate the circadian oscillation of clock genes and clock-controlled genes over a 24-h period in the peripheral blood of control versus PCOS subjects. Additionally, circadian genes in the ovaries of PCOS women could not be evaluated due to limitations in sample availability, hence we employed the androgen excess mouse model of PCOS for ovarian circadian assessment. Clock genes were assessed in the whole ovary of the androgen excess mouse model of PCOS rather than in granulosa cells, which is another limitation of the present work. WIDER IMPLICATIONS OF THE FINDINGS Our observations suggest that the biological clock is one of the contributing factors in androgen excess in PCOS, owing to its potential role in modulating peripheral androgen metabolism. Considering the increasing prevalence of PCOS and the rising frequency of delayed circadian rhythms and insufficient sleep among women, our study emphasizes the potential in modulating circadian rhythm as an important strategy in PCOS management, and further research on this aspect is highly warranted. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the RGCB-DBT Core Funds and a grant (#BT/PR29996/MED/97/472/2020) from the Department of Biotechnology (DBT), India, to M.L. B.S.J. was supported by a DST/INSPIRE Fellowship/2015/IF150361 and M.B.K. was supported by the Research Fellowship from Council of Scientific & Industrial Research (CSIR) (10.2(5)/2007(ii).E.U.II). The authors declare no competing interests. TRIAL REGISTRATION NUMBER N/A.
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Affiliation(s)
- Betcy Susan Johnson
- Female Reproduction and Metabolic Syndromes Laboratory, Division of Molecular Reproduction, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India.,Research Scholar, Research Centre, University of Kerala, Thiruvananthapuram, Kerala, India
| | - Meera B Krishna
- Female Reproduction and Metabolic Syndromes Laboratory, Division of Molecular Reproduction, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Renjini A Padmanabhan
- Female Reproduction and Metabolic Syndromes Laboratory, Division of Molecular Reproduction, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | | | - K Jayakrishnan
- KJK Hospital and Fertility Research Centre, Thiruvananthapuram, Kerala, India
| | - Malini Laloraya
- Female Reproduction and Metabolic Syndromes Laboratory, Division of Molecular Reproduction, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
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Abstract
Introduction: Fatty liver disease, defined by the presence of liver fat infiltration, is part of a cluster of disorders that occur in the context of metabolic syndrome. Epigenetic factors - defined as stable and heritable changes in gene expression without changes in the DNA sequence - may not only play an important role in the disease development in adulthood, but they may start exerting their influence in the prenatal stage.Areas covered: By using systems biology approaches, we review the main epigenetic modifications and highlight their likely roles in the pathogenesis of nonalcoholic fatty liver disease.Expert opinion: Knowledge of the mechanisms by which epigenetic modifications participate in complex disorders would not only help scientists find novel therapeutic strategies but could also aid in implementing preventive care measures at gestation.
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Affiliation(s)
- Carlos Jose Pirola
- School of Medicine, Institute of Medical Research A Lanari, University of Buenos Aires, Buenos Aires, Argentina.,Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council (Conicet)-university of Buenos Aires. Institute of Medical Research (IDIM)
| | - Silvia Sookoian
- School of Medicine, Institute of Medical Research A Lanari, University of Buenos Aires, Buenos Aires, Argentina.,Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council (CONICET)-University of Buenos Aires. Institute of Medical Research (IDIM), Buenos Aires, Argentina
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Chronic Treatment with Metformin Has No Disrupting Effect on the Hepatic Circadian Clock in Mice. Medicina (B Aires) 2022; 58:medicina58020293. [PMID: 35208616 PMCID: PMC8875024 DOI: 10.3390/medicina58020293] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/03/2022] [Accepted: 02/13/2022] [Indexed: 01/23/2023] Open
Abstract
Background and Objectives: The antidiabetic agent metformin is known to activate AMP-activated protein kinase (AMPK) in various tissues. Because AMPK can modulate intracellular circadian clocks through regulating the stability of clock components, a single dose of metformin has been reported to affect circadian clocks in the peripheral tissues. In this study, therefore, we investigated whether chronic treatment with metformin causes the impairment of circadian clocks, especially if given at an inappropriate time. Materials and Methods: Non-diabetic C57BL/6J mice were allowed access to food only during 4 h at the beginning of the dark period, and repeatedly i.p. injected with a nearly maximum non-toxic dose of metformin, once daily either at 4 h after the beginning of the dark period or at the beginning of the light period. Diabetic ob/ob mice were given free access to food and treated with metformin in drinking water. Results: Under the controlled feeding regimen, 8-day treatment with metformin did not alter the mRNA expression rhythms of clock genes in both liver and adipose tissue of C57BL/6J mice, regardless of dosing time. In addition, chronic treatment with metformin for 2 weeks affected hepatic AMPK activation rhythm but did not disrupt the circadian clocks in the liver and adipose tissues of the ob/ob mice. Conclusions: These results mitigate concerns that treatment with metformin impairs peripheral circadian clocks, although confirmation is needed in humans.
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Shon J, Han Y, Park YJ. Effects of Dietary Fat to Carbohydrate Ratio on Obesity Risk Depending on Genotypes of Circadian Genes. Nutrients 2022; 14:nu14030478. [PMID: 35276838 PMCID: PMC8838281 DOI: 10.3390/nu14030478] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/19/2022] [Accepted: 01/19/2022] [Indexed: 02/05/2023] Open
Abstract
Although the impacts of macronutrients and the circadian clock on obesity have been reported, the interactions between macronutrient distribution and circadian genes are unclear. The aim of this study was to explore macronutrient intake patterns in the Korean population and associations between the patterns and circadian gene variants and obesity. After applying the criteria, 5343 subjects (51.6% male, mean age 49.4 ± 7.3 years) from the Korean Genome and Epidemiology Study data and nine variants in seven circadian genes were analyzed. We defined macronutrient intake patterns by tertiles of the fat to carbohydrate ratio (FC). The very low FC (VLFC) was associated with a higher risk of obesity than the optimal FC (OFC). After stratification by the genotypes of nine variants, the obesity risk according to the patterns differed by the variants. In the female VLFC, the major homozygous allele of CLOCK rs11932595 and CRY1 rs3741892 had a higher abdominal obesity risk than those in the OFC. The GG genotype of PER2 rs2304672 in the VLFC showed greater risks for obesity and abdominal obesity. In conclusion, these findings suggest that macronutrient intake patterns were associated with obesity susceptibility, and the associations were different depending on the circadian clock genotypes of the CLOCK, PER2, and CRY1 loci.
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Affiliation(s)
- Jinyoung Shon
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, Korea; (J.S.); (Y.H.)
| | - Yerim Han
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, Korea; (J.S.); (Y.H.)
- Graduate Program in System Health Science & Engineering, Ewha Womans University, Seoul 03760, Korea
| | - Yoon Jung Park
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, Korea; (J.S.); (Y.H.)
- Graduate Program in System Health Science & Engineering, Ewha Womans University, Seoul 03760, Korea
- Correspondence: ; Tel.: +82-2-3277-6533
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Li J, Vungarala S, Somers VK, Di J, Lopez-Jimenez F, Covassin N. Rest-Activity Rhythm Is Associated With Obesity Phenotypes: A Cross-Sectional Analysis. Front Endocrinol (Lausanne) 2022; 13:907360. [PMID: 35837304 PMCID: PMC9273840 DOI: 10.3389/fendo.2022.907360] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 05/26/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND The prevalence of obesity continues to increase in spite of substantial efforts towards its prevention, posing a major threat to health globally. Circadian disruption has been associated with a wide range of preclinical and clinical disorders, including obesity. However, whether rest-activity rhythm (RAR), an expression of the endogenous circadian rhythm, is associated with excess adiposity is poorly understood. Here we aimed to assess the association of RAR with general and abdominal obesity. METHODS Non-institutionalized adults aged ≥20 years participating in the US National Health and Nutrition Examination Survey (NHANES) 2011-2014 who wore accelerometers for at least four 24-hour periods were included (N=7,838). Amplitude, mesor, acrophase and pseudo-F statistic of RAR were estimated using extended cosinor model, and interdaily stability (IS) and intradaily variability (IV) were computed by nonparametric methods. We tested the association between rest-activity rhythm and general obesity defined by body mass index and abdominal obesity by waist circumference. Waist-to-height ratio, sagittal abdominal diameter, and total and trunk fat percentages measured by imaging methods were also analyzed. RESULTS In multivariable analysis, low amplitude (magnitude of the rhythm), mesor (rhythm-corrected average activity level), pseudo-F statistic (robustness of the rhythm), IS (day-to-day rhythm stability), or high IV (rhythm fragmentation) were independently associated with higher likelihood of general or abdominal obesity (all Ps<.05). Consistently, RAR metrics were similarly associated with all adiposity measures (all Ps<.01). Delayed phase of RAR (later acrophase) was only significantly related to general and abdominal obesity in women. CONCLUSIONS Aberrant RAR is independently associated with anthropometric and imaging measures of general and abdominal obesity. Longitudinal studies assessing whether RAR metrics can predict weight gain and incident obesity are warranted.
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Affiliation(s)
- Jingen Li
- Department of Cardiovascular Medicine, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States
| | - Soumya Vungarala
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States
| | - Virend K. Somers
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States
| | - Junrui Di
- Department of Biostatistics, Johns Hopkins University, Baltimore, MA, United States
| | | | - Naima Covassin
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States
- *Correspondence: Naima Covassin,
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Rana S, Fatima N, Bhatti AA. Association of CLOCK gene variants with obesity and adiposity-related anthropometric, metabolic, and behavioral parameters. Facets (Ott) 2022. [DOI: 10.1139/facets-2021-0137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The CLOCK gene is a core component of the circadian clock and regulates various aspects of metabolism. Therefore, any variation that affects the function/expression of the CLOCK gene may contribute to the manifestation of metabolic disorders such as obesity. This study investigated whether the CLOCK variants rs4864548 and rs6843722 are associated with obesity and related traits in Pakistanis. A total of 306 overweight/obese cases and 306 age- and gender-matched control subjects were recruited (males 336 and females 276, age range 12–63 years). Anthropometric and metabolic parameters were taken by standard procedures and biochemical analyses, respectively. Behavior-related information was collected with a questionnaire. The genotypes of the variants were determined by allelic discrimination Taqman assays. Both variants were found to have a significant association with overweight/obesity according to the over-dominant model. The rs4864548 and rs6843722 were observed to escalate the risk of overweight/obesity by 1.611 ( p = 0.004) and 1.657 ( p = 0.002) times, respectively. These variants were also seen to be significantly associated with various other adiposity-related anthropometric parameters ( p < 0.05). However, no association of both variants with metabolic and behavioral parameters was observed ( p > 0.05). Thus, these variants may contribute to increasing the risk of overweight/obesity and related anthropometric traits in Pakistanis.
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Affiliation(s)
- Sobia Rana
- Molecular Biology and Human Genetics Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, 75270, Pakistan
| | - Narjis Fatima
- Molecular Biology and Human Genetics Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, 75270, Pakistan
| | - Adil Anwar Bhatti
- Molecular Biology and Human Genetics Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, 75270, Pakistan
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Variability of the genetic marker CLOCK rs3749474 and its impact on research and clinical trials on obesity and circadian rhythm. NUTR HOSP 2022; 39:1117-1121. [DOI: 10.20960/nh.04230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
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Škrlec I, Talapko J, Džijan S, Cesar V, Lazić N, Lepeduš H. The Association between Circadian Clock Gene Polymorphisms and Metabolic Syndrome: A Systematic Review and Meta-Analysis. BIOLOGY 2021; 11:20. [PMID: 35053018 PMCID: PMC8773381 DOI: 10.3390/biology11010020] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/11/2021] [Accepted: 12/22/2021] [Indexed: 02/07/2023]
Abstract
Metabolic syndrome (MetS) is a combination of cardiovascular risk factors associated with type 2 diabetes, obesity, and cardiovascular diseases. The circadian clock gene polymorphisms are very likely to participate in metabolic syndrome genesis and development. However, research findings of the association between circadian rhythm gene polymorphisms and MetS and its comorbidities are not consistent. In this study, a review of the association of circadian clock gene polymorphisms with overall MetS risk was performed. In addition, a meta-analysis was performed to clarify the association between circadian clock gene polymorphisms and MetS susceptibility based on available data. The PubMed and Scopus databases were searched for studies reporting the association between circadian rhythm gene polymorphisms (ARNTL, BMAL1, CLOCK, CRY, PER, NPAS2, REV-ERBα, REV-ERBβ, and RORα) and MetS, and its comorbidities diabetes, obesity, and hypertension. Thirteen independent studies were analyzed with 17,381 subjects in total. The results revealed that the BMAL1 rs7950226 polymorphism was associated with an increased risk of MetS in the overall population. In contrast, the CLOCK rs1801260 and rs6850524 polymorphisms were not associated with MetS. This study suggests that some circadian rhythm gene polymorphisms might be associated with MetS in different populations and potentially used as predictive biomarkers for MetS.
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Affiliation(s)
- Ivana Škrlec
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (J.T.); (S.D.); (V.C.); (N.L.); (H.L.)
| | - Jasminka Talapko
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (J.T.); (S.D.); (V.C.); (N.L.); (H.L.)
| | - Snježana Džijan
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (J.T.); (S.D.); (V.C.); (N.L.); (H.L.)
- Genos Ltd., DNA Laboratory, 10000 Zagreb, Croatia
| | - Vera Cesar
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (J.T.); (S.D.); (V.C.); (N.L.); (H.L.)
- Department of Biology, Josip Juraj Strossmayer University of Osijek, Ul. Cara Hadrijana 8/A, 31000 Osijek, Croatia
| | - Nikolina Lazić
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (J.T.); (S.D.); (V.C.); (N.L.); (H.L.)
| | - Hrvoje Lepeduš
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (J.T.); (S.D.); (V.C.); (N.L.); (H.L.)
- Faculty of Humanities and Social Sciences Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
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Energy Balance and Control of Body Weight: Possible Effects of Meal Timing and Circadian Rhythm Dysregulation. Nutrients 2021; 13:nu13093276. [PMID: 34579152 PMCID: PMC8470941 DOI: 10.3390/nu13093276] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 09/07/2021] [Accepted: 09/16/2021] [Indexed: 12/12/2022] Open
Abstract
Conservation of the energy equilibrium can be considered a dynamic process and variations of one component (energy intake or energy expenditure) cause biological and/or behavioral compensatory changes in the other part of the system. The interplay between energy demand and caloric intake appears designed to guarantee an adequate food supply in variable life contexts. The circadian rhythm plays a major role in systemic homeostasis by acting as “timekeeper” of the human body, under the control of central and peripheral clocks that regulate many physiological functions such as sleep, hunger and body temperature. Clock-associated biological processes anticipate the daily demands imposed by the environment, being synchronized under ideal physiologic conditions. Factors that interfere with the expected demand, including daily distribution of macronutrients, physical activity and light exposure, may disrupt the physiologic harmony between predicted and actual behavior. Such a desynchronization may favor the development of a wide range of disease-related processes, including obesity and its comorbidities. Evidence has been provided that the main components of 24-h EE may be affected by disruption of the circadian rhythm. The sleep pattern, meal timing and meal composition could mediate these effects. An increased understanding of the crosstalk between disruption of the circadian rhythm and energy balance may shed light on the pathophysiologic mechanisms underlying weight gain, which may eventually lead to design effective strategies to fight the obesity pandemic.
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Martchenko A, Brubaker PL. Effects of Obesogenic Feeding and Free Fatty Acids on Circadian Secretion of Metabolic Hormones: Implications for the Development of Type 2 Diabetes. Cells 2021; 10:cells10092297. [PMID: 34571945 PMCID: PMC8466112 DOI: 10.3390/cells10092297] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 08/27/2021] [Accepted: 08/30/2021] [Indexed: 11/19/2022] Open
Abstract
Circadian rhythms are 24-h internal biological rhythms within organisms that govern virtually all aspects of physiology. Interestingly, metabolic tissues have been found to express cell-autonomous clocks that govern their rhythmic activity throughout the day. Disruption of normal circadian rhythmicity, as induced by environmental factors such as shift work, significantly increases the risk for the development of metabolic diseases, including type 2 diabetes and obesity. More recently, obesogenic feeding and its fatty acid components have also been shown to be potent disruptors of normal circadian biology. Two key hormones that are released in response to nutrient intake are the anti-diabetic incretin hormone glucagon-like peptide-1, from intestinal L cells, and insulin secreted by pancreatic β cells, both of which are required for the maintenance of metabolic homeostasis. This review will focus on the circadian function of the L and β cells and how both obesogenic feeding and the saturated fatty acid, palmitate, affect their circadian clock and function. Following introduction of the core biological clock and the hierarchical organization of the mammalian circadian system, the circadian regulation of normal L and β cell function and the importance of GLP-1 and insulin in establishing metabolic control are discussed. The central focus of the review then considers the circadian-disrupting effects of obesogenic feeding and palmitate exposure in L and β cells, while providing insight into the potential causative role in the development of metabolic disease.
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Affiliation(s)
| | - Patricia Lee Brubaker
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada;
- Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
- Correspondence:
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Gyorik D, Eszlari N, Gal Z, Torok D, Baksa D, Kristof Z, Sutori S, Petschner P, Juhasz G, Bagdy G, Gonda X. Every Night and Every Morn: Effect of Variation in CLOCK Gene on Depression Depends on Exposure to Early and Recent Stress. Front Psychiatry 2021; 12:687487. [PMID: 34512413 PMCID: PMC8428175 DOI: 10.3389/fpsyt.2021.687487] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 07/30/2021] [Indexed: 12/21/2022] Open
Abstract
The role of circadian dysregulation is increasingly acknowledged in the background of depressive symptoms, and is also a promising treatment target. Similarly, stress shows a complex relationship with the circadian system. The CLOCK gene, encoding a key element in circadian regulation has been implicated in previous candidate variant studies in depression with contradictory findings, and only a few such studies considered the interacting effects of stress. We investigated the effect of CLOCK variation with a linkage-disequilibrium-based clumping method, in interaction with childhood adversities and recent negative life events, on two phenotypes of depression, lifetime depression and current depressive symptoms in a general population sample. Methods: Participants in NewMood study completed questionnaires assessing childhood adversities and recent negative life events, the Brief Symptom Inventory to assess current depressive symptoms, provided data on lifetime depression, and were genotyped for 1054 SNPs in the CLOCK gene, 370 of which survived quality control and were entered into linear and logistic regression models with current depressive symptoms and lifetime depression as the outcome variable, and childhood adversities or recent life events as interaction variables followed by a linkage disequilibrium-based clumping process to identify clumps of SNPs with a significant main or interaction effect. Results: No significant clumps with a main effect were found. In interaction with recent life events a significant clump containing 94 SNPs with top SNP rs6825994 for dominant and rs6850524 for additive models on current depression was identified, while in interaction with childhood adversities on current depressive symptoms, two clumps, both containing 9 SNPs were found with top SNPs rs6828454 and rs711533. Conclusion: Our findings suggest that CLOCK contributes to depressive symptoms, but via mediating the effects of early adversities and recent stressors. Given the increasing burden on circadian rhythmicity in the modern lifestyle and our expanding insight into the contribution of circadian disruption in depression especially as a possible mediator of stress, our results may pave the way for identifying those who would be at an increased risk for depressogenic effects of circadian dysregulation in association with stress as well as new molecular targets for intervention in stress-related psychopathologies in mood disorders.
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Affiliation(s)
- Dorka Gyorik
- Faculty of Medicine, Semmelweis University, Budapest, Hungary
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
| | - Nora Eszlari
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
- NAP-2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary
| | - Zsofia Gal
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
| | - Dora Torok
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
| | - Daniel Baksa
- NAP-2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary
- SE-NAP-2 Genetic Brain Imaging Migraine Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary
| | - Zsuliet Kristof
- Doctoral School of Mental Health Sciences, Semmelweis University, Budapest, Hungary
- Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
- Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary
| | - Sara Sutori
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
| | - Peter Petschner
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
| | - Gabriella Juhasz
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
- SE-NAP-2 Genetic Brain Imaging Migraine Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
| | - Gyorgy Bagdy
- Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
- NAP-2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
| | - Xenia Gonda
- NAP-2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary
- Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary
- MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
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Yang HW, Garaulet M, Li P, Bandin C, Lin C, Lo MT, Hu K. Daily Rhythm of Fractal Cardiac Dynamics Links to Weight Loss Resistance: Interaction with CLOCK 3111T/C Genetic Variant. Nutrients 2021; 13:nu13072463. [PMID: 34371977 PMCID: PMC8308644 DOI: 10.3390/nu13072463] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/09/2021] [Accepted: 07/13/2021] [Indexed: 12/31/2022] Open
Abstract
The effectiveness of weight loss treatment displays dramatic inter-individual variabilities, even with well-controlled energy intake/expenditure. This study aimed to determine the association between daily rhythms of cardiac autonomic control and weight loss efficiency and to explore the potential relevance to weight loss resistance in humans carrying the genetic variant C at CLOCK 3111T/C. A total of 39 overweight/obese Caucasian women (20 CLOCK 3111C carriers and 19 non-carriers) completed a behaviour–dietary obesity treatment of ~20 weeks, during which body weight was assessed weekly. Ambulatory electrocardiographic data were continuously collected for up to 3.5 days and used to quantify the daily rhythm of fractal cardiac dynamics (FCD), a non-linear measure of autonomic function. FCD showed a 24 h rhythm (p < 0.001). Independent of energy intake and physical activity level, faster weight loss was observed in individuals with the phase (peak) of the rhythm between ~2–8 p.m. and with a larger amplitude. Interestingly, the phase effect was significant only in C carriers (p = 0.008), while the amplitude effect was only significant in TT carriers (p < 0.0001). The daily rhythm of FCD and CLOCK 3111T/C genotype is linked to weight loss response interactively, suggesting complex interactions between the genetics of the circadian clock, the daily rhythm of autonomic control, and energy balance control.
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Affiliation(s)
- Hui-Wen Yang
- Graduate Institute of Communication Engineering, National Taiwan University, Taipei 10617, Taiwan;
- Institute of Translational and Interdisciplinary Medicine, Department of Biomedical Sciences and Engineering, National Central University, Taoyuan 320317, Taiwan;
- Division of Sleep and Circadian Disorders, Department of Medicine and Neurology, Brigham and Women’s Hospital, Boston, MA 02115, USA;
- Division of Sleep Medicine, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Marta Garaulet
- Division of Sleep Medicine, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Department of Physiology, University of Murcia, IMIB, 30071 Murcia, Spain;
- Correspondence: (M.G.); (M.-T.L.); (K.H.)
| | - Peng Li
- Division of Sleep and Circadian Disorders, Department of Medicine and Neurology, Brigham and Women’s Hospital, Boston, MA 02115, USA;
- Division of Sleep Medicine, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Cristina Bandin
- Department of Physiology, University of Murcia, IMIB, 30071 Murcia, Spain;
| | - Chen Lin
- Institute of Translational and Interdisciplinary Medicine, Department of Biomedical Sciences and Engineering, National Central University, Taoyuan 320317, Taiwan;
| | - Men-Tzung Lo
- Institute of Translational and Interdisciplinary Medicine, Department of Biomedical Sciences and Engineering, National Central University, Taoyuan 320317, Taiwan;
- Correspondence: (M.G.); (M.-T.L.); (K.H.)
| | - Kun Hu
- Division of Sleep and Circadian Disorders, Department of Medicine and Neurology, Brigham and Women’s Hospital, Boston, MA 02115, USA;
- Division of Sleep Medicine, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Correspondence: (M.G.); (M.-T.L.); (K.H.)
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Hasan N, Nagata N, Morishige JI, Islam MT, Jing Z, Harada KI, Mieda M, Ono M, Fujiwara H, Daikoku T, Fujiwara T, Maida Y, Ota T, Shimba S, Kaneko S, Fujimura A, Ando H. Brown adipocyte-specific knockout of Bmal1 causes mild but significant thermogenesis impairment in mice. Mol Metab 2021; 49:101202. [PMID: 33676029 PMCID: PMC8042177 DOI: 10.1016/j.molmet.2021.101202] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 02/18/2021] [Accepted: 02/26/2021] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVE Impaired circadian clocks can cause obesity, but their pathophysiological role in brown adipose tissue (BAT), a major tissue regulating energy metabolism, remains unclear. To address this issue, we investigated the effects of complete disruption of the BAT clock on thermogenesis and energy expenditure. METHODS Mice with brown adipocyte-specific knockout of the core clock gene Bmal1 (BA-Bmal1 KO) were generated and analyzed. RESULTS The BA-Bmal1 KO mice maintained normal core body temperatures by increasing shivering and locomotor activity despite the elevated expression of thermogenic uncoupling protein 1 in BAT. BA-Bmal1 KO disrupted 24 h rhythmicity of fatty acid utilization in BAT and mildly reduced both BAT thermogenesis and whole-body energy expenditure. The impact of BA-Bmal1 KO on the development of obesity became obvious when the mice were fed a high-fat diet. CONCLUSIONS These results reveal the importance of the BAT clock for maintaining energy homeostasis and preventing obesity.
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Affiliation(s)
- Nazmul Hasan
- Department of Cellular and Molecular Function Analysis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Naoto Nagata
- Department of Cellular and Molecular Function Analysis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Jun-Ichi Morishige
- Department of Cellular and Molecular Function Analysis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Md Tarikul Islam
- Department of Integrative Neurophysiology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Zheng Jing
- Department of Cellular and Molecular Function Analysis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Ken-Ichi Harada
- Department of Human Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Michihiro Mieda
- Department of Integrative Neurophysiology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Masanori Ono
- Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Hiroshi Fujiwara
- Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Takiko Daikoku
- Institute for Experimental Animals, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan
| | - Tomoko Fujiwara
- Department of Social Work and Life Design, Kyoto Notre Dame University, Kyoto, Japan
| | - Yoshiko Maida
- Department of Health Development Nursing, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Tsuguhito Ota
- Department of Internal Medicine, Fukui-ken Saiseikai Hospital, Fukui, Japan
| | - Shigeki Shimba
- Department of Health Science, School of Pharmacy, Nihon University, Funabashi, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Akio Fujimura
- Department of Pharmacology, School of Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Hitoshi Ando
- Department of Cellular and Molecular Function Analysis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
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Azevedo PGD, Miranda LR, Nicolau ES, Alves RB, Bicalho MAC, Couto PP, Ramos AV, Souza RPD, Longhi R, Friedman E, Marco LD, Bastos-Rodrigues L. Genetic association of the PERIOD3 (PER3) Clock gene with extreme obesity. Obes Res Clin Pract 2021; 15:334-338. [PMID: 34215556 DOI: 10.1016/j.orcp.2021.06.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 07/28/2020] [Accepted: 06/11/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND Obesity has reached epidemic proportions worldwide, affecting life quality and span. Susceptibility to obesity is partly mediated by genetic differences. Indeed, several genes from the clock gene family have already been shown to be intimately associated with obesity in diverse ethnic groups. In the present study, an association between BMI and the rs707467, rs228697 and rs228729 PER3 (Period Circadian Clock 3) polymorphisms in subjects with class II (BMI ≥ 35.0-39.9 kg/m2) and class III obesity (>40 kg/m2, extreme obesity) were carried out using TaqMan real-time PCR. Overall, 259 Brazilian adults were genotyped, of whom 122 had class II or III obesity (BMI ≥ 35.0 kg/m2) and 137 were controls having normal weight (BMI > 18.5 and <24.9 kg/m2). RESULTS PER3 tag SNP (rs228729) shows a significant association with extreme obesity (1000 permutation p = 0.03 and p = 0.04), for genotype and allele frequency respectively) and a haplotype among the three assessed SNPs (alleles G/T/A, rs228697, rs228729, and rs707467, respectively, 1000 permutation p = 0.03) was significantly more prevalent in the group with obesity. CONCLUSION This exploratory association study suggests that PER3 rs228729 may be associated with extreme obesity in Brazilian adults, however, replication is needed.
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Affiliation(s)
- Pedro Guimarães de Azevedo
- Centro de Tecnologia em Medicina Molecular, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, 30130-100, Brazil
| | - Luana Reis Miranda
- Centro de Tecnologia em Medicina Molecular, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, 30130-100, Brazil
| | - Eduardo Souza Nicolau
- Centro de Tecnologia em Medicina Molecular, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, 30130-100, Brazil
| | - Rayane Benfica Alves
- Centro de Tecnologia em Medicina Molecular, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, 30130-100, Brazil
| | | | - Patrícia Pereira Couto
- Centro de Tecnologia em Medicina Molecular, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, 30130-100, Brazil
| | | | - Renan Pedra de Souza
- Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Rafael Longhi
- Department of Nutrition, Universidade Federal de Minas Gerais, Belo Horizonte, MG 35010-177, Brazil
| | - Eitan Friedman
- The Suzanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Tel Hashomer, the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Luiz De Marco
- Department of Surgery, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Luciana Bastos-Rodrigues
- Department of Nutrition, Universidade Federal de Minas Gerais, Belo Horizonte, MG 35010-177, Brazil.
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Fukuda Y, Kanazawa R, Yao N, Ishida T, Nakaoka A, Tazuhara M, Yao S, Nakatani S, Nakajima H, Nakai M. Nutritional Intake by Meal Time Zone in Geriatric Patients Is Related to Nutritional Assessment Index. J Clin Med Res 2021; 13:334-342. [PMID: 34267841 PMCID: PMC8256911 DOI: 10.14740/jocmr4524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 06/07/2021] [Indexed: 11/11/2022] Open
Abstract
Background The blood metabolome profiles depend on the meal intake time zone regardless of having the same meal. The serum albumin (Alb) level, which is important in managing geriatric patients with chronic diseases, is included in the metabolome analysis. In this study, we aimed to examine the relationship between Alb and the nutritional value of hospital meals consumed at breakfast, lunch, and dinner among geriatric patients. Chrononutrition was considered while drawing inferences. Methods We retrospectively surveyed 52 geriatric patients with chronic diseases (aged 79.7 ± 8.7 years) admitted at a small-scale hospital providing combined healthcare measures and oral nutritional support. The dietary intake per kilogram of body weight of nutritional components for breakfast, lunch, and dinner was individually expressed as the ratio to the whole daily food intake. The dietary pattern was determined by principal component analysis. We also conducted linear regression analysis, with Alb as the dependent variable, and age, sex, and grade assigned in this study as well as the first, second, and third principal components of the dietary patterns as the independent variables. Results Three principal components with an eigenvalue of > 1 were extracted. The second principal component was a significantly negative determinant factor for Alb (B = -0.108, P = 0.016). In patients with high Alb levels, the energy, protein, and fat ratios at lunch were positively correlated, while the energy and carbohydrate ratios at dinner were negatively correlated. Mealtimes were fixed. Conclusions The results of this study showed that the dietary pattern predominantly observed in patients with high Alb levels may be positively associated with Alb synthesis.
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Affiliation(s)
- Yasuko Fukuda
- Department of Food Science and Nutrition, School of Human Environmental Science, Mukogawa Women's University, Ikebiraki-cho, Nishinomiya, Hyogo 663-8558, Japan.,Research Institute for Nutrition Science, Mukogawa Women's University, Ikebiraki-cho, Nishinomiya, Hyogo 663-8558, Japan
| | - Ryouko Kanazawa
- Department of Food Science and Nutrition, School of Human Environmental Science, Mukogawa Women's University, Ikebiraki-cho, Nishinomiya, Hyogo 663-8558, Japan
| | - Narumi Yao
- Department of Food Science and Nutrition, School of Human Environmental Science, Mukogawa Women's University, Ikebiraki-cho, Nishinomiya, Hyogo 663-8558, Japan
| | - Tomoka Ishida
- Department of Food Science and Nutrition, School of Human Environmental Science, Mukogawa Women's University, Ikebiraki-cho, Nishinomiya, Hyogo 663-8558, Japan
| | - Asuka Nakaoka
- Department of Food Science and Nutrition, School of Human Environmental Science, Mukogawa Women's University, Ikebiraki-cho, Nishinomiya, Hyogo 663-8558, Japan
| | - Momoko Tazuhara
- Department of Food Science and Nutrition, School of Human Environmental Science, Mukogawa Women's University, Ikebiraki-cho, Nishinomiya, Hyogo 663-8558, Japan
| | - Sayaka Yao
- Department of Food Science and Nutrition, School of Human Environmental Science, Mukogawa Women's University, Ikebiraki-cho, Nishinomiya, Hyogo 663-8558, Japan
| | - Saki Nakatani
- Department of Food Science and Nutrition, School of Human Environmental Science, Mukogawa Women's University, Ikebiraki-cho, Nishinomiya, Hyogo 663-8558, Japan
| | - Hiromu Nakajima
- Department of Endocrinology and Metabolism/Clinical Laboratory, Osaka International Cancer Institute, Chuo-ku, Osaka 541-8567, Japan
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45
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The Association of Cardiovascular Disease with the T3111C Polymorphism in the CLOCK Gene. MEDICAL SCIENCES FORUM 2021. [DOI: 10.3390/iecmd2021-10314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background and Objectives: Cardiovascular diseases (CVDs) are among the leading causes of death worldwide, although CVD mortality has decreased in developed countries. Numerous pathophysiological processes lead to the development of CVDs. The circadian rhythm coordinates many physiological processes, and its disruption can lead to many pathophysiological changes. One of the significant circadian rhythm genes is the CLOCK gene, whose polymorphisms are associated with CVD risk factors. Research findings of the association between CLOCK gene polymorphism and CVDs and its comorbidities are not consistent. This meta-analysis was conducted to quantify the associations between T3111C polymorphism and the risk of CVDs. Materials and Methods: The PubMed and Scopus databases were searched for studies reporting onthe association between T3111C (rs1801260) in the circadian CLOCK gene and cardiovascular disease and its comorbidities such as obesity, hypertension, insulin resistance, and coronary artery disease. A fixed-effect model was used to calculate the pooled odds ratio and 95% confidence interval by comprehensive meta-analysis software. Results: Five independent studies, including case-control, cross-sectional, and cohort research methods, were analyzed with 3123 subjects in total. The meta-analysis revealed a significant association between T3111C polymorphism and cardiovascular disease (OR = 1.32, 95% CI: 1.16–1.50, p < 0.001) with significant heterogeneity (I2 = 91.1%, p < 0.001) and no publication bias. The subgroup analysis on comorbidity related to CVDs revealed that hypertension was associated with T3111C polymorphism (OR = 2.02, 95% CI: 1.60–2.54, p < 0.001). Conclusions: Our meta-analysis based on available studies using a fixed model shows that T3111C polymorphism in the CLOCK gene is associated with CVD susceptibility.
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Dashti HS, Ordovás JM. Genetics of Sleep and Insights into Its Relationship with Obesity. Annu Rev Nutr 2021; 41:223-252. [PMID: 34102077 DOI: 10.1146/annurev-nutr-082018-124258] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Considerable recent advancements in elucidating the genetic architecture of sleep traits and sleep disorders may provide insight into the relationship between sleep and obesity. Despite the considerable involvement of the circadian clock in sleep and metabolism, few shared genes, including FTO, were implicated in genome-wide association studies (GWASs) of sleep and obesity. Polygenic scores composed of signals from GWASs of sleep traits show largely null associations with obesity, suggesting lead variants are unique to sleep. Modest genome-wide genetic correlations are observed between many sleep traits and obesity and are largest for snoring.Notably, U-shaped positive genetic correlations with body mass index (BMI) exist for both short and long sleep durations. Findings from Mendelian randomization suggest robust causal effects of insomnia on higher BMI and, conversely, of higher BMI on snoring and daytime sleepiness. Bidirectional effects between sleep duration and daytime napping with obesity may also exist. Limited gene-sleep interaction studies suggest that achieving favorable sleep, as part of a healthy lifestyle, may attenuate genetic predisposition to obesity, but whether these improvements produce clinically meaningful reductions in obesity risk remains unclear. Investigations of the genetic link between sleep and obesity for sleep disorders other than insomnia and in populations of non-European ancestry are currently limited. Expected final online publication date for the Annual Review of Nutrition, Volume 41 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Hassan S Dashti
- Center for Genomic Medicine and Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA; .,Broad Institute, Cambridge, Massachusetts 02142, USA
| | - José M Ordovás
- Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111, USA.,Precision Nutrition and Obesity Program, IMDEA Alimentación, 28049 Madrid, Spain
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Wang L, Liu M, Wu Y, Li X, Yin F, Yin L, Liu J. Free fatty acids induce the demethylation of the fructose 1,6-biphosphatase 2 gene promoter and potentiate its expression in hepatocytes. Food Funct 2021; 12:4165-4175. [PMID: 33977939 DOI: 10.1039/d0fo02654a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Obesity is a serious health issue as it is a social burden and the main risk factor for other metabolic diseases. Increasing evidence indicates that a high-fat diet (HFD) is the key factor for the development of obesity, but the key genes and their associated molecular mechanisms are still not fully understood. In this study, we performed integrated bioinformatic analysis and identified that fructose-1,6 biphosphatase 2 (FBP2) was involved in free fatty acids (FFAs)-induced lipid droplet accumulation in hepatocytes and HFD-induced obesity in mice. Our data showed that palmitate (PA) and oleic acid (OA) induced the expression of FBP2 in time- and dose-dependent manners, and accelerated the development of lipid droplets in LO2 human normal liver cells. In HFD-fed C57BL/6 mice, accompanied by insulin resistance and lipid droplet accumulation, the mRNA and protein levels of FBP2 in the livers also increased significantly. The results from the methylation sequencing PCR (MSP) and bisulfite specific PCR (BSP) indicated that PA/OA induced the demethylation of the FBP2 gene promoter in LO2 cells. Moreover, betaine, a methyl donor, attenuated the expression of the FBP2 gene, the accumulation of lipid droplets, and the expression of perilipin-2, a biomarker of lipid droplets, in LO2 cells. All these findings revealed that FBP2 might be involved in HFD-induced obesity, and it is of interest to investigate the role of FBP2 in the treatment and prevention of obesity and its associated complications.
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Affiliation(s)
- Lujing Wang
- Chongqing Key Lab of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China. and College of Pharmacy& Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Min Liu
- Chongqing Key Lab of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China. and College of Pharmacy& Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Yucui Wu
- Chongqing Key Lab of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China. and College of Pharmacy& Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Xingan Li
- Chongqing Key Lab of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China. and College of Pharmacy& Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Fei Yin
- Chongqing Key Lab of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China. and College of Pharmacy& Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Li Yin
- Chongqing Key Lab of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China. and College of Pharmacy& Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Jianhui Liu
- Chongqing Key Lab of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China. and College of Pharmacy& Bioengineering, Chongqing University of Technology, Chongqing 400054, China
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Salazar P, Konda S, Sridhar A, Arbieva Z, Daviglus M, Darbar D, Rehman J. Common genetic variation in circadian clock genes are associated with cardiovascular risk factors in an African American and Hispanic/Latino cohort. IJC HEART & VASCULATURE 2021; 34:100808. [PMID: 34141862 PMCID: PMC8188044 DOI: 10.1016/j.ijcha.2021.100808] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/20/2021] [Accepted: 05/24/2021] [Indexed: 12/14/2022]
Abstract
Misalignment of the internal circadian time with external physical time due to environmental factors or due to genetic variantion in circadian clock genes has been associated with increased incidence of cardiovascular risk factors. Common genetic variation in circadian genes in the United States have been identified predominantly in European ancestry individuals. We therefore examined the association between circadian clock single nucleotide polymorphisms (SNPs) in Clock, Cry1, Cry2, Bmal1 and Per3 genes and cardiovascular risk factors in African Americans and Hispanic/Latinos. We analyzed 17 candidate circadian SNPs in 1,166 subjects who self-identified as African-American or Hispanic/Latino and were enrolled in the UIC Cohort of Patients, Family and Friends. We found significant differences in the minor allele frequencies between African American and Hispanic/Latino subjects. Our analyses also established ethnic-specific SNPs that are associated with cardiovascular risk factors. In Hispanic/Latinos, the rs6850524 in Clock was associated with increased risk for hypertension, meanwhile rs12649507, rs4864546, and rs4864548 reduced the risk, also rs8192440 (Cry1) reduced the risk for type 2 diabetes. In African Americans, the Clock rs1801260 and rs6850524 were negatively associated with the presence of obesity; Bmal1 rs11022775 reduced the risk for dyslipidemia; and the Cry2 rs2292912 increased the risk for dyslipidemia and diabetes. Genetic variations in candidate circadian-clock genes are associated with risk factors for cardiovascular disease in African-Americans and Hispanic/Latinos. Our findings may help to improve cardiovascular risk assessment as well as better understand how circadian misalignment impacts cardiovascular risk in diverse populations.
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Affiliation(s)
- Pablo Salazar
- Department of Medicine, Division of Cardiology, University of Illinois at Chicago, Chicago, IL, USA
| | - Sreenivas Konda
- Division of Epidemiology and Biostatics, School of Public Health, University of Illinois at Chicago, Chicago, IL, USA
| | - Arvind Sridhar
- Department of Medicine, Division of Cardiology, University of Illinois at Chicago, Chicago, IL, USA
| | - Zarema Arbieva
- Genomics Core, Research Resources Center, University of Illinois at Chicago, Chicago, IL, USA
| | - Martha Daviglus
- Department of Medicine, Division of Cardiology, University of Illinois at Chicago, Chicago, IL, USA
- Institute for Minority Health Research, University of Illinois at Chicago, Chicago, IL, USA
| | - Dawood Darbar
- Department of Medicine, Division of Cardiology, University of Illinois at Chicago, Chicago, IL, USA
- Corresponding authors at: The University of Illinois, College of Medicine, 835 South Wolcott Avenue, RM. E403, Mailcode 868, Chicago, IL 60612, USA.
| | - Jalees Rehman
- Department of Medicine, Division of Cardiology, University of Illinois at Chicago, Chicago, IL, USA
- Department of Pharmacology and Regenerative Medicine, The University of Illinois, College of Medicine, Chicago, IL, USA
- Corresponding authors at: The University of Illinois, College of Medicine, 835 South Wolcott Avenue, RM. E403, Mailcode 868, Chicago, IL 60612, USA.
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Škrlec I, Talapko J, Juzbašić M, Steiner R. Sex Differences in Circadian Clock Genes and Myocardial Infarction Susceptibility. J Cardiovasc Dev Dis 2021; 8:53. [PMID: 34066863 PMCID: PMC8151899 DOI: 10.3390/jcdd8050053] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/23/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023] Open
Abstract
The growing body of evidence shows a significant difference in the circadian rhythm of cardiovascular disease based on biological sex. The incidence of cardiovascular disease varies between women and men. Additionally, biological sex is vital for the timely application of therapy-chronotherapy, which benefits both sexes. This study aimed to examine the potential difference of single nucleotide polymorphisms (SNPs) of the circadian rhythm genes ARNTL, CLOCK, CRY2 and PER2 in women and men with myocardial infarction. A cross-sectional study was conducted, including 200 patients with myocardial infarction. Altogether, ten single nucleotide polymorphisms in the ARNTL, CLOCK, CRY2 and PER2 genes were analyzed. The Chi-square test yielded statistically significant differences in CLOCK gene rs11932595 polymorphism in a recessive genotype model between women and men with a p-value of 0.03 and an odds ratio 2.66, and a corresponding 95% confidence interval of 1.07 to 6.66. Other analyzed polymorphisms of the circadian rhythm genes ARNTL, CRY2, and PER2 did not significantly differ between the sexes. According to the study's current results, the CLOCK gene's genetic variability might affect myocardial infarction concerning biological sex.
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Affiliation(s)
- Ivana Škrlec
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, HR-31000 Osijek, Croatia; (J.T.); (M.J.)
| | - Jasminka Talapko
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, HR-31000 Osijek, Croatia; (J.T.); (M.J.)
| | - Martina Juzbašić
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, HR-31000 Osijek, Croatia; (J.T.); (M.J.)
| | - Robert Steiner
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Josipa Huttlera 4, HR-31000 Osijek, Croatia;
- Clinical Department of Cardiovascular Diseases and Intensive Care, Clinic for Internal Medicine, University Hospital Osijek, Josipa Huttlera 4, HR-31000 Osijek, Croatia
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Abstract
The endogenous timekeeping system evolved to anticipate the time of the day through the 24 hours cycle of the Earth's rotation. In mammals, the circadian clock governs rhythmic physiological and behavioral processes, including the daily oscillation in glucose metabolism, food intake, energy expenditure, and whole-body insulin sensitivity. The results from a series of studies have demonstrated that environmental or genetic alterations of the circadian cycle in humans and rodents are strongly associated with metabolic diseases such as obesity and type 2 diabetes. Emerging evidence suggests that astrocyte clocks have a crucial role in regulating molecular, physiological, and behavioral circadian rhythms such as glucose metabolism and insulin sensitivity. Given the concurrent high prevalence of type 2 diabetes and circadian disruption, understanding the mechanisms underlying glucose homeostasis regulation by the circadian clock and its dysregulation may improve glycemic control. In this review, we summarize the current knowledge on the tight interconnection between the timekeeping system, glucose homeostasis, and insulin sensitivity. We focus specifically on the involvement of astrocyte clocks, at the organism, cellular, and molecular levels, in the regulation of glucose metabolism.
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Affiliation(s)
- Olga Barca-Mayo
- Circadian and Glial Biology Lab, Physiology Department, Molecular Medicine and Chronic Diseases Research Centre (CiMUS), University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Miguel López
- NeurObesity Lab, Physiology Department, Molecular Medicine and Chronic Diseases Research Centre (CiMUS), University of Santiago de Compostela, Santiago de Compostela, Spain
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