Publications by authors named "Charna Dibner"

47 Publications

The Effects of Shift Work on Cardio-Metabolic Diseases and Eating Patterns.

Nutrients 2021 Nov 22;13(11). Epub 2021 Nov 22.

Nutrition Unit, Service of Endocrinology, Diabetes, Nutrition and Therapeutic Education, Department of Medicine, Geneva University Hospitals (HUG), 1211 Geneva, Switzerland.

Energy metabolism is tightly linked with circadian rhythms, exposure to ambient light, sleep/wake, fasting/eating, and rest/activity cycles. External factors, such as shift work, lead to a disruption of these rhythms, often called circadian misalignment. Circadian misalignment has an impact on some physiological markers. However, these proxy measurements do not immediately translate into major clinical health outcomes, as shown by later detrimental health effects of shift work and cardio-metabolic disorders. This review focuses on the effects of shift work on circadian rhythms and its implications in cardio-metabolic disorders and eating patterns. Shift work appears to be a risk factor of overweight, obesity, type 2 diabetes, elevated blood pressure, and the metabolic syndrome. However, past studies showed discordant findings regarding the changes of lipid profile and eating patterns. Most studies were either small and short lab studies, or bigger and longer cohort studies, which could not measure health outcomes in a detailed manner. These two designs explain the heterogeneity of shift schedules, occupations, sample size, and methods across studies. Given the burden of non-communicable diseases and the growing concerns about shift workers' health, novel approaches to study shift work in real contexts are needed and would allow a better understanding of the interlocked risk factors and potential mechanisms involved in the onset of metabolic disorders.
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http://dx.doi.org/10.3390/nu13114178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617838PMC
November 2021

Circadian clocks guide dendritic cells into skin lymphatics.

Nat Immunol 2021 11 18;22(11):1375-1381. Epub 2021 Oct 18.

Biomedical Center (BMC), Institute for Cardiovascular Physiology and Pathophysiology, Walter Brendel Center for Experimental Medicine (WBex), Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Planegg-Martinsried, Germany.

Migration of leukocytes from the skin to lymph nodes (LNs) via afferent lymphatic vessels (LVs) is pivotal for adaptive immune responses. Circadian rhythms have emerged as important regulators of leukocyte trafficking to LNs via the blood. Here, we demonstrate that dendritic cells (DCs) have a circadian migration pattern into LVs, which peaks during the rest phase in mice. This migration pattern is determined by rhythmic gradients in the expression of the chemokine CCL21 and of adhesion molecules in both mice and humans. Chronopharmacological targeting of the involved factors abrogates circadian migration of DCs. We identify cell-intrinsic circadian oscillations in skin lymphatic endothelial cells (LECs) and DCs that cogovern these rhythms, as their genetic disruption in either cell type ablates circadian trafficking. These observations indicate that circadian clocks control the infiltration of DCs into skin lymphatics, a process that is essential for many adaptive immune responses and relevant for vaccination and immunotherapies.
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http://dx.doi.org/10.1038/s41590-021-01040-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553624PMC
November 2021

Circadian hepatocyte clocks keep synchrony in the absence of a master pacemaker in the suprachiasmatic nucleus or other extrahepatic clocks.

Genes Dev 2021 03 18;35(5-6):329-334. Epub 2021 Feb 18.

Department of Molecular Biology, Sciences III, University of Geneva, 1211 Geneva, Switzerland.

It has been assumed that the suprachiasmatic nucleus (SCN) synchronizes peripheral circadian oscillators. However, this has never been convincingly shown, since biochemical time series experiments are not feasible in behaviorally arrhythmic animals. By using long-term bioluminescence recording in freely moving mice, we show that the SCN is indeed required for maintaining synchrony between organs. Surprisingly, however, circadian oscillations persist in the livers of mice devoid of an SCN or oscillators in cells other than hepatocytes. Hence, similar to SCN neurons, hepatocytes can maintain phase coherence in the absence of Zeitgeber signals produced by other organs or environmental cycles.
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http://dx.doi.org/10.1101/gad.346460.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919413PMC
March 2021

Proinflammatory Cytokines Perturb Mouse and Human Pancreatic Islet Circadian Rhythmicity and Induce Uncoordinated β-Cell Clock Gene Expression via Nitric Oxide, Lysine Deacetylases, and Immunoproteasomal Activity.

Int J Mol Sci 2020 Dec 23;22(1). Epub 2020 Dec 23.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 3 Blegdamsvej, DK-2200 Copenhagen N, Denmark.

Pancreatic β-cell-specific clock knockout mice develop β-cell oxidative-stress and failure, as well as glucose-intolerance. How inflammatory stress affects the cellular clock is under-investigated. Real-time recording of Per2:luciferase reporter activity in murine and human pancreatic islets demonstrated that the proinflammatory cytokine interleukin-1β (IL-1β) lengthened the circadian period. qPCR-profiling of core clock gene expression in insulin-producing cells suggested that the combination of the proinflammatory cytokines IL-1β and interferon-γ (IFN-γ) caused pronounced but uncoordinated increases in mRNA levels of multiple core clock genes, in particular of reverse-erythroblastosis virus α , in a dose- and time-dependent manner. The REV-ERBα/β agonist SR9009, used to mimic cytokine-mediated induction, reduced constitutive and cytokine-induced brain and muscle arnt-like 1 () mRNA levels in INS-1 cells as expected. SR9009 induced reactive oxygen species (ROS), reduced insulin-1/2 () mRNA and accumulated- and glucose-stimulated insulin secretion, reduced cell viability, and increased apoptosis levels, reminiscent of cytokine toxicity. In contrast, low (<5,0 μM) concentrations of SR9009 increased mRNA and accumulated insulin-secretion without affecting INS-1 cell viability, mirroring low-concentration IL-1β mediated β-cell stimulation. Inhibiting nitric oxide (NO) synthesis, the lysine deacetylase HDAC3 and the immunoproteasome reduced cytokine-mediated increases in clock gene expression. In conclusion, the cytokine-combination perturbed the intrinsic clocks operative in mouse and human pancreatic islets and induced uncoordinated clock gene expression in INS-1 cells, the latter effect associated with NO, HDAC3, and immunoproteasome activity.
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http://dx.doi.org/10.3390/ijms22010083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795908PMC
December 2020

Ether lipids, sphingolipids and toxic 1-deoxyceramides as hallmarks for lean and obese type 2 diabetic patients.

Acta Physiol (Oxf) 2021 05 14;232(1):e13610. Epub 2021 Jan 14.

Division of Endocrinology, Diabetes, Nutrition and Patient Education, Department of Medicine, University Hospital of Geneva, Geneva, Switzerland.

Aim: The worldwide increase in obesity and type 2 diabetes (T2D) represents a major health challenge. Chronically altered lipids induced by obesity further promote the development of T2D, and the accumulation of toxic lipid metabolites in serum and peripheral organs may contribute to the diabetic phenotype.

Methods: To better understand the complex metabolic pattern of lean and obese T2D and non-T2D individuals, we analysed the lipid profile of human serum, skeletal muscle and visceral adipose tissue of two cohorts by systematic mass spectrometry-based lipid analysis.

Results: Lipid homeostasis was strongly altered in a disease- and tissue-specific manner, allowing us to define T2D signatures associated with obesity from those that were obesity independent. Lipid changes encompassed lyso-, diacyl- and ether-phospholipids. Moreover, strong changes in sphingolipids included cytotoxic 1-deoxyceramide accumulation in a disease-specific manner in serum and visceral adipose tissue. The high amounts of non-canonical 1-deoxyceramide present in human adipose tissue most likely come from cell-autonomous synthesis because 1-deoxyceramide production increased upon differentiation to adipocytes in mouse cell culture experiments.

Conclusion: Taken together, the observed lipidome changes in obesity and T2D will facilitate the identification of T2D patient subgroups and represent an important step towards personalized medicine in diabetes.
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http://dx.doi.org/10.1111/apha.13610DOI Listing
May 2021

Circadian Lipidomics: Analysis of Lipid Metabolites Around the Clock.

Methods Mol Biol 2021 ;2130:169-183

Division of Endocrinology, Diabetes and Nutrition Division, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

Lipidomics has been defined as the large-scale analysis of lipids in organelles, cells, tissues, or whole organisms. Including the temporal aspects of lipid metabolic changes into this analysis allows to access yet another important aspect of lipid regulation. The resulting methodology, circadian lipidomics, has thus emerged as a novel tool to address the enormous complexity, which is present among cellular lipids. Here, we describe how mass spectrometry-based circadian lipidomics can be applied to study the impact of peripheral clocks on lipid metabolism in human primary cells and tissues, exemplified by studies in human pancreatic islets and skeletal myotubes.
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http://dx.doi.org/10.1007/978-1-0716-0381-9_13DOI Listing
March 2021

The core clock transcription factor BMAL1 drives circadian β-cell proliferation during compensatory regeneration of the endocrine pancreas.

Genes Dev 2020 12 12;34(23-24):1650-1665. Epub 2020 Nov 12.

Division of Endocrinology, Diabetes, Nutrition, and Patient Education, Department of Medicine, University of Geneva, 1211 Geneva, Switzerland.

Circadian clocks in pancreatic islets participate in the regulation of glucose homeostasis. Here we examined the role of these timekeepers in β-cell regeneration after the massive ablation of β cells by doxycycline-induced expression of diphtheria toxin A (DTA) in Insulin-rtTA/TET-DTA mice. Since we crossed reporter genes expressing α- and β-cell-specific fluorescent proteins into these mice, we could follow the fate of α- and β cells separately. As expected, DTA induction resulted in an acute hyperglycemia, which was accompanied by dramatic changes in gene expression in residual β cells. In contrast, only temporal alterations of gene expression were observed in α cells. Interestingly, β cells entered S phase preferentially during the nocturnal activity phase, indicating that the diurnal rhythm also plays a role in the orchestration of β-cell regeneration. Indeed, in arrhythmic -deficient mice, which lack circadian clocks, no compensatory β-cell proliferation was observed, and the β-cell ablation led to aggravated hyperglycemia, hyperglucagonemia, and fatal diabetes.
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http://dx.doi.org/10.1101/gad.343137.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706703PMC
December 2020

Coupled network of the circadian clocks: a driving force of rhythmic physiology.

FEBS Lett 2020 09 20;594(17):2734-2769. Epub 2020 Aug 20.

Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

The circadian system is composed of coupled endogenous oscillators that allow living beings, including humans, to anticipate and adapt to daily changes in their environment. In mammals, circadian clocks form a hierarchically organized network with a 'master clock' located in the suprachiasmatic nucleus of the hypothalamus, which ensures entrainment of subsidiary oscillators to environmental cycles. Robust rhythmicity of body clocks is indispensable for temporally coordinating organ functions, and the disruption or misalignment of circadian rhythms caused for instance by modern lifestyle is strongly associated with various widespread diseases. This review aims to provide a comprehensive overview of our current knowledge about the molecular architecture and system-level organization of mammalian circadian oscillators. Furthermore, we discuss the regulatory roles of peripheral clocks for cell and organ physiology and their implication in the temporal coordination of metabolism in human health and disease. Finally, we summarize methods for assessing circadian rhythmicity in humans.
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http://dx.doi.org/10.1002/1873-3468.13898DOI Listing
September 2020

The GLP-1R agonist liraglutide limits hepatic lipotoxicity and inflammatory response in mice fed a methionine-choline deficient diet.

Transl Res 2021 01 22;227:75-88. Epub 2020 Jul 22.

Service of Endocrinology, Diabetes, Nutrition and Patient Education, Department of Internal Medicine, Geneva University Hospitals/University of Geneva, Geneva, Switzerland; Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland. Electronic address:

Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disorder related to type 2 diabetes (T2D). The disease can evolve toward nonalcoholic steatohepatitis (NASH), a state of hepatic inflammation and fibrosis. There is presently no drug that effectively improves and/or prevents NAFLD/NASH/fibrosis. GLP-1 receptor agonists (GLP-1Ra) are effective in treating T2D. As with the endogenous gut incretins, GLP-1Ra potentiate glucose-induced insulin secretion. In addition, GLP-1Ra limit food intake and weight gain, additional beneficial properties in the context of obesity/insulin-resistance. Nevertheless, these pleiotropic effects of GLP-1Ra complicate the elucidation of their direct action on the liver. In the present study, we used the classical methionine-choline deficient (MCD) dietary model to investigate the potential direct hepatic actions of the GLP-1Ra liraglutide. A 4-week infusion of liraglutide (570 µg/kg/day) did not impact body weight, fat accretion or glycemic control in MCD-diet fed mice, confirming the suitability of this model for avoiding confounding factors. Liraglutide treatment did not prevent lipid deposition in the liver of MCD-fed mice but limited the accumulation of C16 and C24-ceramide/sphingomyelin species. In addition, liraglutide treatment alleviated hepatic inflammation (in particular accumulation of M1 pro-inflammatory macrophages) and initiation of fibrosis. Liraglutide also influenced the composition of gut microbiota induced by the MCD-diet. This included recovery of a normal Bacteroides proportion and, among the Erysipelotrichaceae family, a shift between Allobaculum and Turicibacter genera. In conclusion, liraglutide prevents accumulation of C16 and C24-ceramides/sphingomyelins species, inflammation and initiation of fibrosis in MCD-diet-fed mice liver, suggesting beneficial hepatic actions independent of weight loss and global hepatic steatosis.
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http://dx.doi.org/10.1016/j.trsl.2020.07.008DOI Listing
January 2021

Circadian Clocks Make Metabolism Run.

J Mol Biol 2020 05 26;432(12):3680-3699. Epub 2020 Jan 26.

Department of Medicine, Division of Endocrinology, Diabetes, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Rue Michel-Servet, 1, CH-1211, Geneva, 14, Switzerland; Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland. Electronic address:

Most organisms adapt to the 24-h cycle of the Earth's rotation by anticipating the time of the day through light-dark cycles. The internal time-keeping system of the circadian clocks has been developed to ensure this anticipation. The circadian system governs the rhythmicity of nearly all physiological and behavioral processes in mammals. In this review, we summarize current knowledge stemming from rodent and human studies on the tight interconnection between the circadian system and metabolism in the body. In particular, we highlight recent advances emphasizing the roles of the peripheral clocks located in the metabolic organs in regulating glucose, lipid, and protein homeostasis at the organismal and cellular levels. Experimental disruption of circadian system in rodents is associated with various metabolic disturbance phenotypes. Similarly, perturbation of the clockwork in humans is linked to the development of metabolic diseases. We discuss recent studies that reveal roles of the circadian system in the temporal coordination of metabolism under physiological conditions and in the development of human pathologies.
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http://dx.doi.org/10.1016/j.jmb.2020.01.018DOI Listing
May 2020

In pancreatic islets from type 2 diabetes patients, the dampened circadian oscillators lead to reduced insulin and glucagon exocytosis.

Proc Natl Acad Sci U S A 2020 02 21;117(5):2484-2495. Epub 2020 Jan 21.

Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Geneva, 1211 Geneva, Switzerland;

Circadian clocks operative in pancreatic islets participate in the regulation of insulin secretion in humans and, if compromised, in the development of type 2 diabetes (T2D) in rodents. Here we demonstrate that human islet α- and β-cells that bear attenuated clocks exhibit strongly disrupted insulin and glucagon granule docking and exocytosis. To examine whether compromised clocks play a role in the pathogenesis of T2D in humans, we quantified parameters of molecular clocks operative in human T2D islets at population, single islet, and single islet cell levels. Strikingly, our experiments reveal that islets from T2D patients contain clocks with diminished circadian amplitudes and reduced in vitro synchronization capacity compared to their nondiabetic counterparts. Moreover, our data suggest that islet clocks orchestrate temporal profiles of insulin and glucagon secretion in a physiological context. This regulation was disrupted in T2D subjects, implying a role for the islet cell-autonomous clocks in T2D progression. Finally, Nobiletin, an agonist of the core-clock proteins RORα/γ, boosted both circadian amplitude of T2D islet clocks and insulin secretion by these islets. Our study emphasizes a link between the circadian clockwork and T2D and proposes that clock modulators hold promise as putative therapeutic agents for this frequent disorder.
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http://dx.doi.org/10.1073/pnas.1916539117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007532PMC
February 2020

Multi-technique comparison of atherogenic and MCD NASH models highlights changes in sphingolipid metabolism.

Sci Rep 2019 11 14;9(1):16810. Epub 2019 Nov 14.

Service of Endocrinology, Diabetes, Hypertension and Nutrition, Department of Internal Medicine, Geneva University Hospitals/University of Geneva, Geneva, Switzerland.

Lipotoxicity is a key player in the pathogenesis of nonalcoholic steatohepatitis (NASH), a progressive subtype of nonalcoholic fatty liver disease (NAFLD). In the present study, we combine histological, transcriptional and lipidomic approaches to dissociate common and specific alterations induced by two classical dietary NASH models (atherogenic (ATH) and methionine/choline deficient (MCD) diet) in C57BL/6J male mice. Despite a similar degree of steatosis, MCD-fed mice showed more pronounced liver damage and a worsened pro-inflammatory and pro-fibrogenic environment than ATH-fed mice. Regarding lipid metabolism, the ATH diet triggered hepatic counter regulatory mechanisms, while the MCD diet worsened liver lipid accumulation by a concomitant increase in lipid import and reduction in lipid export. Liver lipidomics revealed sphingolipid enrichment in both NASH models that was accompanied by an upregulation of the ceramide biosynthesis pathway and a significant rise in dihydroceramide levels. In contrast, the phospholipid composition was not substantially altered by the ATH diet, whereas the livers of MCD-fed mice presented a reduced phosphatidylcholine to phosphatidylethanolamine (PC/PE) ratio and a strong depletion in phospholipids containing the sum of 34-36 carbons in their fatty acid chains. Therefore, the assessment of liver damage at the histological and transcriptional level combined with a lipidomic analysis reveals sphingolipids as shared mediators in liver lipotoxicity and pathogenesis of NASH.
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http://dx.doi.org/10.1038/s41598-019-53346-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856196PMC
November 2019

Validation of molecular biomarkers for preoperative diagnostics of human papillary thyroid carcinoma in fine needle aspirates.

Gland Surg 2019 Aug;8(Suppl 2):S62-S76

Division of Endocrinology, Diabetes, Hypertension and Nutrition, Department of Internal Medicine Specialties, University Hospital of Geneva, Geneva, Switzerland.

Background: Despite substantial efforts, reliable preoperative diagnostic for human thyroid malignancies in case of cytologically indeterminate nodules is still missing, resulting in high number of unnecessary thyroidectomies. In an attempt to increase precision of existing preoperative diagnostics, we aimed at validating the panel of molecular biomarkers predictive for papillary thyroid carcinoma (PTC) in preoperative fine needle aspirate (FNA) samples.

Methods: In this prospective study conducted in preoperative thyroid FNA from 44 thyroid nodules, expression levels of 11 molecular biomarkers previously validated on the postoperative samples of PTCs were measured by Cell-to-CT and QuantiGene Plex methods and correlated with final diagnosis.

Results: The QuantiGene Plex resulted in reliable gene expression measurements for FNA and core-needle biopsy (CNB) samples, however this method was less sensitive than pre-amplification based Cell-to-CT. Measurements conducted on the same samples by the two methods significantly correlated for most of the genes. Expression levels of , and were upregulated in PTC nodules as compared to benign counterparts, supporting previous post-operative studies. Strong correlation was observed between these biomarker alterations in the same samples. Within the sub-group of 15 indeterminate nodules (Bethesda II-V), had 100% specificity and 83% sensitivity for PTC cases.

Conclusions: Assessment of , and core-clock gene expression levels by QuantiGene Plex assay in FNA samples holds promise as an ancillary method to the cytological preoperative diagnostics.
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http://dx.doi.org/10.21037/gs.2018.11.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694023PMC
August 2019

Cellular circadian period length inversely correlates with HbA levels in individuals with type 2 diabetes.

Diabetologia 2019 08 27;62(8):1453-1462. Epub 2019 May 27.

Department of Medicine, Division of Endocrinology, Diabetes, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Rue Michel-Servet, 1, CH-1211, 14, Geneva, Switzerland.

Aims/hypothesis: The circadian system plays an essential role in regulating the timing of human metabolism. Indeed, circadian misalignment is strongly associated with high rates of metabolic disorders. The properties of the circadian oscillator can be measured in cells cultured in vitro and these cellular rhythms are highly informative of the physiological circadian rhythm in vivo. We aimed to discover whether molecular properties of the circadian oscillator are altered as a result of type 2 diabetes.

Methods: We assessed molecular clock properties in dermal fibroblasts established from skin biopsies taken from nine obese and eight non-obese individuals with type 2 diabetes and 11 non-diabetic control individuals. Following in vitro synchronisation, primary fibroblast cultures were subjected to continuous assessment of circadian bioluminescence profiles based on lentiviral luciferase reporters.

Results: We observed a significant inverse correlation (ρ = -0.592; p < 0.05) between HbA values and circadian period length within cells from the type 2 diabetes group. RNA sequencing analysis conducted on samples from this group revealed that ICAM1, encoding the endothelial adhesion protein, was differentially expressed in fibroblasts from individuals with poorly controlled vs well-controlled type 2 diabetes and its levels correlated with cellular period length. Consistent with this circadian link, the ICAM1 gene also displayed rhythmic binding of the circadian locomotor output cycles kaput (CLOCK) protein that correlated with gene expression.

Conclusions/interpretation: We provide for the first time a potential molecular link between glycaemic control in individuals with type 2 diabetes and circadian clock machinery. This paves the way for further mechanistic understanding of circadian oscillator changes upon type 2 diabetes development in humans.

Data Availability: RNA sequencing data and clinical phenotypic data have been deposited at the European Genome-phenome Archive (EGA), which is hosted by the European Bioinformatics Institute (EBI) and the Centre for Genomic Regulation (CRG), ega-box-1210, under accession no. EGAS00001003622.
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http://dx.doi.org/10.1007/s00125-019-4907-0DOI Listing
August 2019

The importance of being rhythmic: Living in harmony with your body clocks.

Authors:
Charna Dibner

Acta Physiol (Oxf) 2020 01 3;228(1):e13281. Epub 2019 May 3.

Division of Endocrinology, Diabetes, Hypertension and Nutrition, Department of Medicine, University Hospital of Geneva, Geneva, Switzerland.

Circadian rhythms have developed in all light-sensitive organisms, including humans, as a fundamental anticipatory mechanism that enables proactive adaptation to environmental changes. The circadian system is organized in a highly hierarchical manner, with clocks operative in most cells of the body ensuring the temporal coordination of physiological processes. Circadian misalignment, stemming from modern life style, draws increasing attention due to its tight association with the development of metabolic, cardiovascular, inflammatory and mental diseases as well as cancer. This review highlights recent findings emphasizing the role of the circadian system in the temporal orchestration of physiology, with a particular focus on implications of circadian misalignment in human pathologies.
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http://dx.doi.org/10.1111/apha.13281DOI Listing
January 2020

Time zones of pancreatic islet metabolism.

Diabetes Obes Metab 2018 09;20 Suppl 2:116-126

Division of Endocrinology, Diabetes, Hypertension and Nutrition, Department of Internal Medicine Specialties, University Hospital of Geneva, Geneva, Switzerland.

Most living beings possess an intrinsic system of circadian oscillators, allowing anticipation of the Earth's rotation around its own axis. The mammalian circadian timing system orchestrates nearly all aspects of physiology and behaviour. Together with systemic signals originating from the central clock that resides in the hypothalamic suprachiasmatic nucleus, peripheral oscillators orchestrate tissue-specific fluctuations in gene transcription and translation, and posttranslational modifications, driving overt rhythms in physiology and behaviour. There is accumulating evidence of a reciprocal connection between the circadian oscillator and most aspects of physiology and metabolism, in particular as the circadian system plays a critical role in orchestrating body glucose homeostasis. Recent reports imply that circadian clocks operative in the endocrine pancreas regulate insulin secretion, and that islet clock perturbation in rodents leads to the development of overt type 2 diabetes. While whole islet clocks have been extensively studied during the last years, the heterogeneity of islet cell oscillators and the interplay between α- and β-cellular clocks for orchestrating glucagon and insulin secretion have only recently gained attention. Here, we review recent findings on the molecular makeup of the circadian clocks operative in pancreatic islet cells in rodents and in humans, and focus on the physiologically relevant synchronizers that are resetting these time-keepers. Moreover, the implication of islet clock functional outputs in the temporal coordination of metabolism in health and disease will be highlighted.
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http://dx.doi.org/10.1111/dom.13383DOI Listing
September 2018

Identification of Differential Transcriptional Patterns in Primary and Secondary Hyperparathyroidism.

J Clin Endocrinol Metab 2018 06;103(6):2189-2198

Division of Endocrinology, Diabetes, Hypertension and Nutrition, University Hospitals of Geneva, Geneva, Switzerland.

Context: Hyperparathyroidism is associated with hypercalcemia and the excess of parathyroid hormone secretion; however, the alterations in molecular pattern of functional genes during parathyroid tumorigenesis have not been unraveled. We aimed at establishing transcriptional patterns of normal and pathological parathyroid glands (PGs) in sporadic primary (HPT1) and secondary hyperparathyroidism (HPT2).

Objective: To evaluate dynamic alterations in molecular patterns as a function of the type of PG pathology, a comparative transcript analysis was conducted in subgroups of healthy samples, sporadic HPT1 adenoma and hyperplasia, and HPT2.

Design: Normal, adenomatous, HPT1, and HPT2 hyperplastic PG formalin-fixed paraffin-embedded samples were subjected to NanoString analysis. In silico microRNA (miRNA) analyses and messenger RNA-miRNA network in PG pathologies were conducted. Individual messenger RNA and miRNA levels were assessed in snap-frozen PG samples.

Results: The expression levels of c-MET, MYC, TIMP1, and clock genes NFIL3 and PER1 were significantly altered in HPT1 adenoma compared with normal PG tissue when assessed by NanoString and quantitative reverse transcription polymerase chain reaction. RET was affected in HPT1 hyperplasia, whereas CaSR and VDR transcripts were downregulated in HPT2 hyperplastic PG tissue. CDH1, c-MET, MYC, and CaSR were altered in adenoma compared with hyperplasia. Correlation analyses suggest that c-MET, MYC, and NFIL3 exhibit collective expression level changes associated with HPT1 adenoma development. miRNAs, predicted in silico to target these genes, did not exhibit a clear tendency upon experimental validation.

Conclusions: The presented gene expression analysis provides a differential molecular characterization of PG adenoma and hyperplasia pathologies, advancing our understanding of their etiology.
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http://dx.doi.org/10.1210/jc.2017-02506DOI Listing
June 2018

Transcriptomic analyses reveal rhythmic and CLOCK-driven pathways in human skeletal muscle.

Elife 2018 04 16;7. Epub 2018 Apr 16.

Division of Endocrinology, Diabetes, Hypertension and Nutrition, Department of Internal Medicine Specialties, University Hospital of Geneva, Geneva, Switzerland.

Circadian regulation of transcriptional processes has a broad impact on cell metabolism. Here, we compared the diurnal transcriptome of human skeletal muscle conducted on serial muscle biopsies in vivo with profiles of human skeletal myotubes synchronized in vitro. More extensive rhythmic transcription was observed in human skeletal muscle compared to in vitro cell culture as a large part of the in vivo mRNA rhythmicity was lost in vitro. siRNA-mediated clock disruption in primary myotubes significantly affected the expression of ~8% of all genes, with impact on glucose homeostasis and lipid metabolism. Genes involved in GLUT4 expression, translocation and recycling were negatively affected, whereas lipid metabolic genes were altered to promote activation of lipid utilization. Moreover, basal and insulin-stimulated glucose uptake were significantly reduced upon depletion. Our findings suggest an essential role for the circadian coordination of skeletal muscle glucose homeostasis and lipid metabolism in humans.
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http://dx.doi.org/10.7554/eLife.34114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902165PMC
April 2018

Lipidomics reveals diurnal lipid oscillations in human skeletal muscle persisting in cellular myotubes cultured in vitro.

Proc Natl Acad Sci U S A 2017 10 25;114(41):E8565-E8574. Epub 2017 Sep 25.

Division of Endocrinology, Diabetology, Hypertension and Nutrition, Department of Internal Medicine Specialties, University of Geneva, CH-1211 Geneva, Switzerland;

Circadian clocks play an important role in lipid homeostasis, with impact on various metabolic diseases. Due to the central role of skeletal muscle in whole-body metabolism, we aimed at studying muscle lipid profiles in a temporal manner. Moreover, it has not been shown whether lipid oscillations in peripheral tissues are driven by diurnal cycles of rest-activity and food intake or are able to persist in vitro in a cell-autonomous manner. To address this, we investigated lipid profiles over 24 h in human skeletal muscle in vivo and in primary human myotubes cultured in vitro. Glycerolipids, glycerophospholipids, and sphingolipids exhibited diurnal oscillations, suggesting a widespread circadian impact on muscle lipid metabolism. Notably, peak levels of lipid accumulation were in phase coherence with core clock gene expression in vivo and in vitro. The percentage of oscillating lipid metabolites was comparable between muscle tissue and cultured myotubes, and temporal lipid profiles correlated with transcript profiles of genes implicated in their biosynthesis. Lipids enriched in the outer leaflet of the plasma membrane oscillated in a highly coordinated manner in vivo and in vitro. Lipid metabolite oscillations were strongly attenuated upon siRNA-mediated clock disruption in human primary myotubes. Taken together, our data suggest an essential role for endogenous cell-autonomous human skeletal muscle oscillators in regulating lipid metabolism independent of external synchronizers, such as physical activity or food intake.
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http://dx.doi.org/10.1073/pnas.1705821114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642690PMC
October 2017

MicroRNAs modulate core-clock gene expression in pancreatic islets during early postnatal life in rats.

Diabetologia 2017 10 4;60(10):2011-2020. Epub 2017 Jul 4.

Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, 1005, Lausanne, Switzerland.

Aims/hypothesis: Evidence continues to emerge detailing a fine-tuning of the regulation of metabolic processes and energy homeostasis by cell-autonomous circadian clocks. Pancreatic beta cell functional maturation occurs after birth and implies transcriptional changes triggered by a shift in the nutritional supply that occurs at weaning, enabling the adaptation of insulin secretion. So far, the developmental timing and exact mechanisms involved in the initiation of the circadian clock in the growing pancreatic islets have never been addressed.

Methods: Circadian gene expression was measured by quantitative RT-PCR in islets of rats at different postnatal ages up to 3 months, and by in vitro bioluminescence recording in newborn (10-day-old) and adult (3-month-old) islets. The effect of the microRNAs miR-17-5p and miR-29b-3p on the expression of target circadian genes was assessed in newborn rat islets transfected with microRNA antisense or mimic oligonucleotides, and luciferase reporter assays were performed on the rat insulin-secreting cell line INS832/13 to determine a direct effect. The global regulatory network between microRNAs and circadian genes was computationally predicted.

Results: We found up to a sixfold-change in the 24 h transcriptional oscillations and overall expression of Clock, Npas2, Bmal1, Bmal2, Rev-erbα, Per1, Per2, Per3 and Cry2 between newborn and adult rat islets. Synchronisation of the clock machinery in cultured islet cells revealed a delayed cell-autonomous rhythmicity of about 1.5 h in newborn compared with adult rats. Computational predictions unveiled the existence of a complex regulatory network linking over 40 microRNAs displaying modifications in their expression profiles during postnatal beta cell maturation and key core-clock genes. In agreement with these computational predictions, we demonstrated that miR-17-5p and miR-29b-3p directly regulated circadian gene expression in the maturing islet cells of 10-day-old rats.

Conclusions/interpretation: These data show that the circadian clock is not fully operational in newborn islets and that microRNAs potently contribute to its regulation during postnatal beta cell maturation. Defects in this process may have long-term consequences on circadian physiology and pancreatic islet function, favouring the manifestation of metabolic diseases such as diabetes.
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http://dx.doi.org/10.1007/s00125-017-4348-6DOI Listing
October 2017

Glucose Uptake Measurement and Response to Insulin Stimulation in In Vitro Cultured Human Primary Myotubes.

J Vis Exp 2017 06 25(124). Epub 2017 Jun 25.

CarMeN Laboratory, INSERM U1060, INRA 1397, University of Lyon;

Skeletal muscle is the largest glucose deposit in mammals and largely contributes to glucose homeostasis. Assessment of insulin sensitivity of muscle cells is of major relevance for all studies dedicated to exploring muscle glucose metabolism and characterizing metabolic alterations. In muscle cells, glucose transporter type 4 (GLUT4) proteins translocate to the plasma membrane in response to insulin, thus allowing massive entry of glucose into the cell. The ability of muscle cells to respond to insulin by increasing the rate of glucose uptake is one of the standard readouts to quantify muscle cell sensitivity to insulin. Human primary myotubes are a suitable in vitro model, as the cells maintain many features of the donor phenotype, including insulin sensitivity. This in vitro model is also suitable for the test of any compounds that could impact insulin responsiveness. Measurements of the glucose uptake rate in differentiated myotubes reflect insulin sensitivity. In this method, human primary muscle cells are cultured in vitro to obtain differentiated myotubes, and glucose uptake rates with and without insulin stimulation are measured. We provide a detailed protocol to quantify passive and active glucose transport rates using radiolabeled [H] 2-deoxy-D-Glucose ([H]2dG). Calculation methods are provided to quantify active basal and insulin-stimulated rates, as well as stimulation fold.
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http://dx.doi.org/10.3791/55743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608504PMC
June 2017

Circadian orchestration of insulin and glucagon release.

Cell Cycle 2017 06 24;16(12):1141-1142. Epub 2017 May 24.

a Division of Endocrinology, Diabetes, Hypertension and Nutrition, Department of Internal Medicine Specialties , University Hospital of Geneva , Geneva , Switzerland.

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http://dx.doi.org/10.1080/15384101.2017.1326768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499916PMC
June 2017

High-Resolution Recording of the Circadian Oscillator in Primary Mouse α- and β-Cell Culture.

Front Endocrinol (Lausanne) 2017 7;8:68. Epub 2017 Apr 7.

Endocrinology, Diabetes, Hypertension and Nutrition Division, Department of Specialties of Medicine, University Hospital of Geneva, Geneva, Switzerland.

Circadian clocks have been developed in evolution as an anticipatory mechanism allowing for adaptation to the constantly changing light environment due to rotation of the Earth. This mechanism is functional in all light-sensitive organisms. There is a considerable body of evidence on the tight connection between the circadian clock and most aspects of physiology and metabolism. Clocks, operative in the pancreatic islets, have caught particular attention in the last years due to recent reports on their critical roles in regulation of insulin secretion and etiology of type 2 diabetes. While β-cell clocks have been extensively studied during the last years, α-cell clocks and their role in islet function and orchestration of glucose metabolism stayed unexplored, largely due to the difficulty to isolate α-cells, which represents a considerable technical challenge. Here, we provide a detailed description of an experimental approach for the isolation of separate mouse α- and β-cell population, culture of isolated primary α- and β-cells, and their subsequent long-term high-resolution circadian bioluminescence recording. For this purpose, a triple reporter -/RIP-/: mouse line was established, carrying specific fluorescent reporters for α- and β-cells, and luciferase reporter for monitoring the molecular clockwork. Flow cytometry fluorescence-activated cell sorting allowed separating pure α- and β-cell populations from isolated islets. Experimental conditions, developed by us for the culture of functional primary mouse α- and β-cells for at least 10 days, will be highlighted. Importantly, temporal analysis of freshly isolated α- and β-cells around-the-clock revealed preserved rhythmicity of core clock genes expression. Finally, we describe the setting to assess circadian rhythm in cultured α- and β-cells synchronized . The here-described methodology allows to analyze the functional properties of primary α- and β-cells under physiological or pathophysiological conditions and to assess the islet cellular clock properties.
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http://dx.doi.org/10.3389/fendo.2017.00068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383706PMC
April 2017

Glucose Homeostasis: Regulation by Peripheral Circadian Clocks in Rodents and Humans.

Endocrinology 2017 05;158(5):1074-1084

Division of Endocrinology, Diabetes, Hypertension and Nutrition, Department of Internal Medicine Specialties, University Hospital of Geneva, CH-1211 Geneva, Switzerland.

Most organisms, including humans, have developed an intrinsic system of circadian oscillators, allowing the anticipation of events related to the rotation of Earth around its own axis. The mammalian circadian timing system orchestrates nearly all aspects of physiology and behavior. Together with systemic signals, emanating from the central clock that resides in the hypothalamus, peripheral oscillators orchestrate tissue-specific fluctuations in gene expression, protein synthesis, and posttranslational modifications, driving overt rhythms in physiology and behavior. There is increasing evidence on the essential roles of the peripheral oscillators, operative in metabolically active organs in the regulation of body glucose homeostasis. Here, we review some recent findings on the molecular and cellular makeup of the circadian timing system and its implications in the temporal coordination of metabolism in health and disease.
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http://dx.doi.org/10.1210/en.2017-00218DOI Listing
May 2017

Pancreatic α- and β-cellular clocks have distinct molecular properties and impact on islet hormone secretion and gene expression.

Genes Dev 2017 02 8;31(4):383-398. Epub 2017 Mar 8.

Endocrinology, Diabetes, Hypertension, and Nutrition, University Hospital of Geneva, CH-1211 Geneva, Switzerland.

A critical role of circadian oscillators in orchestrating insulin secretion and islet gene transcription has been demonstrated recently. However, these studies focused on whole islets and did not explore the interplay between α-cell and β-cell clocks. We performed a parallel analysis of the molecular properties of α-cell and β-cell oscillators using a mouse model expressing three reporter genes: one labeling α cells, one specific for β cells, and a third monitoring circadian gene expression. Thus, phase entrainment properties, gene expression, and functional outputs of the α-cell and β-cell clockworks could be assessed in vivo and in vitro at the population and single-cell level. These experiments showed that α-cellular and β-cellular clocks are oscillating with distinct phases in vivo and in vitro Diurnal transcriptome analysis in separated α and β cells revealed that a high number of genes with key roles in islet physiology, including regulators of glucose sensing and hormone secretion, are differentially expressed in these cell types. Moreover, temporal insulin and glucagon secretion exhibited distinct oscillatory profiles both in vivo and in vitro. Altogether, our data indicate that differential entrainment characteristics of circadian α-cell and β-cell clocks are an important feature in the temporal coordination of endocrine function and gene expression.
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http://dx.doi.org/10.1101/gad.290379.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358758PMC
February 2017

The search for preoperative biomarkers for thyroid carcinoma: application of the thyroid circadian clock properties.

Biomark Med 2017 Mar 16;11(3):285-293. Epub 2017 Feb 16.

Department of Cell Physiology & Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

Accumulating evidence suggests that alterations in the molecular clocks underlying the circadian time-keeping system might be connected to changes in cell cycle, resulting in oncogenic transformation. The hypothalamic-pituitary-thyroid axis is driven by a circadian clock at several levels, with an endocrine feedback loop regulating thyroid-stimulating hormone. Changes in the expression levels of circadian and cell cycle markers may correlate with clinic-pathological characteristics in differentiated follicular thyroid carcinomas. Here we summarize recent advances in exploring complex regulation of the thyroid gland transcriptome and function by the circadian oscillator. We particularly focus on clinical implications of the parallel assessment of the circadian clock, cell-cycle and cell functionality markers in human thyroid tissue, which might help improving preoperative diagnostics of thyroid malignancies.
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http://dx.doi.org/10.2217/bmm-2016-0316DOI Listing
March 2017

Parallel Measurement of Circadian Clock Gene Expression and Hormone Secretion in Human Primary Cell Cultures.

J Vis Exp 2016 11 11(117). Epub 2016 Nov 11.

Department of Medical Specialties, Division of Endocrinology, Diabetes, Hypertension and Nutrition, Diabetes Center, University of Geneva Medical School, Institute of Genetics and Genomics in Geneva (iGE3);

Circadian clocks are functional in all light-sensitive organisms, allowing for an adaptation to the external world by anticipating daily environmental changes. Considerable progress in our understanding of the tight connection between the circadian clock and most aspects of physiology has been made in the field over the last decade. However, unraveling the molecular basis that underlies the function of the circadian oscillator in humans stays of highest technical challenge. Here, we provide a detailed description of an experimental approach for long-term (2-5 days) bioluminescence recording and outflow medium collection in cultured human primary cells. For this purpose, we have transduced primary cells with a lentiviral luciferase reporter that is under control of a core clock gene promoter, which allows for the parallel assessment of hormone secretion and circadian bioluminescence. Furthermore, we describe the conditions for disrupting the circadian clock in primary human cells by transfecting siRNA targeting CLOCK. Our results on the circadian regulation of insulin secretion by human pancreatic islets, and myokine secretion by human skeletal muscle cells, are presented here to illustrate the application of this methodology. These settings can be used to study the molecular makeup of human peripheral clocks and to analyze their functional impact on primary cells under physiological or pathophysiological conditions.
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http://dx.doi.org/10.3791/54673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226219PMC
November 2016

Identification of CHEK1, SLC26A4, c-KIT, TPO and TG as new biomarkers for human follicular thyroid carcinoma.

Oncotarget 2016 Jul;7(29):45776-45788

Department of Medical Specialties, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

The search for preoperative biomarkers for thyroid malignancies, in particular for follicular thyroid carcinoma (FTC) diagnostics, is of utmost clinical importance. We thus aimed at screening for potential biomarker candidates for FTC. To evaluate dynamic alterations in molecular patterns as a function of thyroid malignancy progression, a comparative analysis was conducted in clinically distinct subgroups of FTC and poorly differentiated thyroid carcinoma (PDTC) nodules. NanoString analysis of FFPE samples was performed in 22 follicular adenomas, 56 FTC and 25 PDTC nodules, including oncocytic and non-oncocytic subgroups. The expression levels of CHEK1, c-KIT, SLC26A4, TG and TPO were significantly altered in all types of thyroid carcinomas. Based on collective changes of these biomarkers which correlating among each other, a predictive score has been established, allowing for discrimination between benign and FTC samples with high sensitivity and specificity. Additional transcripts related to thyroid function, cell cycle, circadian clock, and apoptosis regulation were altered in the more aggressive oncocytic subgroups only, with expression levels correlating with disease progression. Distinct molecular patterns were observed for oncocytic and non-oncocytic FTCs and PDTCs. A predictive score correlation coefficient based on collective alterations of identified here biomarkers might help to improve the preoperative diagnosis of FTC nodules.
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http://dx.doi.org/10.18632/oncotarget.10166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216760PMC
July 2016

Paraoxonase 1 (PON1) and pomegranate influence circadian gene expression and period length.

Chronobiol Int 2016 24;33(4):453-61. Epub 2016 Mar 24.

a Division of Endocrinology, Diabetes and Nutrition, Department of Clinical Medicine, Faculty of Medicine , University of Geneva , Geneva , Switzerland.

The circadian timing system regulates key aspects of mammalian physiology. Here, we analyzed the effect of the endogenous antioxidant paraoxonase 1 (PON1), a high-density lipoprotein-associated lipolactonase that hydrolyses lipid peroxides and attenuates atherogenesis, on circadian gene expression in C57BL/6J and PON1KO mice fed a normal chow diet or a high-fat diet (HFD). Expression levels of core-clock transcripts Nr1d1, Per2, Cry2 and Bmal1 were altered in skeletal muscle in PON1-deficient mice in response to HFD. These findings were supported by circadian bioluminescence reporter assessments in mouse C2C12 and human primary myotubes, synchronized in vitro, where administration of PON1 or pomegranate juice modulated circadian period length.
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http://dx.doi.org/10.3109/07420528.2016.1154067DOI Listing
February 2017

Human skeletal myotubes display a cell-autonomous circadian clock implicated in basal myokine secretion.

Mol Metab 2015 Nov 6;4(11):834-45. Epub 2015 Aug 6.

Division of Endocrinology, Diabetes and Nutrition, Department of Clinical Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

Objective: Circadian clocks are functional in all light-sensitive organisms, allowing an adaptation to the external world in anticipation of daily environmental changes. In view of the potential role of the skeletal muscle clock in the regulation of glucose metabolism, we aimed to characterize circadian rhythms in primary human skeletal myotubes and investigate their roles in myokine secretion.

Methods: We established a system for long-term bioluminescence recording in differentiated human myotubes, employing lentivector gene delivery of the Bmal1-luciferase and Per2-luciferase core clock reporters. Furthermore, we disrupted the circadian clock in skeletal muscle cells by transfecting siRNA targeting CLOCK. Next, we assessed the basal secretion of a large panel of myokines in a circadian manner in the presence or absence of a functional clock.

Results: Bioluminescence reporter assays revealed that human skeletal myotubes, synchronized in vitro, exhibit a self-sustained circadian rhythm, which was further confirmed by endogenous core clock transcript expression. Moreover, we demonstrate that the basal secretion of IL-6, IL-8 and MCP-1 by synchronized skeletal myotubes has a circadian profile. Importantly, the secretion of IL-6 and several additional myokines was strongly downregulated upon siClock-mediated clock disruption.

Conclusions: Our study provides for the first time evidence that primary human skeletal myotubes possess a high-amplitude cell-autonomous circadian clock, which could be attenuated. Furthermore, this oscillator plays an important role in the regulation of basal myokine secretion by skeletal myotubes.
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http://dx.doi.org/10.1016/j.molmet.2015.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632112PMC
November 2015
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