scholarly journals Ghrelin Restores the Disruption of the Circadian Clock in Steatotic Liver

2018 ◽  
Vol 19 (10) ◽  
pp. 3134 ◽  
Author(s):  
Qin Wang ◽  
Yue Yin ◽  
Weizhen Zhang
Keyword(s):  
Circadian Rhythm ◽  
Circadian Clock ◽  
Clock Gene ◽  
Clock Genes ◽  
Obese Mice ◽  
Cultured Hepatocytes ◽  
Steatotic Liver ◽  
Protein Levels ◽  
Feeding Cycle ◽  
Circadian Clock Genes

Obese mice demonstrate disruption of the circadian clock and feeding cycle. Circulating ghrelin, a hormone secreted mainly by gastric X/Alike cells, is significantly reduced in obese humans and animals. Here, we examined whether ghrelin improves the disruption of the circadian rhythm in steatotic hepatocytes and liver. The effects of ghrelin on hepatic circadian clock genes were studied in steatotic hepatocytes and liver of mice fed a high-fat diet (HFD) for 12 weeks. The circadian clock of cultured hepatocytes was synchronized by treatment with 100 nM dexamethasone for 1 h. Ghrelin was administrated to the cultured hepatocytes (10−8 M) or to mice at a dose of 11 nmol/kg/d for two weeks via a subcutaneous minipump. The mRNA and protein levels of core clock genes were analyzed. Steatosis significantly blunted the circadian pattern of clock genes such as Bmal1, Clock, and Per in cultured hepatocytes and liver. Treatment with ghrelin markedly restored the daily rhythm of the clock genes, with a robust oscillation between peak and trough in cultured hepatocytes isolated from obese mice. It also increased the abundance and expression amplitude of clock genes in steatotic liver, causing the peak of Clock to shift to the dark period and the peak of Per2 to shift to the light period compared with the control groups. Deletion of GHSR1a further deteriorated the derangement of clock gene patterns in obese mice. Ghrelin significantly increased the oscillations of mTOR/S6 signaling. We demonstrate that ghrelin restored the derangement of the circadian rhythm in steatotic liver via mTOR signaling.

scholarly journals Ablation of Sirtuin 1 Deacetylase Activity Induces Pulmonary Emphysema by Inducing Cellular Senescence and Disrupting Circadian Clock in Mice (P01-022-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Xiang-Dong Wang ◽  
Kang-Quan Hu ◽  
Chun Liu ◽  
Michael McBurney
Keyword(s):  
Circadian Clock ◽  
Mrna Expression ◽  
Cellular Senescence ◽  
Pulmonary Emphysema ◽  
Clock Genes ◽  
Causal Effect ◽  
Sirtuin 1 ◽  
Wild Type ◽  
Protein Levels ◽  
Circadian Clock Genes

Abstract Objectives Sirtuin 1 (SIRT1), a NAD+-dependent protein/histone deacetylase has the capability to extend life span, delay aging, and prevent aging-related diseases. There are several reports showing that there is no significant decline in SIRT1 protein with age, indicating that SIRT1 protein levels alone may not reflect its deacetylase activity. We investigated the causal effect of systemic ablation of SIRT1 deacetylase activity on aging-related pulmonary disease development in mice. Methods We used Sirt1y/y homozygous male mice carrying a point mutation (H355Y) that ablates the deacetylase activity, along with their wild type littermates (Sirt1+/+), and followed them for 6, 10 and 18 months of age. Results Sirt1y/y homozygous mice developed severe pulmonary emphysema at the ages of 6, 10 and 18 months, with the respective incidences of 33%, 100% and 100%, while the Sirt1+/+wild-type mice only developed emphysema (13% incidence) at 18 months of age. The development of emphysema in Sirt1y/y mice was accompanied with higher protein levels of matrix metalloproteinase (MMP)-2, MMP9, and tissue inhibitor of metalloproteinase-1, and ratio of cleaved/total anti-poly (ADP-ribose) polymerase. The ablation of SIRT1 activity significantly up-regulated mRNA expression of hypoxia-inducible factor-1α and retinoic acid receptor-b, while p21 protein and phosphorylated AMPK increased and phosphorylated ribosomal S6 decreased, suggesting the association of ablation of SIRT1 activity with cellular quiescence and senescence. Additionally, the lack of SIRT1 activity down-regulated the mRNA expression of circadian clock genes (BMAL1, NPAS2, CRY1, CRY2) in the lungs of Sirt1y/y mice, as compared with that of Sirt1+/+ mice. There were no inflammatory responses in the lungs (e.g., inflammatory cell infiltrations, mRNA expressions of IL-6 and TNFα) in Sirt1y/y homozygous mice compared to Sirt1+/+ mice. Conclusions The lacking of SIRT1 enzymatic activity plays a major role in the susceptibility of organs to aging and pulmonary emphysema development by inducing cellular senescence and disrupting circadian clock genes. Funding Sources USDA/ARS (58-1950-0074) and NIFA/AFRI (2017-67017-26363).

scholarly journals The Molecular Evolution of Circadian Clock Genes in Spotted Gar (Lepisosteus oculatus)

Genes ◽  
2019 ◽  
Vol 10 (8) ◽  
pp. 622 ◽  
Author(s):  
Yi Sun ◽  
Chao Liu ◽  
Moli Huang ◽  
Jian Huang ◽  
Changhong Liu ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Teleost Fish ◽  
Clock Gene ◽  
Genome Duplication ◽  
Clock Genes ◽  
Gene Families ◽  
Regulatory Mechanisms ◽  
Spotted Gar ◽  
Circadian Clock Genes ◽  
Lepisosteus Oculatus

Circadian rhythms are biological rhythms with a period of approximately 24 h. While canonical circadian clock genes and their regulatory mechanisms appear highly conserved, the evolution of clock gene families is still unclear due to several rounds of whole genome duplication in vertebrates. The spotted gar (Lepisosteus oculatus), as a non-teleost ray-finned fish, represents a fish lineage that diverged before the teleost genome duplication (TGD), providing an outgroup for exploring the evolutionary mechanisms of circadian clocks after whole-genome duplication. In this study, we interrogated the spotted gar draft genome sequences and found that spotted gar contains 26 circadian clock genes from 11 families. Phylogenetic analysis showed that 9 of these 11 spotted gar circadian clock gene families have the same number of genes as humans, while the members of the nfil3 and cry families are different between spotted gar and humans. Using phylogenetic and syntenic analyses, we found that nfil3-1 is conserved in vertebrates, while nfil3-2 and nfil3-3 are maintained in spotted gar, teleost fish, amphibians, and reptiles, but not in mammals. Following the two-round vertebrate genome duplication (VGD), spotted gar retained cry1a, cry1b, and cry2, and cry3 is retained in spotted gar, teleost fish, turtles, and birds, but not in mammals. We hypothesize that duplication of core clock genes, such as (nfil3 and cry), likely facilitated diversification of circadian regulatory mechanisms in teleost fish. We also found that the transcription factor binding element (Ahr::Arnt) is retained only in one of the per1 or per2 duplicated paralogs derived from the TGD in the teleost fish, implicating possible subfuctionalization cases. Together, these findings help decipher the repertoires of the spotted gar’s circadian system and shed light on how the vertebrate circadian clock systems have evolved.

Modulatory effects of 5-fluorouracil on the rhythmic expression of circadian clock genes: A possible mechanism of chemotherapy-induced circadian rhythm disturbances

2008 ◽  
Vol 75 (8) ◽  
pp. 1616-1622 ◽  
Author(s):  
Hideyuki Terazono ◽  
Ahmed Hamdan ◽  
Naoya Matsunaga ◽  
Naoto Hayasaka ◽  
Hiroaki Kaji ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Circadian Clock ◽  
Clock Genes ◽  
Rhythmic Expression ◽  
Circadian Clock Genes

scholarly journals Poor Sleep Quality Is Associated with Dawn Phenomenon and Impaired Circadian Clock Gene Expression in Subjects with Type 2 Diabetes Mellitus

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Yuxin Huang ◽  
Haidong Wang ◽  
Yuan Li ◽  
Xiaoming Tao ◽  
Jiao Sun
Keyword(s):  
Sleep Quality ◽  
Circadian Clock ◽  
Clock Gene ◽  
Clock Genes ◽  
Poor Sleep ◽  
Poor Sleep Quality ◽  
Clock Gene Expression ◽  
Dawn Phenomenon ◽  
Circadian Clock Genes ◽  
Good Sleep

Aims. We investigated whether poor sleep quality is associated with both dawn phenomenon and impaired circadian clock gene expression in subjects with diabetes. Methods. 81 subjects with diabetes on continuous glucose monitoring were divided into two groups according to the Pittsburgh Sleep Quality Index. The magnitude of dawn phenomenon was quantified by its increment from nocturnal nadir to prebreakfast. Peripheral leucocytes were sampled from 81 subjects with diabetes and 28 normal controls at 09:00. Transcript levels of circadian clock genes (BMAL1, PER1, PER2, and PER3) were determined by real-time quantitative polymerase chain reaction. Results. The levels of HbA1c and fasting glucose and the magnitude of dawn phenomenon were significantly higher in the diabetes group with poor sleep quality than that with good sleep quality. Peripheral leucocytes from subjects with poor sleep quality expressed significantly lower transcript levels of BMAL1 and PER1 compared with those with good sleep quality. Poor sleep quality was significantly correlated with magnitude of dawn phenomenon. Multiple linear regression showed that sleep quality and PER1 were significantly independently correlated with dawn phenomenon. Conclusions. Dawn phenomenon is associated with sleep quality. Furthermore, mRNA expression of circadian clock genes is dampened in peripheral leucocytes of subjects with poor sleep quality.

scholarly journals Differential Expression of Circadian Clock Genes in the Bovine Neuroendocrine Adrenal System

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A66-A67
Author(s):  
Audrey L Earnhardt ◽  
David G Riley ◽  
Noushin Ghaffari ◽  
Penny K Riggs ◽  
Charles R Long ◽  
...  
Keyword(s):  
Gene Expression ◽  
Circadian Clock ◽  
Clock Gene ◽  
Target Genes ◽  
Clock Genes ◽  
Expression Profiles ◽  
Primary Objective ◽  
Clock Gene Expression ◽  
Adrenal System ◽  
Circadian Clock Genes

Abstract The primary objective of this investigation was to determine whether circadian clock genes were differentially expressed within or among bovine hypothalamic paraventricular nucleus (PVN), anterior pituitary gland (AP), adrenocortical (AC) and adrenomedullary (AM) tissues. The PVN, AP, AC, and AM were isolated from 5-yr-old Brahman cows (n = 8) harvested humanely at an abattoir between 0800-1100 h. Expression of target genes in each sample was evaluated via RNA-sequencing analyses. Gene counts were normalized using the trimmed mean of M values (TMM) method in the edgeR Package from Bioconductor, R. The normalized gene counts of genes important for circadian rhythm were statistically analyzed using the GLM Procedure of SAS. The genes analyzed were circadian locomotor output cycles protein kaput (CLOCK), cryptochrome circadian regulator 1 and 2 (CRY1 and CRY2), aryl hydrocarbon receptor nuclear translocator like (ARNTL), period circadian regulator 1 and 2 (PER1 and PER2), neuronal PAS domain protein 2 (NPAS2), and nuclear receptor subfamily 1 group D member 1 (NR1D1). Overall, relative expression profiles of clock genes differed (P < 0.01) within each tissue with PER1 having greater expression in all tissues (P < 0.01). Within the PVN expression of CLOCK, CRY1, ARNTL, and PER2 was less than that of CRY2, NPAS2, and NR1D1 (P < 0.01). In the AP, with the exception of PER1, no other clock gene differed in degree of expression. In the AC, expression of CLOCK and NPAS2 was greater than CRY1, ARNTL, PER2, and NR1D1 (P < 0.05), whereas CRY2 expression exceeded only CRY1 (P < 0.05). Within the AM, CLOCK and CRY2 expression was greater than CRY1 and ARNTL (P < 0.05). Overall, clock gene expression among tissues differed (P < 0.01) for each individual clock gene. The AC and AM had similar clock gene expression, except expression of CRY2 and PER2 was greater in AM (P < 0.05). The AC and AM had greater expression of CLOCK than the PVN and AP (P < 0.01), with PVN having greater expression than AP (P < 0.01). The AP had greater expression of NPAS2, followed by PVN, with the least expression in the AC and AM (P < 0.01). Both PVN and AP had greater CRY1 and NR1D1 expression than AC or AM (P < 0.01). The AP had greater PER1 expression than PVN, AC, and AM (P < 0.01), whereas PVN, AC, and AM had greater ARNTL expression than AP (P < 0.05). Both AP and AM had greater expression of PER2 than PVN or AC (P < 0.01). The PVN had greater expression of CRY2 than the AP, AC, and AM (P < 0.01). These results indicated that within each tissue the various clock genes were expressed in different quantities. Also, the clock genes were expressed differentially among the tissues of the bovine neuroendocrine adrenal system. Temporal relationships of these genes with the primary endocrine products of these tissues should be investigated to define the roles of peripheral clock genes in regulation of metabolism and health.

scholarly journals Aging attenuates the ovarian circadian rhythm

2020 ◽  
Author(s):  
Ziru Jiang ◽  
Kexin Zou ◽  
Xia Liu ◽  
Hangchao Gu ◽  
Yicong Meng ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Circadian Clock ◽  
Granulosa Cells ◽  
Clock Genes ◽  
University Hospital ◽  
Vitro Fertilization ◽  
Human Granulosa Cells ◽  
Circadian Clock Genes ◽  
Young Mice

Abstract Objective To study the effect of aging on ovarian circadian rhythm. Design Human and animal study. Setting University hospital and research laboratory. Patients/animals Human granulosa cells were obtained by follicular aspiration from women undergoing in vitro fertilization (IVF), and ovarian and liver tissues were obtained from female C57BL/6 mice. Intervention(s) None. Main outcome measure(s) Expression of circadian genes in young and older human granulosa cells and circadian rhythm in ovaries and livers of young and older mice. Result(s) All examined circadian clock genes in human granulosa cells showed a downward trend in expression with aging, and their mRNA expression levels were negatively correlated with age (P < 0.05). Older patients (≥ 40 years of age) had significantly reduced serum anti-Müllerian hormone (AMH) levels. Except for Rev-erbα, all other examined circadian clock genes were positively correlated with the level of AMH (P < 0.05). The circadian rhythm in the ovaries of older mice (8 months) was changed significantly relative to that in ovaries of young mice (12 weeks), although the circadian rhythm in the livers of older mice was basically consistent with that of young mice. Conclusion(s) Lower ovarian reserve in older women is partially due to ovarian circadian dysrhythmia as a result of aging.

scholarly journals Circadian Regulation of a Drosophila Homolog of the Mammalian Clock Gene: PER and TIM Function as Positive Regulators

1998 ◽  
Vol 18 (10) ◽  
pp. 6142-6151 ◽  
Author(s):  
Kiho Bae ◽  
Choogon Lee ◽  
David Sidote ◽  
Keng-yu Chuang ◽  
Isaac Edery
Keyword(s):  
Circadian Clock ◽  
Clock Gene ◽  
Clock Genes ◽  
Temporal Regulation ◽  
Helix Loop Helix ◽  
Circadian Oscillators ◽  
Drosophila Homolog ◽  
Circadian Clock Genes ◽  
Positive Regulators

ABSTRACT The Clock gene plays an essential role in the manifestation of circadian rhythms (≅24 h) in mice and is a member of the basic helix-loop-helix (bHLH) PER-ARNT-SIM (PAS) superfamily of transcription factors. Here we report the characterization of a novelDrosophila bHLH-PAS protein that is highly homologous to mammalian CLOCK. (Similar findings were recently described by Allada et al. Cell 93:791–804, 1998, and Darlington et al., Science 280:1599–1603, 1998.) Transcripts from this putative Clockortholog (designated dClock) undergo daily rhythms in abundance that are antiphase to the cycling observed for the RNA products from the Drosophila melanogaster circadian clock genes period (per) and timeless(tim). Furthermore, dClock RNA cycling is abolished and the levels are at trough values in the absence of either PER or TIM, suggesting that these two proteins can function as transcriptional activators, a possibility which is in stark contrast to their previously characterized role in transcriptional autoinhibition. Finally, the temporal regulation of dClock expression is quickly perturbed by shifts in light-dark cycles, indicating that this molecular rhythm is closely connected to the photic entrainment pathway. The isolation of a Drosophila homolog ofClock together with the recent discovery of mammalian homologs of per indicate that there is high structural conservation in the integral components underlying circadian oscillators in Drosophila and mammals. Nevertheless, because mammalian Clock mRNA is constitutively expressed, our findings are a further example of striking differences in the regulation of putative circadian clock orthologs in different species.

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