Rev-erb-α: an integrator of circadian rhythms and metabolism

The endogenous circadian clock ensures daily rhythms in diverse behavioral and physiological processes, including locomotor activity and sleep/wake cycles, but also food intake patterns. Circadian rhythms are generated by an internal clock system, which synchronizes these daily variations to the day/night alternance. In addition, circadian oscillations may be reset by the time of food availability in peripheral metabolic organs. Circadian rhythms are seen in many metabolic pathways (glucose and lipid metabolism, etc.) and endocrine secretions (insulin, etc.). As a consequence, misalignment of the internal timing system vs. environmental zeitgebers (light, for instance), as experienced during jetlag or shift work, may result in disruption of physiological cycles of fuel utilization or energy storage. A large body of evidence from both human and animal studies now points to a relationship between circadian disorders and altered metabolic response, suggesting that circadian and metabolic regulatory networks are tightly connected. After a review of the current understanding of the molecular circadian core clock, we will discuss the hypothesis that clock genes themselves link the core molecular clock and metabolic regulatory networks. We propose that the nuclear receptor and core clock component Rev-erb-α behaves as a gatekeeper to timely coordinate the circadian metabolic response.

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Disruptions of Circadian Rhythms and Thrombolytic Therapy During Ischemic Stroke Intervention

Frontiers in Neuroscience ◽

10.3389/fnins.2021.675732 ◽

2021 ◽

Vol 15 ◽

Author(s):

Jennifer A. Liu ◽

James C. Walton ◽

A. Courtney DeVries ◽

Randy J. Nelson

Keyword(s):

Circadian Rhythms ◽

Thrombolytic Therapy ◽

Clock Genes ◽

Expression Patterns ◽

Distribution Patterns ◽

Hemorrhagic Transformation ◽

Clock Gene Expression ◽

Physiological Processes ◽

Cerebrovascular Events ◽

Exogenous Factors

Several endogenous and exogenous factors interact to influence stroke occurrence, in turn contributing to discernable daily distribution patterns in the frequency and severity of cerebrovascular events. Specifically, strokes that occur during the morning tend to be more severe and are associated with elevated diastolic blood pressure, increased hospital stay, and worse outcomes, including mortality, compared to strokes that occur later in the day. Furthermore, disrupted circadian rhythms are linked to higher risk for stroke and play a role in stroke outcome. In this review, we discuss the interrelation among core clock genes and several factors contributing to ischemic outcomes, sources of disrupted circadian rhythms, the implications of disrupted circadian rhythms in foundational stroke scientific literature, followed by a review of clinical implications. In addition to highlighting the distinct daily pattern of onset, several aspects of physiology including immune response, endothelial/vascular and blood brain barrier function, and fibrinolysis are under circadian clock regulation; disrupted core clock gene expression patterns can adversely affect these physiological processes, leading to a prothrombotic state. Lastly, we discuss how the timing of ischemic onset increases morning resistance to thrombolytic therapy and the risk of hemorrhagic transformation.

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Circadian Clock Component BMAL1 in the Paraventricular Nucleus Regulates Glucose Metabolism

Nutrients ◽

10.3390/nu13124487 ◽

2021 ◽

Vol 13 (12) ◽

pp. 4487

Author(s):

Masanori Nakata ◽

Parmila Kumari ◽

Rika Kita ◽

Nanako Katsui ◽

Yuriko Takeuchi ◽

...

Keyword(s):

Circadian Rhythm ◽

Glucose Metabolism ◽

Glucose Tolerance ◽

Paraventricular Nucleus ◽

Clock Gene ◽

Clock Genes ◽

Circadian Variation ◽

Glucose And Lipid Metabolism ◽

Clock Component

It is suggested that clock genes link the circadian rhythm to glucose and lipid metabolism. In this study, we explored the role of the clock gene Bmal1 in the hypothalamic paraventricular nucleus (PVN) in glucose metabolism. The Sim1-Cre-mediated deletion of Bmal1 markedly reduced insulin secretion, resulting in impaired glucose tolerance. The pancreatic islets’ responses to glucose, sulfonylureas (SUs) and arginine vasopressin (AVP) were well maintained. To specify the PVN neuron subpopulation targeted by Bmal1, the expression of neuropeptides was examined. In these knockout (KO) mice, the mRNA expression of Avp in the PVN was selectively decreased, and the plasma AVP concentration was also decreased. However, fasting suppressed Avp expression in both KO and Cre mice. These results demonstrate that PVN BMAL1 maintains Avp expression in the PVN and release to the circulation, possibly providing islet b-cells with more AVP. This action helps enhance insulin release and, consequently, glucose tolerance. In contrast, the circadian variation of Avp expression is regulated by feeding, but not by PVN BMAL1.

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9. Evolution and another look at the clock

Circadian Rhythms: A Very Short Introduction ◽

10.1093/actrade/9780198717683.003.0009 ◽

2017 ◽

pp. 122-130

Author(s):

Russell G. Foster ◽

Leon Kreitzman

Keyword(s):

Circadian Rhythms ◽

Empirical Evidence ◽

Clock Genes ◽

Internal Clock ◽

Circadian System ◽

Mrna Levels ◽

Vital Importance ◽

Living Things ◽

History Of ◽

Molecular Components

‘Evolution and another look at the clock’ concludes that the circadian system controls every key aspect of biochemistry, physiology, and behaviour. All plants, fungi, protista, algae, invertebrates, vertebrates, cyanobacteria, and at least one archaeon display circadian rhythms. These rhythms have many molecular components conserved between diverse species and are thought to be generated by molecular transcription–translation feedback loops in which a group of core clock genes regulate each other to ensure that their mRNA levels oscillate with a period of approximately 24 hours. Although the empirical evidence has been difficult to demonstrate, there is a consensus that the internal clock has been of vital importance in the evolutionary history of living things.

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Disentangling transcriptional responses in plant defense against arthropod herbivores

Scientific Reports ◽

10.1038/s41598-021-92468-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Alejandro Garcia ◽

M. Estrella Santamaria ◽

Isabel Diaz ◽

Manuel Martinez

Keyword(s):

Regulatory Networks ◽

Pieris Rapae ◽

Meta Analysis ◽

Plant Response ◽

Plant Responses ◽

Transcriptional Responses ◽

Crop Species ◽

Physiological Processes ◽

Meta Analyses ◽

Plant Herbivore

AbstractThe success in the response of a plant to a pest depends on the regulatory networks that connect plant perception and plant response. Meta-analyses of transcriptomic responses are valuable tools to discover novel mechanisms in the plant/herbivore interplay. Considering the quantity and quality of available transcriptomic analyses, Arabidopsis thaliana was selected to test the ability of comprehensive meta-analyses to disentangle plant responses. The analysis of the transcriptomic data showed a general induction of biological processes commonly associated with the response to herbivory, like jasmonate signaling or glucosinolate biosynthesis. However, an uneven induction of many genes belonging to these biological categories was found, which was likely associated with the particularities of each specific Arabidopsis-herbivore interaction. A thorough analysis of the responses to the lepidopteran Pieris rapae and the spider mite Tetranychus urticae highlighted specificities in the perception and signaling pathways associated with the expression of receptors and transcription factors. This information was translated to a variable alteration of secondary metabolic pathways. In conclusion, transcriptomic meta-analysis has been revealed as a potent way to sort out relevant physiological processes in the plant response to herbivores. Translation of these transcriptomic-based analyses to crop species will permit a more appropriate design of biotechnological programs.

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Shared Components of the FRQ-Less Oscillator and TOR Pathway Maintain Rhythmicity in Neurospora

Journal of Biological Rhythms ◽

10.1177/0748730421999948 ◽

2021 ◽

pp. 074873042199994

Author(s):

Rosa Eskandari ◽

Lalanthi Ratnayake ◽

Patricia L. Lakin-Thomas

Keyword(s):

Circadian Rhythms ◽

Clock Genes ◽

Nutrient Sensing ◽

Mass Spectrometry Analysis ◽

Growth Responses ◽

Tor Pathway ◽

Spectrometry Analysis ◽

Binding Partner ◽

Binding Partners ◽

Free Running

Molecular models for the endogenous oscillators that drive circadian rhythms in eukaryotes center on rhythmic transcription/translation of a small number of “clock genes.” Although substantial evidence supports the concept that negative and positive transcription/translation feedback loops (TTFLs) are responsible for regulating the expression of these clock genes, certain rhythms in the filamentous fungus Neurospora crassa continue even when clock genes ( frq, wc-1, and wc-2) are not rhythmically expressed. Identification of the rhythmic processes operating outside of the TTFL has been a major unresolved area in circadian biology. Our lab previously identified a mutation ( vta) that abolishes FRQ-less rhythmicity of the conidiation rhythm and also affects rhythmicity when FRQ is functional. Further studies identified the vta gene product as a component of the TOR (Target of Rapamycin) nutrient-sensing pathway that is conserved in eukaryotes. We now report the discovery of TOR pathway components including GTR2 (homologous to the yeast protein Gtr2, and RAG C/D in mammals) as binding partners of VTA through co-immunoprecipitation (IP) and mass spectrometry analysis using a VTA-FLAG strain. Reciprocal IP with GTR2-FLAG found VTA as a binding partner. A Δ gtr2 strain was deficient in growth responses to amino acids. Free-running conidiation rhythms in a FRQ-less strain were abolished in Δ gtr2. Entrainment of a FRQ-less strain to cycles of heat pulses demonstrated that Δ gtr2 is defective in entrainment. In all of these assays, Δ gtr2 is similar to Δ vta. In addition, expression of GTR2 protein was found to be rhythmic across two circadian cycles, and functional VTA was required for GTR2 rhythmicity. FRQ protein exhibited the expected rhythm in the presence of GTR2 but the rhythmic level of FRQ dampened in the absence of GTR2. These results establish association of VTA with GTR2, and their role in maintaining functional circadian rhythms through the TOR pathway.

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Comment on “Circadian rhythms in the absence of the clock gene Bmal1”

Science ◽

10.1126/science.abe9230 ◽

2021 ◽

Vol 372 (6539) ◽

pp. eabe9230 ◽

Cited By ~ 1

Author(s):

Elan Ness-Cohn ◽

Ravi Allada ◽

Rosemary Braun

Keyword(s):

Circadian Rhythms ◽

Clock Gene ◽

Insufficient Evidence ◽

The Core ◽

Clock Component ◽

Mouse Tissues ◽

Associated Data

Ray et al. (Reports, 14 February 2020, p. 800) report apparent transcriptional circadian rhythms in mouse tissues lacking the core clock component BMAL1. To better understand these surprising results, we reanalyzed the associated data. We were unable to reproduce the original findings, nor could we identify reliably cycling genes. We conclude that there is insufficient evidence to support circadian transcriptional rhythms in the absence of Bmal1.

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Alteration of circadian machinery in monocytes underlies chronic kidney disease-associated cardiac inflammation and fibrosis

Nature Communications ◽

10.1038/s41467-021-23050-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yuya Yoshida ◽

Naoya Matsunaga ◽

Takaharu Nakao ◽

Kengo Hamamura ◽

Hideaki Kondo ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Clock Genes ◽

Serum Levels ◽

Serum Retinol ◽

Cardiac Inflammation ◽

Physiological Processes ◽

G Protein Coupled ◽

Clock Protein

AbstractDysfunction of the circadian clock has been implicated in the pathogenesis of cardiovascular disease. The CLOCK protein is a core molecular component of the circadian oscillator, so that mice with a mutated Clock gene (Clk/Clk) exhibit abnormal rhythms in numerous physiological processes. However, here we report that chronic kidney disease (CKD)-induced cardiac inflammation and fibrosis are attenuated in Clk/Clk mice even though they have high blood pressure and increased serum angiotensin II levels. A search for the underlying cause of the attenuation of heart disorder in Clk/Clk mice with 5/6 nephrectomy (5/6Nx) led to identification of the monocytic expression of G protein-coupled receptor 68 (GPR68) as a risk factor of CKD-induced inflammation and fibrosis of heart. 5/6Nx induces the expression of GPR68 in circulating monocytes via altered CLOCK activation by increasing serum levels of retinol and its binding protein (RBP4). The high-GPR68-expressing monocytes have increased potential for producing inflammatory cytokines, and their cardiac infiltration under CKD conditions exacerbates inflammation and fibrosis of heart. Serum retinol and RBP4 levels in CKD patients are also sufficient to induce the expression of GPR68 in human monocytes. Our present study reveals an uncovered role of monocytic clock genes in CKD-induced heart failure.

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Circadian Rhythm: Potential Therapeutic Target for Atherosclerosis and Thrombosis

International Journal of Molecular Sciences ◽

10.3390/ijms22020676 ◽

2021 ◽

Vol 22 (2) ◽

pp. 676

Author(s):

Andy W. C. Man ◽

Huige Li ◽

Ning Xia

Keyword(s):

Circadian Rhythm ◽

Cardiovascular Diseases ◽

Circadian Rhythms ◽

Circadian Clock ◽

Therapeutic Target ◽

Environmental Changes ◽

Clock Genes ◽

Vascular System ◽

Peripheral Tissues ◽

Inflammatory Processes

Every organism has an intrinsic biological rhythm that orchestrates biological processes in adjusting to daily environmental changes. Circadian rhythms are maintained by networks of molecular clocks throughout the core and peripheral tissues, including immune cells, blood vessels, and perivascular adipose tissues. Recent findings have suggested strong correlations between the circadian clock and cardiovascular diseases. Desynchronization between the circadian rhythm and body metabolism contributes to the development of cardiovascular diseases including arteriosclerosis and thrombosis. Circadian rhythms are involved in controlling inflammatory processes and metabolisms, which can influence the pathology of arteriosclerosis and thrombosis. Circadian clock genes are critical in maintaining the robust relationship between diurnal variation and the cardiovascular system. The circadian machinery in the vascular system may be a novel therapeutic target for the prevention and treatment of cardiovascular diseases. The research on circadian rhythms in cardiovascular diseases is still progressing. In this review, we briefly summarize recent studies on circadian rhythms and cardiovascular homeostasis, focusing on the circadian control of inflammatory processes and metabolisms. Based on the recent findings, we discuss the potential target molecules for future therapeutic strategies against cardiovascular diseases by targeting the circadian clock.

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Early Developmental Conditioning of Later Health and Disease: Physiology or Pathophysiology?

Physiological Reviews ◽

10.1152/physrev.00029.2013 ◽

2014 ◽

Vol 94 (4) ◽

pp. 1027-1076 ◽

Cited By ~ 500

Author(s):

M. A. Hanson ◽

P. D. Gluckman

Keyword(s):

Animal Studies ◽

Developmental Plasticity ◽

Current Knowledge ◽

Evolutionary Developmental Biology ◽

Noncommunicable Disease ◽

Normal Range ◽

Physiological Processes ◽

New Concepts ◽

Health And Disease ◽

Underlying Mechanisms

Extensive experimental animal studies and epidemiological observations have shown that environmental influences during early development affect the risk of later pathophysiological processes associated with chronic, especially noncommunicable, disease (NCD). This field is recognized as the developmental origins of health and disease (DOHaD). We discuss the extent to which DOHaD represents the result of the physiological processes of developmental plasticity, which may have potential adverse consequences in terms of NCD risk later, or whether it is the manifestation of pathophysiological processes acting in early life but only becoming apparent as disease later. We argue that the evidence suggests the former, through the operation of conditioning processes induced across the normal range of developmental environments, and we summarize current knowledge of the physiological processes involved. The adaptive pathway to later risk accords with current concepts in evolutionary developmental biology, especially those concerning parental effects. Outside the normal range, effects on development can result in nonadaptive processes, and we review their underlying mechanisms and consequences. New concepts concerning the underlying epigenetic and other mechanisms involved in both disruptive and nondisruptive pathways to disease are reviewed, including the evidence for transgenerational passage of risk from both maternal and paternal lines. These concepts have wider implications for understanding the causes and possible prevention of NCDs such as type 2 diabetes and cardiovascular disease, for broader social policy and for the increasing attention paid in public health to the lifecourse approach to NCD prevention.

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