scholarly journals Clock proteins and training modify exercise capacity in a daytime-dependent manner

2021 ◽  
Vol 118 (35) ◽  
pp. e2101115118
Author(s):  
Yaarit Adamovich ◽  
Vaishnavi Dandavate ◽  
Saar Ezagouri ◽  
Gal Manella ◽  
Ziv Zwighaft ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Feeding Behavior ◽  
Exercise Capacity ◽  
Active Phase ◽  
Liver Glycogen ◽  
Dependent Manner ◽  
Muscle Lipid ◽  
Clock Proteins ◽  
Glycogen Stores

Exercise and circadian biology are closely intertwined with physiology and metabolism, yet the functional interaction between circadian clocks and exercise capacity is only partially characterized. Here, we tested different clock mutant mouse models to examine the effect of the circadian clock and clock proteins, namely PERIODs and BMAL1, on exercise capacity. We found that daytime variance in endurance exercise capacity is circadian clock controlled. Unlike wild-type mice, which outperform in the late compared with the early part of their active phase, PERIODs- and BMAL1-null mice do not show daytime variance in exercise capacity. It appears that BMAL1 impairs and PERIODs enhance exercise capacity in a daytime-dependent manner. An analysis of liver and muscle glycogen stores as well as muscle lipid utilization suggested that these daytime effects mostly relate to liver glycogen levels and correspond to the animals’ feeding behavior. Furthermore, given that exercise capacity responds to training, we tested the effect of training at different times of the day and found that training in the late compared with the early part of the active phase improves exercise performance. Overall, our findings suggest that clock proteins shape exercise capacity in a daytime-dependent manner through changes in liver glycogen levels, likely due to their effect on animals’ feeding behavior.

scholarly journals Cross-scale Analysis of Temperature Compensation in the Cyanobacterial Circadian Clock System

2021 ◽  
Author(s):  
Yoshihiko Furuike ◽  
Dongyan Ouyang ◽  
Taiki Tominaga ◽  
Tatsuhito Matsuo ◽  
Atsushi Mukaiyama ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Temperature Compensation ◽  
Thermal Fluctuation ◽  
System Level ◽  
Dependent Manner ◽  
Clock System ◽  
Terminal Domain ◽  
Internal Motions ◽  
Clock Proteins ◽  
Quasielastic Neutron

Clock proteins maintain constant enzymatic activity regardless of temperature, even though thermal fluctuation is accelerated as temperature increases. We investigated temperature influences on the dynamics of KaiC, a temperature-compensated ATPase in the cyanobacterial circadian clock system, using quasielastic neutron scattering. The frequency of picosecond to sub-nanosecond incoherent local motions in KaiC was accelerated very slightly in a temperature-dependent manner. Our mutation studies revealed that internal motions of KaiC include several contributions of opposing temperature sensitivities. To take advantage of this balancing effect, the motional frequency of local dynamics in KaiC needs to exceed ~0.3 ps-1. Some of the mutation sites may be in a pathway through which the motional frequency in the C-terminal domain of KaiC is fed back to the active site of ATPase in its N-terminal domain. The temperature-compensating ability at the dynamics level is likely crucial for circadian clock systems, into which the clock proteins are incorporated, to achieve reaction- or even system-level temperature compensation of the oscillation frequency.

scholarly journals The Circadian Clock, Light, and Cryptochrome Regulate Feeding and Metabolism in Drosophila

2011 ◽  
Vol 26 (6) ◽  
pp. 497-506 ◽  
Author(s):  
Daniel J. Seay ◽  
Carl S. Thummel
Keyword(s):  
Circadian Clock ◽  
Feeding Behavior ◽  
Critical Role ◽  
Fruit Fly ◽  
Lipid Homeostasis ◽  
Dependent Manner ◽  
Daily Rhythms ◽  
Circadian Control ◽  
Carbohydrate Levels ◽  
Feeding Bout

Recent studies in mammals have demonstrated a central role for the circadian clock in maintaining metabolic homeostasis. In spite of these advances, however, little is known about how these complex pathways are coordinated. Here, we show that fundamental aspects of the circadian control of metabolism are conserved in the fruit fly Drosophila. We assay feeding behavior and basic metabolite levels in individual flies and show that, like mammals, Drosophila display a rapid increase in circulating sugar following a meal, which is subsequently stored in the form of glycogen. These daily rhythms in carbohydrate levels are disrupted in clock mutants, demonstrating a critical role for the circadian clock in the postprandial response to feeding. We also show that basic metabolite levels are coordinated in a clock-dependent manner and that clock function is required to maintain lipid homeostasis. By examining feeding behavior, we show that flies feed primarily during the first 4 hours of the day and that light suppresses a late day feeding bout through the cryptochrome photoreceptor. These studies demonstrate that central aspects of feeding and metabolism are dependent on the circadian clock in Drosophila. Our work also uncovers novel roles for light and cryptochrome on both feeding behavior and metabolism.

scholarly journals Direct Association between Mouse PERIOD and CKIε Is Critical for a Functioning Circadian Clock

2004 ◽  
Vol 24 (2) ◽  
pp. 584-594 ◽  
Author(s):  
Choogon Lee ◽  
David R. Weaver ◽  
Steven M. Reppert
Keyword(s):  
Circadian Clock ◽  
Double Mutant ◽  
Mutant Mice ◽  
Chimeric Proteins ◽  
Posttranslational Regulation ◽  
Dependent Manner ◽  
Clock Proteins ◽  
Deficient Mice

ABSTRACT The mPER1 and mPER2 proteins have important roles in the circadian clock mechanism, whereas mPER3 is expendable. Here we examine the posttranslational regulation of mPER3 in vivo in mouse liver and compare it to the other mPER proteins to define the salient features required for clock function. Like mPER1 and mPER2, mPER3 is phosphorylated, changes cellular location, and interacts with other clock proteins in a time-dependent manner. Consistent with behavioral data from mPer2/3 and mPer1/3 double-mutant mice, either mPER1 or mPER2 alone can sustain rhythmic posttranslational events. However, mPER3 is unable to sustain molecular rhythmicity in mPer1/2 double-mutant mice. Indeed, mPER3 is always cytoplasmic and is not phosphorylated in the livers of mPer1-deficient mice, suggesting that mPER3 is regulated by mPER1 at a posttranslational level. In vitro studies with chimeric proteins suggest that the inability of mPER3 to support circadian clock function results in part from lack of direct and stable interaction with casein kinase Iε (CKIε). We thus propose that the CKIε-binding domain is critical not only for mPER phosphorylation but also for a functioning circadian clock.

scholarly journals Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth

2019 ◽  
Vol 5 (1) ◽  
pp. eaau9060 ◽  
Author(s):  
Tsuyoshi Oshima ◽  
Yoshimi Niwa ◽  
Keiko Kuwata ◽  
Ashutosh Srivastava ◽  
Tomoko Hyoda ◽  
...  
Keyword(s):  
Cell Growth ◽  
Circadian Clock ◽  
Cancer Cell ◽  
Direct Interaction ◽  
Cancer Cell Growth ◽  
X Ray ◽  
Clock Proteins ◽  
Target Deconvolution ◽  
Phenotypic Screen ◽  
Dependent Inhibition

Compounds targeting the circadian clock have been identified as potential treatments for clock-related diseases, including cancer. Our cell-based phenotypic screen revealed uncharacterized clock-modulating compounds. Through affinity-based target deconvolution, we identified GO289, which strongly lengthened circadian period, as a potent and selective inhibitor of CK2. Phosphoproteomics identified multiple phosphorylation sites inhibited by GO289 on clock proteins, including PER2 S693. Furthermore, GO289 exhibited cell type–dependent inhibition of cancer cell growth that correlated with cellular clock function. The x-ray crystal structure of the CK2α-GO289 complex revealed critical interactions between GO289 and CK2-specific residues and no direct interaction of GO289 with the hinge region that is highly conserved among kinases. The discovery of GO289 provides a direct link between the circadian clock and cancer regulation and reveals unique design principles underlying kinase selectivity.

scholarly journals How is the inner circadian clock controlled by interactive clock proteins?

FEBS Letters ◽  
2015 ◽  
Vol 589 (14) ◽  
pp. 1516-1529 ◽  
Author(s):  
Torsten Merbitz-Zahradnik ◽  
Eva Wolf
Keyword(s):  
Circadian Clock ◽  
Clock Proteins

Temporal patterns of tissue glycogen, glucose, and glycogen phosphorylase activity prior to hibernation in freeze-tolerant chorus frogs, Pseudacris triseriata

2008 ◽  
Vol 86 (10) ◽  
pp. 1095-1100 ◽  
Author(s):  
Steve C. Dinsmore ◽  
David L. Swanson
Keyword(s):  
Glycogen Phosphorylase ◽  
Threshold Level ◽  
Liver Glycogen ◽  
Critical Threshold ◽  
Hepatic Glycogen ◽  
Phosphorylase Activity ◽  
Continuous Increase ◽  
Glycogen Accumulation ◽  
Chorus Frogs ◽  
Glycogen Stores

Freezing survival may differ among winters in chorus frogs ( Pseudacris triseriata (Wied-Neuwied, 1838)), and low freezing survival is associated with low hepatic glycogen stores. The pattern of prehibernation liver glycogen accumulation in chorus frogs is unknown. Frogs might accumulate hepatic glycogen stores until a threshold level sufficient for winter survival is attained, after which frogs enter hibernation (critical threshold hypothesis). According to this model, frogs active late in the season should only be those with low hepatic glycogen stores. Alternatively, hepatic glycogen levels might continue to increase throughout the fall as long as frogs remain active (continuous increase hypothesis). We tested these hypotheses by measuring liver and leg muscle glycogen, glucose, and glycogen phosphorylase activities in chorus frogs throughout the fall prehibernation period in southeastern South Dakota. Hepatic glycogen levels were significantly related to date and increased throughout the fall period, consistent with the continuous increase hypothesis. This suggests that hepatic glycogen levels do not serve as a cue for entrance into hibernation. Liver phosphorylase activity did not vary significantly with progression of the fall season and activity was lower than in winter, suggesting that the winter increment of phosphorylase activity requires some stimulus during hibernation (e.g., low temperatures).

Central and Peripheral Clock Control of Circadian Feeding Rhythms

2021 ◽  
pp. 074873042110458
Author(s):  
Carson V. Fulgham ◽  
Austin P. Dreyer ◽  
Anita Nasseri ◽  
Asia N. Miller ◽  
Jacob Love ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Circadian Clock ◽  
Feeding Behavior ◽  
Molecular Clock ◽  
Fat Body ◽  
Molecular Clocks ◽  
Central Brain ◽  
Feeding Rhythms ◽  
Free Running ◽  
The Brain

Many behaviors exhibit ~24-h oscillations under control of an endogenous circadian timing system that tracks time of day via a molecular circadian clock. In the fruit fly, Drosophila melanogaster, most circadian research has focused on the generation of locomotor activity rhythms, but a fundamental question is how the circadian clock orchestrates multiple distinct behavioral outputs. Here, we have investigated the cells and circuits mediating circadian control of feeding behavior. Using an array of genetic tools, we show that, as is the case for locomotor activity rhythms, the presence of feeding rhythms requires molecular clock function in the ventrolateral clock neurons of the central brain. We further demonstrate that the speed of molecular clock oscillations in these neurons dictates the free-running period length of feeding rhythms. In contrast to the effects observed with central clock cell manipulations, we show that genetic abrogation of the molecular clock in the fat body, a peripheral metabolic tissue, is without effect on feeding behavior. Interestingly, we find that molecular clocks in the brain and fat body of control flies gradually grow out of phase with one another under free-running conditions, likely due to a long endogenous period of the fat body clock. Under these conditions, the period of feeding rhythms tracks with molecular oscillations in central brain clock cells, consistent with a primary role of the brain clock in dictating the timing of feeding behavior. Finally, despite a lack of effect of fat body selective manipulations, we find that flies with simultaneous disruption of molecular clocks in multiple peripheral tissues (but with intact central clocks) exhibit decreased feeding rhythm strength and reduced overall food intake. We conclude that both central and peripheral clocks contribute to the regulation of feeding rhythms, with a particularly dominant, pacemaker role for specific populations of central brain clock cells.

Load-matched acute and chronic exercise induce changes in mitochondrial biogenesis and metabolic markers

2021 ◽  
Author(s):  
Natalia Almeida Rodrigues ◽  
Claudio Alexandre Gobatto ◽  
Lucas Dantas Maia Forte ◽  
Filipe Antônio de Barros Sousa ◽  
Adriana Souza Torsoni ◽  
...  
Keyword(s):  
Aerobic Capacity ◽  
Skeletal Muscles ◽  
Acute Exercise ◽  
Citrate Synthase ◽  
Liver Glycogen ◽  
Chronic Exercise ◽  
Total Load ◽  
Metabolic Markers ◽  
Target Proteins ◽  
Glycogen Stores

We investigated the effects of the acute and chronic exercise, prescribed in different intensity zones, but with total load-matched on mitochondrial markers (COX-IV, Tfam, and citrate synthase (CS) activity in skeletal muscles, heart, and liver), glycogen stores, aerobic capacity and anaerobic index in swimming rats. For this, two experimental designs were performed (acute and chronic efforts). Load-matched exercises were prescribed below and above and on the anaerobic threshold (AnT), determined by the Lactate Minimum test. In chronic programs, two training prescription strategies were assessed (monotonous and linear periodized model). Results show changes in glycogen stores but no modification in the COX-IV and Tfam contents after acute exercises. In the chronic protocols, COX-IV and Tfam proteins and CS adaptations were intensity and tissue dependents. Monotonous training promoted better adaptations than the periodized model. Training at 80% of the AnT improved both performance variables, emphasizing the anaerobic index, concomitant to CS and COX-IV improvement (soleus muscle). The aerobic capacity and CS activity (gastrocnemius) were increased after 120% AnT training. In conclusion, acute exercise protocol did not promote responses in mitochondrial target proteins. An intensity and tissue dependence are reported in the chronic protocols, highlighting training at 80 and 120% of the AnT. Novelty: • Load-matched acute exercise did not enhance COX-IV and Tfam contents in skeletal muscles, heart, and liver. • In chronic exercise, COX-IV, Tfam, and citrate synthase activity adaptations were intensity and tissue dependents. •Monotonous training was more efficient than the periodized linear model in adaptations of target proteins and enzymatic activity.

Liver Glycogen Reserves of Interacting Resident and Introduced Trout Populations

1961 ◽  
Vol 18 (1) ◽  
pp. 125-135 ◽  
Author(s):  
P. W. Hochachka
Keyword(s):  
Population Density ◽  
Liver Glycogen ◽  
Salmo Gairdneri ◽  
Recovery Rates ◽  
Introduced Populations ◽  
Wild Trout ◽  
Low Levels ◽  
Glycogen Stores ◽  
Salmo Clarki

Three groups of trout, two introduced populations of Salmo gairdneri and a resident Salmo clarki, were studied in stream sections. Liver glycogen deposits, which were reduced to low levels during transportation to the stream, were restored in 2 to 3 weeks in all groups, with recovery rates being approximately inverse to the population density. Within the hatchery groups, larger fish laid down greater glycogen stores. Wild trout maintained their high glycogen reserves throughout the experiment.

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