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Temporal Control of Metabolic Amplitude by Nocturnin.

ABSTRACT: The timing of food intake and nutrient utilization is critical to health and regulated partly by the circadian clock. Increased amplitude of circadian oscillations and metabolic output has been found to improve health in diabetic and obesity mouse models. Here, we report a function for the circadian deadenylase Nocturnin as a regulator of metabolic amplitude across the day/night cycle and in response to nutrient challenge. We show that mice lacking Nocturnin (Noct-/-) display significantly increased amplitudes of mRNA expression of hepatic genes encoding key metabolic enzymes regulating lipid and cholesterol synthesis, both over the daily circadian cycle and in response to fasting and refeeding. Noct-/- mice have increased plasma triglyceride throughout the night and increased amplitude of hepatic cholesterol levels. Therefore, posttranscriptional control by Nocturnin regulates the amplitude of these critical metabolic pathways, and loss of this activity results in increased metabolic flux and reduced obesity.

SUBMITTER: Stubblefield JJ

PROVIDER: S-EPMC5815321 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Temporal Control of Metabolic Amplitude by Nocturnin.

Stubblefield Jeremy J JJ Gao Peng P Kilaru Gokhul G Mukadam Bilal B Terrien Jeremy J Green Carla B CB

Cell reports 20180101 5

The timing of food intake and nutrient utilization is critical to health and regulated partly by the circadian clock. Increased amplitude of circadian oscillations and metabolic output has been found to improve health in diabetic and obesity mouse models. Here, we report a function for the circadian deadenylase Nocturnin as a regulator of metabolic amplitude across the day/night cycle and in response to nutrient challenge. We show that mice lacking Nocturnin (Noct<sup>-/-</sup>) display signific ...[more]

PMID: 29386110

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Temporal control of metabolic amplitude by Nocturnin

Project description:The timing of food intake and nutrient utilization is critical to health and regulated in part by the circadian clock. Recently, increased amplitude of circadian oscillations and metabolic output was found to improve health in diabetic and obesity mouse models. Here, we report a novel function for the circadian deadenylase Nocturnin as a regulator of metabolic amplitude across the day/night cycle and in response to nutrient challenge. We show that mice lacking Nocturnin (Noct-/-) display significantly increased amplitudes of mRNA expression of hepatic genes encoding key metabolic enzymes regulating lipid and cholesterol synthesis, both over the daily circadian cycle and in response to fasting and refeeding. Noct-/- mice have increased plasma triglyceride throughout the night and increased amplitude of hepatic cholesterol levels. Therefore, posttranscriptional control by Nocturnin regulates the amplitude of these critical metabolic pathways and loss of this activity results in increased metabolic flux and reduced obesity.

2018-02-01 | GSE105413 | GEO

Temporal control of metabolic amplitude by Nocturnin

Project description:Temporal control of metabolic amplitude by Nocturnin

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The Circadian Protein Nocturnin Regulates Metabolic Adaptation in Brown Adipose Tissue.

Project description:Fine-tuning of transcriptional responses can be critical for long-term outcomes in response to an environmental challenge. The circadian protein Nocturnin belongs to a family of proteins that include exonucleases, endonucleases, and phosphatases and is most closely related to the CCR4 family of deadenylases that regulate the cellular transcriptome via control of poly(A) tail length of RNA transcripts. In this study, we investigate the role of Nocturnin in regulating the transcriptional response and downstream metabolic adaptations during cold exposure in brown adipose tissue. We find that Nocturnin exhibits dual localization within the cytosol and mitochondria, and loss of Nocturnin causes changes in expression of networks of mRNAs involved in mitochondrial function. Furthermore, Nocturnin-/- animals display significantly elevated levels of tricarboxylic acid cycle intermediates, indicating that they have distinct metabolic adaptations during a prolonged cold exposure. We conclude that cold-induced stimulation of Nocturnin levels can regulate long-term metabolic adaptations to environmental challenges.

| S-EPMC6664146 | biostudies-literature

Integration of temporal analysis and control analysis of metabolic systems.

Project description:A theory is developed that integrates approaches to the analysis of pathway transient response and metabolic control analysis. A Temporal Control Coefficient is defined that is a measure of the system's transient response to modulation of enzyme activity or concentration. The approach allows for the analysis of the establishment of a steady state from rest, of the system's 'agility' of response to minor perturbations of a pre-existing steady state and of the macroscopic transition between steady states. In the last-mentioned case it is shown that, like the transient time itself, the control of transient response retains the property of independence from the mechanism of the transition. In consequence, the Temporal Control Coefficient can be defined in terms of the control properties of the initial and final states alone without reference to the mechanism of transition. A summation property is shown to apply to the Temporal Control Coefficients in each case. Connectivity relationships between elasticities and Temporal Control Coefficients are also established.

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The Circadian Protein Nocturnin Regulates Metabolic Adaptation in Brown Adipose Tissue

Project description:Fine-tuning of transcriptional responses can be critical for long-term outcomes in response to an environmental challenge. The circadian protein Nocturnin belongs to a family of proteins that include exonucleases, endonucleases and phosphatases and is most closely related to the CCR4 family of deadenylases that regulate the cellular transcriptome via control of polyA tail length of RNA transcripts. In this study, we investigate the role of Nocturnin in regulating the transcriptional response and downstream metabolic adaptations during cold exposure in brown adipose tissue. We find that Nocturnin exhibits dual localization within the cytosol and mitochondria, and loss of Nocturnin causes changes in expression of networks of mRNAs involved in mitochondrial function. Furthermore, Nocturnin-/- animals display significantly elevated levels of TCA cycle intermediates indicating that they have distinct metabolic adaptations during a prolonged cold exposure. We conclude that cold-induced stimulation of Nocturnin levels can regulate long-term metabolic adaptations to environmental challenges.

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Thalamocortical control of propofol phase-amplitude coupling.

Project description:The anesthetic propofol elicits many different spectral properties on the EEG, including alpha oscillations (8-12 Hz), Slow Wave Oscillations (SWO, 0.1-1.5 Hz), and dose-dependent phase-amplitude coupling (PAC) between alpha and SWO. Propofol is known to increase GABAA inhibition and decrease H-current strength, but how it generates these rhythms and their interactions is still unknown. To investigate both generation of the alpha rhythm and its PAC to SWO, we simulate a Hodgkin-Huxley network model of a hyperpolarized thalamus and corticothalamic inputs. We find, for the first time, that the model thalamic network is capable of independently generating the sustained alpha seen in propofol, which may then be relayed to cortex and expressed on the EEG. This dose-dependent sustained alpha critically relies on propofol GABAA potentiation to alter the intrinsic spindling mechanisms of the thalamus. Furthermore, the H-current conductance and background excitation of these thalamic cells must be within specific ranges to exhibit any intrinsic oscillations, including sustained alpha. We also find that, under corticothalamic SWO UP and DOWN states, thalamocortical output can exhibit maximum alpha power at either the peak or trough of this SWO; this implies the thalamus may be the source of propofol-induced PAC. Hyperpolarization level is the main determinant of whether the thalamus exhibits trough-max PAC, which is associated with lower propofol dose, or peak-max PAC, associated with higher dose. These findings suggest: the thalamus generates a novel rhythm under GABAA potentiation such as under propofol, its hyperpolarization may determine whether a patient experiences trough-max or peak-max PAC, and the thalamus is a critical component of propofol-induced cortical spectral phenomena. Changes to the thalamus may be a critical part of how propofol accomplishes its effects, including unconsciousness.

| S-EPMC5739502 | biostudies-other

LFP beta amplitude is linked to mesoscopic spatio-temporal phase patterns.

Project description:Beta oscillations observed in motor cortical local field potentials (LFPs) recorded on separate electrodes of a multi-electrode array have been shown to exhibit non-zero phase shifts that organize into planar waves. Here, we generalize this concept to additional classes of salient patterns that fully describe the spatial organization of beta oscillations. During a delayed reach-to-grasp task we distinguish planar, synchronized, random, circular, and radial phase patterns in monkey primary motor and dorsal premotor cortices. We observe that patterns correlate with the beta amplitude (envelope): Coherent planar/radial wave propagation accelerates with growing amplitude, and synchronized patterns are observed at largest amplitudes. In contrast, incoherent random or circular patterns are observed almost exclusively when beta is strongly attenuated. The occurrence probability of a particular pattern modulates with behavioral epochs in the same way as beta amplitude: Coherent patterns are more present during movement preparation where amplitudes are large, while incoherent phase patterns are dominant during movement execution where amplitudes are small. Thus, we uncover a trigonal link between the spatial arrangement of beta phases, beta amplitude, and behavior. Together with previous findings, we discuss predictions on the spatio-temporal organization of precisely coordinated spiking on the mesoscopic scale as a function of beta power.

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Temporal Cortex Control (mesial temporal lobe epilepsy control)

Project description:Ion channel splice array data from temporal cortex brain tissue samples collected from control subjects (no mesial temporal lobe epilepsy). Keywords: disease associated splicing changes Temporal cortex samples from control subjects were compared to temporal neocortex of patients with mesial temporal lobe epilepsy

2007-01-23 | E-GEOD-6771 | biostudies-arrayexpress

fMRI study of mesial temporal lobe epilepsy using amplitude of low-frequency fluctuation analysis.

Project description:Various functional imaging tools have been used to detect epileptic activity in the neural network underlying mesial temporal lobe epilepsy (mTLE). In the present fMRI study, a data-driven approach was employed to map interictal epileptic activity in mTLE patients by measuring the amplitude of low-frequency fluctuation (ALFF) of the blood oxygen level-dependent (BOLD) signal. Twenty-four left mTLE patients and 26 right mTLE patients were investigated by comparing with 25 healthy subjects. In the patients, the regions showing increased ALFF were consistently distributed in the mesial temporal lobe, thalamus, and a few of other cortical and subcortical structures composing a mesial temporal epilepsy network proposed previously, while the regions showing decreased ALFF were mostly located in the areas of so-called default-mode network. Data of simultaneous EEG-fMRI from a portion of the patients suggested that the increases in ALFF might be associated with the interictal epileptic activity. Individual analyses based on statistic parametric mapping revealed a moderate sensitivity and a fairly high specificity for the lateralization of unilateral mTLE. We conclude that the ALFF analysis may provide a useful tool in fMRI study of epilepsy.

| S-EPMC6870704 | biostudies-literature

Crystal Structure of Human Nocturnin Catalytic Domain.

Project description:Nocturnin (NOCT) helps the circadian clock to adjust metabolism according to day and night activity. NOCT is upregulated in early evening and it has been proposed that NOCT serves as a deadenylase for metabolic enzyme mRNAs. We present a 2.7-Å crystal structure of the catalytic domain of human NOCT. Our structure shows that NOCT has a close overall similarity to CCR4 deadenylase family members, PDE12 and CNOT6L, and to a DNA repair enzyme TDP2. All the key catalytic residues present in PDE12, CNOT6L and TDP2 are conserved in NOCT and have the same conformations. However, we observe substantial differences in the surface properties of NOCT, an unexpectedly narrow active site pocket, and conserved structural elements in the vicinity of the catalytic center, which are unique to NOCT and absent in the deadenylases PDE12/CNOT6L. Moreover, we show that in contrast to human PDE12 and CNOT6L, NOCT is completely inactive against poly-A RNA. Our work thus reveals the structure of an intriguing circadian protein and suggests that NOCT has considerable differences from the related deadenylases, which may point to a unique cellular function of this enzyme.

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