scholarly journals The Contribution of Ketone Bodies to Basal and Activity-Dependent Neuronal Oxidation in Vivo

2014 ◽  
Vol 34 (7) ◽  
pp. 1233-1242 ◽  
Author(s):  
Golam MI Chowdhury ◽  
Lihong Jiang ◽  
Douglas L Rothman ◽  
Kevin L Behar
Keyword(s):  
Ketone Bodies ◽  
Ex Vivo ◽  
Brain Activity ◽  
Tca Cycle ◽  
Blood Levels ◽  
Neuronal Function ◽  
Energy Needs ◽  
Activity Dependent ◽  
Sufficient Concentration

The capacity of ketone bodies to replace glucose in support of neuronal function is unresolved. Here, we determined the contributions of glucose and ketone bodies to neocortical oxidative metabolism over a large range of brain activity in rats fasted 36 hours and infused intravenously with [2,4- 13 C2]-D-β-hydroxybutyrate (BHB). Three animal groups and conditions were studied: awake ex vivo, pentobarbital-induced isoelectricity ex vivo, and halothane-anesthetized in vivo, the latter data reanalyzed from a recent study. Rates of neuronal acetyl-CoA oxidation from ketone bodies ( VaccoA-kbN) and pyruvate ( VpdhN), and the glutamate-glutamine cycle ( Vcyc) were determined by metabolic modeling of 13C label trapped in major brain amino acid pools. VacCoA-kbN increased gradually with increasing activity, as compared with the steeper change in tricarboxylic acid (TCA) cycle rate ( VtcaN), supporting a decreasing percentage of neuronal ketone oxidation: ˜100% (isoelectricity), 56% (halothane anesthesia), 36% (awake) with the BHB plasma levels achieved in our experiments (6 to 13 mM). In awake animals ketone oxidation reached saturation for blood levels > 17 mM, accounting for 62% of neuronal substrate oxidation, the remainder (38%) provided by glucose. We conclude that ketone bodies present at sufficient concentration to saturate metabolism provides full support of basal (housekeeping) energy needs and up to approximately half of the activity-dependent oxidative needs of neurons.

scholarly journals Cardiac Metabolism and Contractile Function in Mice with Reduced Trans-Endothelial Fatty Acid Transport

Metabolites ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 889
Author(s):  
Tatsuya Iso ◽  
Masahiko Kurabayashi
Keyword(s):  
Alternative Fuels ◽  
Molecular Mechanisms ◽  
Ketone Bodies ◽  
Contractile Function ◽  
Tca Cycle ◽  
Cardiac Metabolism ◽  
Capillary Endothelium ◽  
Fatty Acid Transport ◽  
Contractile Dysfunction

The heart is a metabolic omnivore that combusts a considerable amount of energy substrates, mainly long-chain fatty acids (FAs) and others such as glucose, lactate, ketone bodies, and amino acids. There is emerging evidence that muscle-type continuous capillaries comprise the rate-limiting barrier that regulates FA uptake into cardiomyocytes. The transport of FAs across the capillary endothelium is composed of three major steps—the lipolysis of triglyceride on the luminal side of the endothelium, FA uptake by the plasma membrane, and intracellular FA transport by cytosolic proteins. In the heart, impaired trans-endothelial FA (TEFA) transport causes reduced FA uptake, with a compensatory increase in glucose use. In most cases, mice with reduced FA uptake exhibit preserved cardiac function under unstressed conditions. When the workload is increased, however, the total energy supply relative to its demand (estimated with pool size in the tricarboxylic acid (TCA) cycle) is significantly diminished, resulting in contractile dysfunction. The supplementation of alternative fuels, such as medium-chain FAs and ketone bodies, at least partially restores contractile dysfunction, indicating that energy insufficiency due to reduced FA supply is the predominant cause of cardiac dysfunction. Based on recent in vivo findings, this review provides the following information related to TEFA transport: (1) the mechanisms of FA uptake by the heart, including TEFA transport; (2) the molecular mechanisms underlying the induction of genes associated with TEFA transport; (3) in vivo cardiac metabolism and contractile function in mice with reduced TEFA transport under unstressed conditions; and (4) in vivo contractile dysfunction in mice with reduced TEFA transport under diseased conditions, including an increased afterload and streptozotocin-induced diabetes.

scholarly journals Magnetic resonance spectroscopy of paragangliomas: new insights into in vivo metabolomics

2015 ◽  
Vol 22 (4) ◽  
pp. M1-M8 ◽  
Author(s):  
Arthur Varoquaux ◽  
Yann le Fur ◽  
Alessio Imperiale ◽  
Antony Reyre ◽  
Marion Montava ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Ex Vivo ◽  
Tca Cycle ◽  
Resonance Spectroscopy ◽  
Variants Of Unknown Significance ◽  
Neck Tumors ◽  
Single Voxel ◽  
Unknown Significance ◽  
Genetically Determined

Paragangliomas (PGLs) can be associated with mutations in genes of the tricarboxylic acid (TCA) cycle. Succinate dehydrogenase (SDHx) mutations are the prime examples of genetically determined TCA cycle defects with accumulation of succinate. Succinate, which acts as an oncometabolite, can be detected by ex vivo metabolomics approaches. The aim of this study was to evaluate the potential role of proton magnetic resonance (MR) spectroscopy (1H-MRS) for identifying SDHx-related PGLs in vivo and noninvasively. Eight patients were prospectively evaluated with single voxel 1H-MRS. MR spectra from eight tumors (four SDHx-related PGLs, two sporadic PGLs, one cervical schwannoma, and one cervical neurofibroma) were acquired and interpreted qualitatively. Compared to other tumors, a succinate resonance peak was detected only in SDHx-related tumor patients. Spectra quality was considered good in three cases, medium in two cases, poor in two cases, and uninterpretable in the latter case. Smaller lesions had lower spectra quality compared to larger lesions. Jugular PGLs also exhibited a poorer spectra quality compared to other locations. 1H-MRS has always been challenging in terms of its technical requisites. This is even more true for the evaluation of head and neck tumors. However, 1H-MRS might be added to the classical MR sequences for metabolomic characterization of PGLs. In vivo detection of succinate might guide genetic testing, characterize SDHx variants of unknown significance (in the absence of available tumor sample), and even optimize a selection of appropriate therapies.

scholarly journals Simultaneous measurement and quantitation of 4-hydroxyphenylacetic acid and dopamine with fast-scan cyclic voltammetry

The Analyst ◽  
2015 ◽  
Vol 140 (9) ◽  
pp. 3039-3047 ◽  
Author(s):  
Mimi Shin ◽  
Sam V. Kaplan ◽  
Kayla D. Raider ◽  
Michael A. Johnson
Keyword(s):  
Cell Culture ◽  
Cyclic Voltammetry ◽  
Simultaneous Measurement ◽  
Ex Vivo ◽  
Neuronal Function ◽  
Fast Scan Cyclic Voltammetry ◽  
Tissue Samples ◽  
Caged Compounds ◽  
Hydroxyphenylacetic Acid

Caged compounds have been used extensively to investigate neuronal function in a variety of preparations, including cell culture,ex vivotissue samples, andin vivo.

Glucose alleviates ammonia-induced inhibition of short-chain fatty acid metabolism in rat colonic epithelial cells

2003 ◽  
Vol 285 (1) ◽  
pp. G105-G114 ◽  
Author(s):  
John D. Cremin ◽  
Mark D. Fitch ◽  
Sharon E. Fleming
Keyword(s):  
Fatty Acid ◽  
Epithelial Cells ◽  
Short Chain Fatty Acid ◽  
Ketone Bodies ◽  
Tca Cycle ◽  
Chain Fatty Acid ◽  
Short Chain ◽  
Colonic Epithelial Cells ◽  
The Tca Cycle

Ammonia decreased metabolism by rat colonic epithelial cells of butyrate and acetate to CO2 and ketones but increased oxidation of glucose and glutamine. Ammonia decreased cellular concentrations of oxaloacetate for all substrates evaluated. The extent to which butyrate carbon was oxidized to CO2 after entering the tricarboxylic acid (TCA) cycle was not significantly influenced by ammonia, suggesting there was no major shift toward efflux of carbon from the TCA cycle. Ammonia reduced entry of butyrate carbon into the TCA cycle, and the proportion of CoA esterified with acetate and butyrate correlated positively with the production of CO2 and ketone bodies. Also, ammonia reduced oxidation of propionate but had no effect on oxidation of 3-hydroxybutyrate. Inclusion of glucose, lactate, or glutamine with butyrate and acetate counteracted the ability of ammonia to decrease their oxidation. In rat colonocytes, it appears that ammonia suppresses short-chain fatty acid (SCFA) oxidation by inhibiting a step before or during their activation. This inhibition is alleviated by glucose and other energy-generating compounds. These results suggest that ammonia may only affect SCFA metabolism in vivo when glucose availability is compromised.

scholarly journals Activity dependent translation in astrocytes

2020 ◽  
Author(s):  
D. Sapkota ◽  
K. Sakers ◽  
Y. Liu ◽  
A.M. Lake ◽  
R. Khazanchi ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Brain Activity ◽  
Affinity Purification ◽  
Cell Communication ◽  
Transcriptional Response ◽  
Tyrosine Kinase Signaling ◽  
Rapid Responses ◽  
System Functioning ◽  
Activity Dependent

AbstractGene expression requires two steps – transcription and translation – which can be regulated independently to allow nuanced, localized, and rapid responses to cellular stimuli. Neurons are known to respond transcriptionally and translationally to bursts of brain activity, and a transcriptional response to this activation has also been recently characterized in astrocytes. However, the extent to which astrocytes respond translationally is unknown. We tested the hypothesis that astrocytes also have a programmed translational response by characterizing the change in transcript ribosome occupancy in astrocytes using Translating Ribosome Affinity Purification subsequent to a robust induction of neuronal activity in vivo via acute seizure. We identified a reproducible change in transcripts on astrocyte ribosomes, highlighted by a rapid decrease in housekeeping transcripts, such as ribosomal and mitochondrial components, and a rapid increase in transcripts related to cytoskeleton, motor activity, ion transport, and cell communication. This indicates a dynamic response, some of which might be secondary to activation of Receptor Tyrosine Kinase signaling. Using acute slices, we quantified the extent to which individual cues and sequela of neuronal activity can activate translation acutely in astrocytes. This identified both BDNF and KCl as contributors to translation induction, the latter with both action-potential sensitive and insensitive components. Finally, we show that this translational response requires the presence of neurons, indicating the response is acutely or chronically non-cell autonomous. Regulation of translation in astrocytes by neuronal activity suggests an additional mechanism by which astrocytes may dynamically modulate nervous system functioning.

scholarly journals Brain activity regulates loose coupling between mitochondrial and cytosolic Ca2+ transients

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuan Lin ◽  
Lin-Lin Li ◽  
Wei Nie ◽  
Xiaolei Liu ◽  
Avital Adler ◽  
...  
Keyword(s):  
Visual Stimulation ◽  
Brain Activity ◽  
Cytosolic Calcium ◽  
Treadmill Running ◽  
V1 Neurons ◽  
Two Photon ◽  
Energy Demands ◽  
Calmodulin Kinase ◽  
Activity Dependent

AbstractMitochondrial calcium ([Ca2+]mito) dynamics plays vital roles in regulating fundamental cellular and organellar functions including bioenergetics. However, neuronal [Ca2+]mito dynamics in vivo and its regulation by brain activity are largely unknown. By performing two-photon Ca2+ imaging in the primary motor (M1) and visual cortexes (V1) of awake behaving mice, we find that discrete [Ca2+]mito transients occur synchronously over somatic and dendritic mitochondrial network, and couple with cytosolic calcium ([Ca2+]cyto) transients in a probabilistic, rather than deterministic manner. The amplitude, duration, and frequency of [Ca2+]cyto transients constitute important determinants of the coupling, and the coupling fidelity is greatly increased during treadmill running (in M1 neurons) and visual stimulation (in V1 neurons). Moreover, Ca2+/calmodulin kinase II is mechanistically involved in modulating the dynamic coupling process. Thus, activity-dependent dynamic [Ca2+]mito-to-[Ca2+]cyto coupling affords an important mechanism whereby [Ca2+]mito decodes brain activity for the regulation of mitochondrial bioenergetics to meet fluctuating neuronal energy demands as well as for neuronal information processing.

LPS-induced bronchial hyperreactivity: interference by mIL-10 differs according to site of delivery

2004 ◽  
Vol 286 (1) ◽  
pp. L98-L105 ◽  
Author(s):  
Virginie Deleuze ◽  
Jean Lefort ◽  
Michel F. Bureau ◽  
Daniel Scherman ◽  
B. Boris Vargaftig
Keyword(s):  
Protective Effect ◽  
Lung Inflammation ◽  
Inflammatory Cytokine ◽  
Ex Vivo ◽  
Blood Levels ◽  
Tnf Α ◽  
Circulating Levels ◽  
Anti Inflammatory Cytokine ◽  
Intranasal Instillation

When administered to mice systemically or via the airways, LPS induces bronchoconstriction (BC) and/or bronchopulmonary hyperreactivity (BHR), associated with inflammation. Accordingly, a relationship between inflammation and allergic and nonallergic BHR can be hypothesized. We therefore studied the interference of the anti-inflammatory cytokine murine IL-10 (mIL-10) with LPS-induced lung inflammation, BC, and BHR. mIL-10 was administered directly into the airways by intranasal instillation or generated in vivo after muscle electrotransfer of mIL-10-encoding plasmid. Electrotransfer led to high mIL-10 circulating levels for a longer time than after the injection of recombinant mIL-10 (rmIL-10). rmIL-10 administered intranasally reduced lung inflammation and BHR after LPS administration into airways. It also reduced the ex vivo production of TNF-α by LPS-stimulated lung tissue explants. Two days after electrotransfer, mIL-10 blood levels were elevated, but lung inflammation, BC, and BHR persisted unaffected. Blood mIL-10 reaches the airways poorly, which probably accounts for the ineffectiveness of mIL-10-encoding plasmid electrotransfer. When LPS was aerosolized 15 days after electrotransfer, lung inflammation persisted but BHR was significantly reduced, an effect that may be related to the longer exposure of the relevant cells to mIL-10. The dissociation between inflammation and BHR indicates that both are not directly correlated. In conclusion, this study shows that mIL-10 is efficient against BHR when present in the airway compartment. Despite this, the muscle electrotransfer with mIL-10-encoding plasmid showed a protective effect against BHR after a delay of 2 wk that should be further investigated.

scholarly journals A Subconvulsive Dose of Kainate Selectively Compromises Astrocytic Metabolism in the Mouse Brain In Vivo

2014 ◽  
Vol 34 (8) ◽  
pp. 1340-1346 ◽  
Author(s):  
Anne B Walls ◽  
Elvar M Eyjolfsson ◽  
Arne Schousboe ◽  
Ursula Sonnewald ◽  
Helle S Waagepetersen
Keyword(s):  
Seizure Activity ◽  
Cerebral Metabolism ◽  
Tca Cycle ◽  
Resonance Spectroscopy ◽  
Neuronal Function ◽  
Limbic Seizures ◽  
Adult Mice ◽  
Neuronal Metabolism ◽  
Instantaneous Increase

Despite the well-established use of kainate as a model for seizure activity and temporal lobe epilepsy, most studies have been performed at doses giving rise to general limbic seizures and have mainly focused on neuronal function. Little is known about the effect of lower doses of kainate on cerebral metabolism and particularly that associated with astrocytes. We investigated astrocytic and neuronal metabolism in the cerebral cortex of adult mice after treatment with saline (controls), a subconvulsive or a mildly convulsive dose of kainate. A combination of [1,2-13C]acetate and [1-13C]glucose was injected and subsequent nuclear magnetic resonance spectroscopy of cortical extracts was employed to distinctively map astrocytic and neuronal metabolism. The subconvulsive dose of kainate led to an instantaneous increase in the cortical lactate content, a subsequent reduction in the amount of [4,5-13C]glutamine and an increase in the calculated astrocytic TCA cycle activity. In contrast, the convulsive dose led to decrements in the cortical content and 13C labeling of glutamate, glutamine, GABA, and aspartate. Evidence is provided that astrocytic metabolism is affected by a subconvulsive dose of kainate, whereas a higher dose is required to affect neuronal metabolism. The cerebral glycogen content was dose-dependently reduced by kainate supporting a role for glycogen during seizure activity.

scholarly journals A new organotypic model of synaptic competition reveals activity-dependent localization of C1q

2017 ◽  
Author(s):  
Ryuta Koyama ◽  
Yuwen Wu ◽  
Allison R. Bialas ◽  
Andrew Thompson ◽  
Christina A. Welsh ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Neural Circuits ◽  
Ex Vivo ◽  
Molecular Pathways ◽  
Synapse Elimination ◽  
Synaptic Competition ◽  
Coculture Model ◽  
First Time ◽  
Activity Dependent

AbstractImmature neural circuits undergo synaptic refinement, in which activity-dependent competition between synapses results in pruning of inappropriate connections and maintenance of appropriate ones. A longstanding question is how neuronal activity eliminates specific synapses based on their strength. The technical challenges of in vivo studies have made it difficult to identify a molecular link between decreased activity and synapse elimination. We developed an organotypic coculture model of the mouse retinogeniculate system that facilitates real-time imaging and elucidation of molecular mechanisms underlying the removal of less active synapses during synaptic competition. Using this model we show for the first time that complement component C1q is necessary for activity-dependent synaptic competition and preferentially localizes to less active, competing presynaptic inputs. In conjunction with classic in vivo and ex vivo models, this coculture model is a new tool to reveal molecular pathways underlying CNS circuit refinement.

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

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