scholarly journals Perturbed Brain Glucose Metabolism Caused by Absent SIRT3 Activity

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2348
Author(s):  
Tibor Kristian ◽  
Arman J. Karimi ◽  
Adam Fearnow ◽  
Jaylyn Waddell ◽  
Mary C. McKenna
Keyword(s):  
Glucose Metabolism ◽  
Ex Vivo ◽  
Tca Cycle ◽  
13C Nmr Spectroscopy ◽  
Mitochondrial Enzymes ◽  
Post Translational Modification ◽  
Oxidative Energy Metabolism ◽  
Activity Of Enzymes ◽  
The Impact ◽  
The Brain

Acetylation is a post-translational modification that regulates the activity of enzymes fundamentally involved in cellular and mitochondrial bioenergetic metabolism. NAD+ dependent deacetylase sirtuin 3 (SIRT3) is localized to mitochondria where it plays a key role in regulating acetylation of TCA cycle enzymes and the mitochondrial respiratory complexes. Although the SIRT3 target proteins in mitochondria have been identified, the effect of SIRT3 activity on mitochondrial glucose metabolism in the brain remains elusive. The impact of abolished SIRT3 activity on glucose metabolism was determined in SIRT3 knockout (KO) and wild type (WT) mice injected with [1,6-13C]glucose using ex vivo 13C-NMR spectroscopy. The 1H-NMR spectra and amino acid analysis showed no differences in the concentration of lactate, glutamate, alanine, succinate, or aspartate between SIRT3 KO and WT mice. However, glutamine, total creatine (Cr), and GABA were lower in SIRT3 KO brain. Incorporation of label from [1,6-13C]glucose metabolism into lactate or alanine was not affected in SIRT3 KO brain. However, the incorporation of the label into all isotopomers of glutamate, glutamine, GABA and aspartate was lower in SIRT3 KO brain, reflecting decreased activity of mitochondrial and TCA cycle metabolism in both neurons and astrocytes. This is most likely due to hyperacetylation of mitochondrial enzymes due to suppressed SIRT3 activity in the brain of SIRT3 KO mice. Thus, the absence of Sirt3 results in impaired mitochondrial oxidative energy metabolism and neurotransmitter synthesis in the brain. Since the SIRT3 activity is NAD+ dependent, these results might parallel changes in glucose metabolism under pathologic reduction in mitochondrial NAD+ pools.

scholarly journals Glutamatergic and GABAergic TCA Cycle and Neurotransmitter Cycling Fluxes in Different Regions of Mouse Brain

2013 ◽  
Vol 33 (10) ◽  
pp. 1523-1531 ◽  
Author(s):  
Vivek Tiwari ◽  
Susmitha Ambadipudi ◽  
Anant B Patel
Keyword(s):  
Cerebral Cortex ◽  
Mouse Brain ◽  
Ex Vivo ◽  
Tca Cycle ◽  
Metabolic Model ◽  
Nmr Studies ◽  
Inhibitory Function ◽  
The Tca Cycle ◽  
The Brain ◽  
C Nmr

The 13C nuclear magnetic resonance (NMR) studies together with the infusion of 13C-labeled substrates in rats and humans have provided important insight into brain energy metabolism. In the present study, we have extended a three-compartment metabolic model in mouse to investigate glutamatergic and GABAergic tricarboxylic acid (TCA) cycle and neurotransmitter cycle fluxes across different regions of the brain. The 13C turnover of amino acids from [1,6-13C2]glucose was monitored ex vivo using qH-[13C]-NMR spectroscopy. The astroglial glutamate pool size, one of the important parameters of the model, was estimated by a short infusion of [2-13C]acetate. The ratio Vcyc/VTCA was calculated from the steady-state acetate experiment. The 13C turnover curves of [4-13C]/[3-13C]glutamate, [4-13C]glutamine, [2-13C]/[3-13C]GABA, and [3-13C]aspartate from [1,6-13C2]glucose were analyzed using a three-compartment metabolic model to estimate the rates of the TCA cycle and neurotransmitter cycle associated with glutamatergic and GABAergic neurons. The glutamatergic TCA cycle rate was found to be highest in the cerebral cortex (0.91±0.05 μmol/g per minute) and least in the hippocampal region (0.64±0.07 μmol/g per minute) of the mouse brain. In contrast, the GABAergic TCA cycle flux was found to be highest in the thalamus-hypothalamus (0.28±0.01 μmol/g per minute) and least in the cerebral cortex (0.24±0.02 μmol/g per minute). These findings indicate that the energetics of excitatory and inhibitory function is distinct across the mouse brain.

scholarly journals Effects of Natural Monoamine Oxidase Inhibitors on Anxiety-Like Behavior in Zebrafish

2021 ◽  
Vol 12 ◽  
Author(s):  
Oihane Jaka ◽  
Iñaki Iturria ◽  
Marco van der Toorn ◽  
Jorge Hurtado de Mendoza ◽  
Diogo A. R. S. Latino ◽  
...  
Keyword(s):  
Prediction Models ◽  
Ex Vivo ◽  
Critical Role ◽  
Mitochondrial Enzymes ◽  
Dependent Manner ◽  
Mao Inhibitors ◽  
Concentration Dependent Manner ◽  
Mao Inhibitor ◽  
Novel Environment ◽  
The Brain

Monoamine oxidases (MAO) are a valuable class of mitochondrial enzymes with a critical role in neuromodulation. In this study, we investigated the effect of natural MAO inhibitors on novel environment-induced anxiety by using the zebrafish novel tank test (NTT). Because zebrafish spend more time at the bottom of the tank when they are anxious, anxiolytic compounds increase the time zebrafish spend at the top of the tank and vice versa. Using this paradigm, we found that harmane, norharmane, and 1,2,3,4-tetrahydroisoquinoline (TIQ) induce anxiolytic-like effects in zebrafish, causing them to spend more time at the top of the test tank and less time at the bottom. 2,3,6-trimethyl-1,4-naphtoquinone (TMN) induced an interesting mix of both anxiolytic- and anxiogenic-like effects during the first and second halves of the test, respectively. TIQ was unique in having no observable effect on general movement. Similarly, a reference MAO inhibitor clorgyline—but not pargyline—increased the time spent at the top in a concentration-dependent manner. We also demonstrated that the brain bioavailability of these compounds are high based on the ex vivo bioavailability assay and in silico prediction models, which support the notion that the observed effects on anxiety-like behavior in zebrafish were most likely due to the direct effect of these compounds in the brain. This study is the first investigation to demonstrate the anxiolytic-like effects of MAO inhibitors on novel environment-induced anxiety in zebrafish.

scholarly journals Acute and chronic stage adaptations of vascular architecture and cerebral blood flow in a mouse model of TBI

2018 ◽  
Author(s):  
Joe Steinman ◽  
Lindsay S. Cahill ◽  
Margaret M. Koletar ◽  
Bojana Stefanovic ◽  
John G. Sled
Keyword(s):  
Blood Flow ◽  
Ex Vivo ◽  
Vessel Density ◽  
Vascular Architecture ◽  
Two Photon ◽  
Brain Vasculature ◽  
The Impact ◽  
The Brain ◽  
Time Point

AbstractThe 3D organization of cerebral blood vessels determines the overall capacity of the cerebral circulation to meet the metabolic requirements of the brain. This study used Arterial Spin Labeling (ASL) MRI with a hypercapnic challenge and ex vivo Serial Two-Photon Tomography (STPT) to examine the relationship between blood flow and 3D microvascular structure following traumatic brain injury (TBI) in a mouse. Mice were exposed to a controlled cortical impact TBI and allowed to recover for either 1 day or 4 weeks. At each time point, ASL MRI was performed to quantify cerebral perfusion and the brain vasculature was imaged in 3D with STPT. Registration of ASL to STPT enabled flow changes to be related to the underlying microvascular structure in each ASL voxel. Hypoperfusion under rest and hypercapnia was observed both 1 day and 4 weeks post-TBI. Vessel density and vascular volume were reduced 1 day post-TBI, recovering by 4 weeks; however, the reorganized vasculature at the latter time point possessed an abnormal radial pattern. Our findings demonstrate functionally significant long-term changes in the vascular architecture following injury and illustrate why metrics beyond traditional measures of vessel density are required to understand the impact of vascular structure on function.

scholarly journals Liver glucose metabolism in humans

2016 ◽  
Vol 36 (6) ◽  
Author(s):  
María M. Adeva-Andany ◽  
Noemi Pérez-Felpete ◽  
Carlos Fernández-Fernández ◽  
Cristóbal Donapetry-García ◽  
Cristina Pazos-García
Keyword(s):  
Glucose Metabolism ◽  
De Novo ◽  
Tca Cycle ◽  
Pentose Phosphate ◽  
Post Translational Modification ◽  
Acetyl Coa ◽  
Hepatic Glucose Metabolism ◽  
Congenital Deficiency ◽  
Obesity And Diabetes ◽  
Hexosamine Pathway

Information about normal hepatic glucose metabolism may help to understand pathogenic mechanisms underlying obesity and diabetes mellitus. In addition, liver glucose metabolism is involved in glycosylation reactions and connected with fatty acid metabolism. The liver receives dietary carbohydrates directly from the intestine via the portal vein. Glucokinase phosphorylates glucose to glucose 6-phosphate inside the hepatocyte, ensuring that an adequate flow of glucose enters the cell to be metabolized. Glucose 6-phosphate may proceed to several metabolic pathways. During the post-prandial period, most glucose 6-phosphate is used to synthesize glycogen via the formation of glucose 1-phosphate and UDP–glucose. Minor amounts of UDP–glucose are used to form UDP–glucuronate and UDP–galactose, which are donors of monosaccharide units used in glycosylation. A second pathway of glucose 6-phosphate metabolism is the formation of fructose 6-phosphate, which may either start the hexosamine pathway to produce UDP-N-acetylglucosamine or follow the glycolytic pathway to generate pyruvate and then acetyl-CoA. Acetyl-CoA may enter the tricarboxylic acid (TCA) cycle to be oxidized or may be exported to the cytosol to synthesize fatty acids, when excess glucose is present within the hepatocyte. Finally, glucose 6-phosphate may produce NADPH and ribose 5-phosphate through the pentose phosphate pathway. Glucose metabolism supplies intermediates for glycosylation, a post-translational modification of proteins and lipids that modulates their activity. Congenital deficiency of phosphoglucomutase (PGM)-1 and PGM-3 is associated with impaired glycosylation. In addition to metabolize carbohydrates, the liver produces glucose to be used by other tissues, from glycogen breakdown or from de novo synthesis using primarily lactate and alanine (gluconeogenesis).

scholarly journals Reversal of Metabolic Deficits by Lipoic Acid in a Triple Transgenic Mouse Model of Alzheimer's Disease: A 13C NMR Study

2013 ◽  
Vol 34 (2) ◽  
pp. 288-296 ◽  
Author(s):  
Harsh Sancheti ◽  
Keiko Kanamori ◽  
Ishan Patil ◽  
Roberta Díaz Brinton ◽  
Brian D Ross ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glucose Metabolism ◽  
Mouse Model ◽  
Lipoic Acid ◽  
Ex Vivo ◽  
Tca Cycle ◽  
Model Of Alzheimer’S Disease ◽  
Age Related ◽  
Nmr Study

Alzheimer's disease is an age-related neurodegenerative disease characterized by deterioration of cognition and loss of memory. Several clinical studies have shown Alzheimer's disease to be associated with disturbances in glucose metabolism and the subsequent tricarboxylic acid (TCA) cycle-related metabolites like glutamate (Glu), glutamine (Gln), and N-acetylaspartate (NAA). These metabolites have been viewed as biomarkers by (a) assisting early diagnosis of Alzheimer's disease and (b) evaluating the efficacy of a treatment regimen. In this study, 13-month-old triple transgenic mice (a mouse model of Alzheimer's disease (3xTg-AD)) were given intravenous infusion of [1-13C]glucose followed by an ex vivo13C NMR to determine the concentrations of 13C-labeled isotopomers of Glu, Gln, aspartate (Asp), GABA, myo-inositol, and NAA. Total (12C+13C) Glu, Gln, and Asp were quantified by high-performance liquid chromatography to calculate enrichment. Furthermore, we examined the effects of lipoic acid in modulating these metabolites, based on its previously established insulin mimetic effects. Total 13C labeling and percent enrichment decreased by ∼50% in the 3xTg-AD mice. This hypometabolism was partially or completely restored by lipoic acid feeding. The ability of lipoic acid to restore glucose metabolism and subsequent TCA cycle-related metabolites further substantiates its role in overcoming the hypometabolic state inherent in early stages of Alzheimer's disease.

scholarly journals Measuring Glycolytic Activity with Hyperpolarized [2H7, U-13C6] D-Glucose in the Naive Mouse Brain under Different Anesthetic Conditions

Metabolites ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 413
Author(s):  
Emmanuelle Flatt ◽  
Bernard Lanz ◽  
Yves Pilloud ◽  
Andrea Capozzi ◽  
Mathilde Hauge Lerche ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
Glucose Metabolism ◽  
De Novo ◽  
Cerebral Metabolism ◽  
Resonance Spectroscopy ◽  
Hyperpolarized 13C ◽  
Glycolytic Activity ◽  
The Difference ◽  
The Impact ◽  
The Brain

Glucose is the primary fuel for the brain; its metabolism is linked with cerebral function. Different magnetic resonance spectroscopy (MRS) techniques are available to assess glucose metabolism, providing complementary information. Our first aim was to investigate the difference between hyperpolarized 13C-glucose MRS and non-hyperpolarized 2H-glucose MRS to interrogate cerebral glycolysis. Isoflurane anesthesia is commonly employed in preclinical MRS, but it affects cerebral hemodynamics and functional connectivity. A combination of low doses of isoflurane and medetomidine is routinely used in rodent fMRI and shows similar functional connectivity, as in awake animals. As glucose metabolism is tightly linked to neuronal activity, our second aim was to assess the impact of these two anesthetic conditions on the cerebral metabolism of glucose. Brain metabolism of hyperpolarized 13C-glucose and 2H-glucose was monitored in two groups of mice in a 9.4 T MRI system. We found that the very different duration and temporal resolution of the two techniques enable highlighting the different aspects in glucose metabolism. We demonstrate (by numerical simulations) that hyperpolarized 13C-glucose reports on de novo lactate synthesis and is sensitive to CMRGlc. We show that variations in cerebral glucose metabolism, under different anesthesia, are reflected differently in hyperpolarized and non-hyperpolarized X-nuclei glucose MRS.

scholarly journals Peroxisome proliferator-activated receptor α deficiency modifies glucose handling by isolated mouse adipocytes

2007 ◽  
Vol 193 (1) ◽  
pp. 39-43 ◽  
Author(s):  
C G Walker ◽  
M C Sugden ◽  
G F Gibbons ◽  
M J Holness
Keyword(s):  
Glucose Metabolism ◽  
High Glucose ◽  
Ex Vivo ◽  
Whole Body ◽  
Glucose Turnover ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Total Glucose ◽  
The Impact

Peroxisome proliferator-activated receptor α (PPARα) is a transcription factor that regulates enzymes involved in fatty acid (FA) utilisation. PPARα null mice have recently been demonstrated to have increased whole-body glucose turnover in vivo. This has been attributed to increased glucose uptake by adipose tissue, but the impact of PPARα deficiency on the characteristics of glucose handling by isolated adipocytes ex vivo is unknown. To determine directly the impact of PPARα deficiency on adipocyte glucose handling, thereby excluding any influence of humoral/neuronal factors, we examined total glucose metabolism as well as glucose disposition towards alternative fates in epididymal adipocytes isolated from wild-type and PPARαnull mice. Total glucose metabolism (oxidation, incorporation into FA and glycerol moieties of triglyceride (TAG) and conversion to lactate) was measured under basal conditions (low glucose) and ‘stimulated lipogenic’ conditions (high glucose + insulin). Adipocytes from PPARα null mice had higher rates of glucose metabolism under both basal and stimulated lipogenic conditions, with increased glucose utilisation both for oxidation and entry into the synthesis of the FA and glycerol components of lipid. In particular, the capacity of adipocytes from PPARα-deficient mice to utilise glucose for synthesis of the glycerol backbone of TAG was greatly enhanced under stimulated (high glucose + insulin) conditions. The increased use of glucose for the glycerol moiety of adipocyte TAG may therefore contribute to, and provide explanation for, enhanced glucose turnover in PPARα null mice.

scholarly journals Biocompatibility of Platinum Nanoparticles in Brain ex vivo Models in Physiological and Pathological Conditions

2021 ◽  
Vol 15 ◽  
Author(s):  
Maurizio Gulino ◽  
Sofia Duque Santos ◽  
Ana Paula Pêgo
Keyword(s):  
Pyramidal Cell ◽  
Platinum Nanoparticles ◽  
Cell Activation ◽  
Ex Vivo ◽  
Tissue Response ◽  
Pathological Conditions ◽  
Cell Layers ◽  
Hippocampal Cultures ◽  
The Impact ◽  
The Brain

Platinum nanoparticles (PtNPs) have unique physico-chemical properties that led to their use in many branches of medicine. Recently, PtNPs gathered growing interest as delivery vectors for drugs, biosensors and as surface coating on chronically implanted biomedical devices for improving electrochemical properties. However, there are contradictory statements about their biocompatibility and impact on target organs such as the brain tissue, where these NPs are finding many applications. Furthermore, many of the reported studies are conducted in homeostasis conditions and, consequently, neglect the impact of the pathologic conditions on the tissue response. To expand our knowledge on the effects of PtNPs on neuronal and glial cells, we investigated the acute effects of monodisperse sodium citrate-coated PtNPs on rat organotypic hippocampal cultures in physiological or neuronal excitotoxic conditions induced by kainic acid (KA). The cellular responses of the PtNPs were evaluated through cytotoxic assays and confocal microscopy analysis. To mimic a pathologic scenario, 7-day organotypic hippocampal cultures were exposed to KA for 24 h. Subsequently, PtNPs were added to each slice. We show that incubation of the slices with PtNPs for 24 h, does not severely impact cell viability in normal conditions, with no significant differences when comparing the dentate gyrus (DG), as well as CA3 and CA1 pyramidal cell layers. Such effects are not exacerbated in KA-treated slices, where the presence of PtNPs does not cause additional neuronal propidium iodide (PI) uptake in CA3 and CA1 pyramidal cell layers. However, PtNPs cause microglial cell activation and morphological alterations in CA3 and DG regions indicating the establishment of an inflammatory reaction. Morphological analysis revealed that microglia acquire activated ameboid morphology with loss of ramifications, as a result of their response to PtNPs contact. Surprisingly, this effect is not increased in pathological conditions. Taken together, these results show that PtNPs cause microglia alterations in short-term studies. Additionally, there is no worsening of the tissue response in a neuropathological induced scenario. This work highlights the need of further research to allow for the safe use of PtNPs. Also, it supports the demand of the development of novel and more biocompatible NPs to be applied in the brain.

scholarly journals Metabolic changes in brain slices over time: a multiplatform metabolomics approach

2020 ◽  
Author(s):  
Carolina Gonzalez-Riano ◽  
Silvia Tapia-González ◽  
Gertrudis Perea ◽  
Candela González-Arias ◽  
Javier DeFelipe ◽  
...  
Keyword(s):  
Brain Slice ◽  
Ex Vivo ◽  
Brain Slices ◽  
Tca Cycle ◽  
Electrophysiological Recording ◽  
Slice Preparation ◽  
Experimental Conditions ◽  
The Status ◽  
The Brain ◽  
Brain Slice Preparation

ABSTRACTBrain slice preparations are widely used for research in neuroscience. However, a high-quality preparation is essential and there is no consensus regarding stable parameters that can be used to define the status of the brain slice preparation after its collection at different time points. Thus, it is critical to establish the best experimental conditions for ex-vivo studies using brain slices for electrophysiological recording. In this study, we used a multiplatform (LC-MS and GC-MS) untargeted metabolomics-based approach to shed light on the metabolome and lipidome changes induced by the brain slice preparation process. We have found significant modifications in the levels of 300 compounds, including several lipid classes and their derivatives, as well as metabolites involved in the GABAergic pathway and the TCA cycle. All these preparation-dependent changes in the brain biochemistry should be taken into consideration for future studies to facilitate non-biased interpretations of the experimental results.

scholarly journals Mild Hyperthermia Aggravates Glucose Metabolic Consequences in Repetitive Concussion

2020 ◽  
Vol 21 (2) ◽  
pp. 609
Author(s):  
Meghan Blaya ◽  
Jessie Truettner ◽  
Weizhao Zhao ◽  
Helen Bramlett ◽  
William Dalton Dietrich
Keyword(s):  
Brain Injury ◽  
Glucose Metabolism ◽  
Brain Temperature ◽  
Brain Regions ◽  
Cerebral Glucose Metabolism ◽  
Temperature Management ◽  
Diagnostic Tools ◽  
Neurological Outcomes ◽  
The Impact ◽  
The Brain

Traumatic brain injury (TBI) is one of the leading causes of mortality and disability around the world. Mild TBI (mTBI) makes up approximately 80% of reported cases and often results in transient psychological abnormalities and cognitive disruption. At-risk populations for mTBI include athletes and other active individuals who may sustain repetitive concussive injury during periods of exercise and exertion when core temperatures are elevated. Previous studies have emphasized the impact that increased brain temperature has on adverse neurological outcomes. A lack of diagnostic tools to assess concussive mTBI limits the ability to effectively identify the post-concussive period during which the brain is uniquely susceptible to damage upon sustaining additional injury. Studies have suggested that a temporal window of increased vulnerability that exists corresponds to a period of injury-induced depression of cerebral glucose metabolism. In the current study, we sought to evaluate the relationship between repetitive concussion, local cerebral glucose metabolism, and brain temperature using the Marmarou weight drop model to generate mTBI. Animals were injured three consecutive times over a period of 7 days while exposed to either normothermic or hyperthermic temperatures for 15 min prior to and 1 h post each injury. A 14C-2-deoxy-d-glucose (2DG) autoradiography was used to measure local cerebral metabolic rate of glucose (lCMRGlc) in 10 diverse brain regions across nine bregma levels 8 days after the initial insult. We found that repetitive mTBI significantly decreased glucose utilization bilaterally in several cortical areas, such as the cingulate, visual, motor, and retrosplenial cortices, as well as in subcortical areas, including the caudate putamen and striatum, compared to sham control animals. lCMRGlc was significant in both normothermic and hyperthermic repetitive mTBI animals relative to the sham group, but to a greater degree when exposed to hyperthermic conditions. Taken together, we report significant injury-induced glucose hypometabolism after repetitive concussion in the brain, and additionally highlight the importance of temperature management in the acute period after brain injury.

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