| 1. |
- Soares, Ana Francisca, et al.
(author)
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Glycogen metabolism is impaired in the brain of male type 2 diabetic Goto-Kakizaki rats
- 2019
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In: Journal of Neuroscience Research. - : Wiley. - 1097-4547 .- 0360-4012. ; 97:8, s. 1004-1017
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Journal article (peer-reviewed)abstract
- Diabetes impacts the central nervous system predisposing to cognitive decline. While glucose is the main source of energy fueling the adult brain, brain glycogen is necessary for adequate neuronal function, synaptic plasticity and memory. In this study, we tested the hypothesis that brain glycogen metabolism is impaired in type 2 diabetes (T2D). 13 C magnetic resonance spectroscopy (MRS) during [1-13 C]glucose i.v. infusion was employed to detect 13 C incorporation into whole-brain glycogen in male Goto-Kakizaki (GK) rats, a lean model of T2D, and control Wistar rats. Labeling from [1-13 C]glucose into brain glycogen occurred at a rate of 0.25 ± 0.12 and 0.48 ± 0.22 µmol/g/h in GK and Wistar rats, respectively (p = 0.028), despite similar brain glycogen concentrations. In addition, the appearance of [1-13 C]glucose in the brain was used to evaluate glucose transport and consumption. T2D caused a 31% reduction (p = 0.031) of the apparent maximum transport rate (Tmax ) and a tendency for reduced cerebral metabolic rate of glucose (CMRglc ; -29%, p = 0.062), indicating impaired glucose utilization in T2D. After MRS in vivo, gas chromatography-mass spectrometry was employed to measure regional 13 C fractional enrichment of glucose and glycogen in the cortex, hippocampus, striatum, and hypothalamus. The diabetes-induced reduction in glycogen labeling was most prominent in the hippocampus and hypothalamus, which are crucial for memory and energy homeostasis, respectively. These findings were further supported by changes in the phosphorylation rate of glycogen synthase, as analyzed by Western blotting. Altogether, the present results indicate that T2D is associated with impaired brain glycogen metabolism.
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| 2. |
- Belenguer, Pascale, et al.
(author)
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Mitochondria and the Brain : Bioenergetics and Beyond
- 2019
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In: Neurotoxicity Research. - : Springer Science and Business Media LLC. - 1029-8428 .- 1476-3524. ; 36:2, s. 219-238
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Journal article (peer-reviewed)abstract
- The view of mitochondria acting solely as a powerhouse of the cell is no longer accurate. Besides cell bioenergetics, primary targets of mitochondrial studies include their interplay with essential processes within the cell, including redox and calcium homeostasis, and apoptosis. Recent studies evidence the dynamic behavior of mitochondria, continuously moving, fusing, and dividing, and the interaction of these events with cellular degeneration and plasticity in neural cells. Our review summarizes novel data and technologies that are developed and applied to the identification and clarification of the mitochondrial role in neural plasticity using both cultured cells and in vivo approaches. The complete understanding and modulation of such mechanisms may represent a novel and promising therapeutic approach for treatment of diseases affecting central and peripheral nervous system.
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| 3. |
- Duarte, João M N, et al.
(author)
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Impact of Caffeine Consumption on Type 2 Diabetes-Induced Spatial Memory Impairment and Neurochemical Alterations in the Hippocampus
- 2019
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In: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 12, s. 1-15
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Journal article (peer-reviewed)abstract
- Diabetes affects the morphology and plasticity of the hippocampus, and leads to learning and memory deficits. Caffeine has been proposed to prevent memory impairment upon multiple chronic disorders with neurological involvement. We tested whether long-term caffeine consumption prevents type 2 diabetes (T2D)-induced spatial memory impairment and hippocampal alterations, including synaptic degeneration, astrogliosis, and metabolic modifications. Control Wistar rats and Goto-Kakizaki (GK) rats that develop T2D were treated with caffeine (1 g/L in drinking water) for 4 months. Spatial memory was evaluated in a Y-maze. Hippocampal metabolic profile and glucose homeostasis were investigated by 1H magnetic resonance spectroscopy. The density of neuronal, synaptic, and glial-specific markers was evaluated by Western blot analysis. GK rats displayed reduced Y-maze spontaneous alternation and a lower amplitude of hippocampal long-term potentiation when compared to controls, suggesting impaired hippocampal-dependent spatial memory. Diabetes did not impact the relation of hippocampal to plasma glucose concentrations, but altered the neurochemical profile of the hippocampus, such as increased in levels of the osmolites taurine (P < 0.001) and myo-inositol (P < 0.05). The diabetic hippocampus showed decreased density of the presynaptic proteins synaptophysin (P < 0.05) and SNAP25 (P < 0.05), suggesting synaptic degeneration, and increased GFAP (P < 0.001) and vimentin (P < 0.05) immunoreactivities that are indicative of astrogliosis. The effects of caffeine intake on hippocampal metabolism added to those of T2D, namely reducing myo-inositol levels (P < 0.001) and further increasing taurine levels (P < 0.05). Caffeine prevented T2D-induced alterations of GFAP, vimentin and SNAP25, and improved memory deficits. We conclude that caffeine consumption has beneficial effects counteracting alterations in the hippocampus of GK rats, leading to the improvement of T2D-associated memory impairment.
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| 4. |
- Duarte, João M.N., et al.
(author)
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Magnetic Resonance Spectroscopy in Schizophrenia : Evidence for Glutamatergic Dysfunction and Impaired Energy Metabolism
- 2019
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In: Neurochemical Research. - : Springer Science and Business Media LLC. - 0364-3190 .- 1573-6903. ; 44:1, s. 102-116
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Journal article (peer-reviewed)abstract
- In the past couple of decades, major efforts were made to increase reliability of metabolic assessments by magnetic resonance methods. Magnetic resonance spectroscopy (MRS) has been valuable for providing in vivo evidence and investigating biomarkers in neuropsychiatric disorders, namely schizophrenia. Alterations of glutamate and glutamine levels in brains of schizophrenia patients relative to healthy subjects are generally interpreted as markers of glutamatergic dysfunction. However, only a small fraction of MRS-detectable glutamate is involved in neurotransmission. Here we review and discuss brain metabolic processes that involve glutamate and that are likely to be implicated in neuropsychiatric disorders.
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| 5. |
- Lizarbe, Blanca, et al.
(author)
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High-fat diet consumption alters energy metabolism in the mouse hypothalamus
- 2019
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In: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 43:6, s. 1295-1304
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Journal article (peer-reviewed)abstract
- Background/Objectives: High-fat diet consumption is known to trigger an inflammatory response in the hypothalamus, which has been characterized by an initial expression of pro-inflammatory genes followed by hypothalamic astrocytosis, microgliosis, and the appearance of neuronal injury markers. The specific effects of high-fat diet on hypothalamic energy metabolism and neurotransmission are however not yet known and have not been investigated before. Subjects/Methods: We used 1H and 13C magnetic resonance spectroscopy (MRS) and immunofluorescence techniques to evaluate in vivo the consequences of high-saturated fat diet administration to mice, and explored the effects on hypothalamic metabolism in three mouse cohorts at different time points for up to 4 months. Results: We found that high-fat diet increases significantly the hypothalamic levels of glucose (P < 0.001), osmolytes (P < 0.001), and neurotransmitters (P < 0.05) from 2 months of diet, and alters the rates of metabolic (P < 0.05) and neurotransmission fluxes (P < 0.001), and the contribution of non-glycolytic substrates to hypothalamic metabolism (P < 0.05) after 10 weeks of high-fat feeding. Conclusions/interpretation: We report changes that reveal a high-fat diet-induced alteration of hypothalamic metabolism and neurotransmission that is quantifiable by 1H and 13C MRS in vivo, and present the first evidence of the extension of the inflammation pathology to a localized metabolic imbalance.
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| 6. |
- Lizarbe, Blanca, et al.
(author)
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Neurochemical Modifications in the Hippocampus, Cortex and Hypothalamus of Mice Exposed to Long-Term High-Fat Diet
- 2018
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In: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 12
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Journal article (peer-reviewed)abstract
- Metabolic syndrome and diabetes impact brain function and metabolism. While it is well established that rodents exposed to diets rich in saturated fat develop brain dysfunction, contrasting results abound in the literature, likely as result of exposure to different high-fat diet (HFD) compositions and for varied periods of time. In the present study, we investigated alterations of hippocampal-dependent spatial memory by measuring Y-maze spontaneous alternation, metabolic profiles of the hippocampus, cortex and hypothalamus by 1H magnetic resonance spectroscopy (MRS), and levels of proteins specific to synaptic and glial compartments in mice exposed for 6 months to different amounts of fat (10, 45, or 60% of total energy intake). Increasing the dietary amount of fat from 10 to 45% or 60% resulted in obesity accompanied by increased leptin, fasting blood glucose and insulin, and reduced glucose tolerance. In comparison to controls (10%-fat), only mice fed the 60%-fat diet showed increased fed glycemia, as well as plasma corticosterone that has a major impact on brain function. HFD-induced metabolic profile modifications measured by 1H MRS were observed across the three brain areas in mice exposed to 60%- but not 45%-fat diet, while both HFD groups displayed impaired hippocampal-dependent memory. HFD also affected systems involved in neuro- or gliotransmission in the hippocampus. Namely, relative to controls, 60%-fat-fed mice showed reduced SNAP-25, PSD-95 and syntaxin-4 immunoreactivity, while 45%-fat-fed mice showed reduced gephyrin and syntaxin-4 immunoreactivity. For both HFD levels, reductions of the vesicular glutamate transporter vGlut1 and levels of the vesicular GABA transporter were observed in the hippocampus and hypothalamus, relative to controls. Immunoreactivity against GFAP and/or Iba-1 in the hypothalamus was higher in mice exposed to HFD than controls, suggesting occurrence of gliosis. We conclude that different levels of dietary fat result in distinct neurochemical alterations in the brain.
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| 7. |
- Sonnay, Sarah, et al.
(author)
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Astrocytic and neuronal oxidative metabolism are coupled to the rate of glutamate–glutamine cycle in the tree shrew visual cortex
- 2018
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In: GLIA. - : Wiley. - 0894-1491. ; 66:3, s. 477-491
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Journal article (peer-reviewed)abstract
- Astrocytes play an important role in glutamatergic neurotransmission, namely by clearing synaptic glutamate and converting it into glutamine that is transferred back to neurons. The rate of this glutamate–glutamine cycle (VNT) has been proposed to couple to that of glucose utilization and of neuronal tricarboxylic acid (TCA) cycle. In this study, we tested the hypothesis that glutamatergic neurotransmission is also coupled to the TCA cycle rate in astrocytes. For that we investigated energy metabolism by means of magnetic resonance spectroscopy (MRS) in the primary visual cortex of tree shrews (Tupaia belangeri) under light isoflurane anesthesia at rest and during continuous visual stimulation. After identifying the activated cortical volume by blood oxygenation level-dependent functional magnetic resonance imaging, 1H MRS was performed to measure stimulation-induced variations in metabolite concentrations. Relative to baseline, stimulation of cortical activity for 20 min caused a reduction of glucose concentration by −0.34 ± 0.09 µmol/g (p < 0.001), as well as a −9% ± 1% decrease of the ratio of phosphocreatine-to-creatine (p < 0.05). Then 13C MRS during [1,6-13C]glucose infusion was employed to measure fluxes of energy metabolism. Stimulation of glutamatergic activity, as indicated by a 20% increase of VNT, resulted in increased TCA cycle rates in neurons by 12% ((VTCA n, p < 0.001), p < 0.001) and in astrocytes by 24% ((VTCA g, p = 0.007). We further observed linear relationships between VNT and both VTCA n and VTCA g. Altogether, these results suggest that in the tree shrew primary visual cortex glutamatergic neurotransmission is linked to overall glucose oxidation and to mitochondrial metabolism in both neurons and astrocytes.
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