| 1. |
- Garcia-Serrano, Alba M., et al.
(författare)
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Brain Metabolism Alterations in Type 2 Diabetes : What Did We Learn From Diet-Induced Diabetes Models?
- 2020
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 14
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Forskningsöversikt (refereegranskat)abstract
- Type 2 diabetes (T2D) is a metabolic disease with impact on brain function through mechanisms that include glucose toxicity, vascular damage and blood–brain barrier (BBB) impairments, mitochondrial dysfunction, oxidative stress, brain insulin resistance, synaptic failure, neuroinflammation, and gliosis. Rodent models have been developed for investigating T2D, and have contributed to our understanding of mechanisms involved in T2D-induced brain dysfunction. Namely, mice or rats exposed to diabetogenic diets that are rich in fat and/or sugar have been widely used since they develop memory impairment, especially in tasks that depend on hippocampal processing. Here we summarize main findings on brain energy metabolism alterations underlying dysfunction of neuronal and glial cells promoted by diet-induced metabolic syndrome that progresses to a T2D phenotype.
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| 2. |
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| 3. |
- Pedro, Joana Reis, et al.
(författare)
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Transient gain of function of cannabinoid CB1 receptors in the control of frontocortical glucose consumption in a rat model of Type-1 diabetes
- 2020
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Ingår i: Brain Research Bulletin. - : Elsevier BV. - 0361-9230. ; 161, s. 106-115
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Tidskriftsartikel (refereegranskat)abstract
- Here we aimed to unify some previous controversial reports on changes in both cannabinoid CB1 receptor (CB1R) expression and glucose metabolism in the forebrain of rodent models of diabetes. We determined how glucose metabolism and its modulation by CB1R ligands evolve in the frontal cortex of young adult male Wistar rats, in the first 8 weeks of streptozotocin-induced type-1 diabetes (T1D). We report that frontocortical CB1R protein density was biphasically altered in the first month of T1D, which was accompanied with a reduction of resting glucose uptake ex vivo in acute frontocortical slices that was normalized after eight weeks in T1D. This early reduction of glucose uptake in slices was also restored by ex vivo treatment with both the non-selective CB1R agonists, WIN55212−2 (500 nM) and the CB1R-selective agonist, ACEA (3 μM) while it was exacerbated by the CB1R-selective antagonist, O-2050 (500 nM). These results suggest a gain-of-function for the cerebrocortical CB1Rs in the control of glucose uptake in diabetes. Although insulin and IGF-1 receptor protein densities remained unaffected, phosphorylated GSKα and GSKβ levels showed different profiles 2 and 8 weeks after T1D induction in the frontal cortex. Altogether, the biphasic response in frontocortical CB1R density within a month after T1D induction resolves previous controversial reports on forebrain CB1R levels in T1D rodent models. Furthermore, this study also hints that cannabinoids may be useful to alleviate impaired glucoregulation in the diabetic cortex.
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| 4. |
- Rafiee, Zeinab, et al.
(författare)
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Taurine Supplementation as a Neuroprotective Strategy upon Brain Dysfunction in Metabolic Syndrome and Diabetes
- 2022
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 14:6
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Forskningsöversikt (refereegranskat)abstract
- Obesity, type 2 diabetes, and their associated comorbidities impact brain metabolism and function and constitute risk factors for cognitive impairment. Alterations to taurine homeostasis can impact a number of biological processes, such as osmolarity control, calcium homeostasis, and inhibitory neurotransmission, and have been reported in both metabolic and neurodegenerative disorders. Models of neurodegenerative disorders show reduced brain taurine concentrations. On the other hand, models of insulin-dependent diabetes, insulin resistance, and diet-induced obesity display taurine accumulation in the hippocampus. Given the possible cytoprotective actions of taurine, such cerebral accumulation of taurine might constitute a compensatory mechanism that attempts to prevent neurodegeneration. The present article provides an overview of brain taurine homeostasis and reviews the mechanisms by which taurine can afford neuroprotection in individuals with obesity and diabetes. We conclude that further research is needed for understanding taurine homeostasis in metabolic disorders with an impact on brain function.
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| 5. |
- Skoug, Cecilia, et al.
(författare)
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Density of Sphingosine-1-Phosphate Receptors Is Altered in Cortical Nerve-Terminals of Insulin-Resistant Goto-Kakizaki Rats and Diet-Induced Obese Mice
- 2023
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Ingår i: Neurochemical Research. - 0364-3190.
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Tidskriftsartikel (refereegranskat)abstract
- Sphingosine-1-phosphate (S1P) is a phosphosphingolipid with pleiotropic biological functions. S1P acts as an intracellular second messenger, as well as extracellular ligand to five G-protein coupled receptors (S1PR1-5). In the brain, S1P regulates neuronal proliferation, apoptosis, synaptic activity and neuroglia activation. Moreover, S1P metabolism alterations have been reported in neurodegenerative disorders. We have previously reported that S1PRs are present in nerve terminals, exhibiting distinct sub-synaptic localization and neuromodulation actions. Since type 2 diabetes (T2D) causes synaptic dysfunction, we hypothesized that S1P signaling is modified in nerve terminals. In this study, we determined the density of S1PRs in cortical synaptosomes from insulin-resistant Goto-Kakizaki (GK) rats and Wistar controls, and from mice fed a high-fat diet (HFD) and low-fat-fed controls. Relative to their controls, GK rats showed similar cortical S1P concentration despite higher S1P levels in plasma, yet lower density of S1PR1, S1PR2 and S1PR4 in nerve-terminal-enriched membranes. HFD-fed mice exhibited increased plasma and cortical concentrations of S1P, and decreased density of S1PR1 and S1PR4. These findings point towards altered S1P signaling in synapses of insulin resistance and diet-induced obesity models, suggesting a role of S1P signaling in T2D-associated synaptic dysfunction.
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| 6. |
- Duarte, João M.N.
(författare)
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Loss of brain energy metabolism control as a driver for memory impairment upon insulin resistance
- 2023
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Ingår i: Biochemical Society Transactions. - 0300-5127. ; 51:1, s. 287-301
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Forskningsöversikt (refereegranskat)abstract
- The pathophysiological mechanisms intersecting metabolic and neurodegenerative disorders include insulin resistance, which has a strong involvement of environmental factors. Besides central regulation of whole-body homeostasis, insulin in the central nervous system controls molecular signalling that is critical for cognitive performance, namely signalling through pathways that modulate synaptic transmission and plasticity, and metabolism in neurons and astrocytes. This review provides an overview on how insulin signalling in the brain might regulate brain energy metabolism, and further identified molecular mechanisms by which brain insulin resistance might impair synaptic fuelling, and lead to cognitive deterioration.
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| 7. |
- Duarte, João M.N.
(författare)
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Serine racemase modulation for improving brain insulin resistance : An Editorial Highlight for “Deletion of serine racemase reverses neuronal insulin signaling inhibition by amyloid-β oligomers”
- 2022
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 163:1, s. 6-7
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Tidskriftsartikel (refereegranskat)abstract
- This Editorial highlights an interesting study in the current issue of the Journal of Neurochemistry in which Zhou et al. report new data showing that the ablation of serine racemase increases local insulin production in neurons of the hippocampus. The authors explored some of the possible mechanisms mediating the interaction between dampening production of D-serine and the local synthesis of insulin, and they further propose that stimulating insulin production could counteract hippocampal insulin resistance in Alzheimer's disease (AD). Most importantly, they leave open a number of questions that need to be experimentally addressed to ascertain whether D-serine modulation of neuronal insulin expression can effectively improve insulin sensitivity in AD, as well as in metabolic disease with neurological impact.
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| 8. |
- Kubota, Manabu, et al.
(författare)
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Dynamic alterations in the central glutamatergic status following food and glucose intake : in vivo multimodal assessments in humans and animal models
- 2021
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - 0271-678X. ; 41:11, s. 2928-2943
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Tidskriftsartikel (refereegranskat)abstract
- Fluctuations of neuronal activities in the brain may underlie relatively slow components of neurofunctional alterations, which can be modulated by food intake and related systemic metabolic statuses. Glutamatergic neurotransmission plays a major role in the regulation of excitatory tones in the central nervous system, although just how dietary elements contribute to the tuning of this system remains elusive. Here, we provide the first demonstration by bimodal positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) that metabotropic glutamate receptor subtype 5 (mGluR5) ligand binding and glutamate levels in human brains are dynamically altered in a manner dependent on food intake and consequent changes in plasma glucose levels. The brain-wide modulations of central mGluR5 ligand binding and glutamate levels and profound neuronal activations following systemic glucose administration were further proven by PET, MRS, and intravital two-photon microscopy, respectively, in living rodents. The present findings consistently support the notion that food-associated glucose intake is mechanistically linked to glutamatergic tones in the brain, which are translationally accessible in vivo by bimodal PET and MRS measurements in both clinical and non-clinical settings.
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| 9. |
- Skoug, Cecilia, et al.
(författare)
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Sphingosine 1-Phoshpate Receptors are Located in Synapses and Control Spontaneous Activity of Mouse Neurons in Culture
- 2022
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Ingår i: Neurochemical Research. - : Springer Science and Business Media LLC. - 1573-6903 .- 0364-3190. ; 47:10, s. 3114-3125
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Tidskriftsartikel (refereegranskat)abstract
- Sphingosine-1-phosphate (S1P) is best known for its roles as vascular and immune regulator. Besides, it is also present in the central nervous system (CNS) where it can act as neuromodulator via five S1P receptors (S1PRs), and thus control neurotransmitter release. The distribution of S1PRs in the active zone and postsynaptic density of CNS synapses remains unknown. In the current study, we investigated the localization of S1PR1-5 in synapses of the mouse cortex. Cortical nerve terminals purified in a sucrose gradient were endowed with all five S1PRs. Further subcellular fractionation of cortical nerve terminals revealed S1PR2 and S1PR4 immunoreactivity in the active zone of presynaptic nerve terminals. Interestingly, only S1PR2 and S1PR3 immunoreactivity was found in the postsynaptic density. All receptors were present outside the active zone of nerve terminals. Neurons in the mouse cortex and primary neurons in culture showed immunoreactivity against all five S1PRs, and Ca 2+ imaging revealed that S1P inhibits spontaneous neuronal activity in a dose-dependent fashion. When testing selective agonists for each of the receptors, we found that only S1PR1, S1PR2 and S1PR4 control spontaneous neuronal activity. We conclude that S1PR2 and S1PR4 are located in the active zone of nerve terminals and inhibit neuronal activity. Future studies need to test whether these receptors modulate stimulation-induced neurotransmitter release.
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| 11. |
- Vanherle, Lotte, et al.
(författare)
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Restoring myocardial infarction-induced long-term memory impairment by targeting the cystic fibrosis transmembrane regulator
- 2022
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 86
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cognitive impairment is a serious comorbidity in heart failure patients, but effective therapies are lacking. We investigated the mechanisms that alter hippocampal neurons following myocardial infarction (MI).METHODS: MI was induced in male C57Bl/6 mice by left anterior descending coronary artery ligation. We utilised standard procedures to measure cystic fibrosis transmembrane regulator (CFTR) protein levels, inflammatory mediator expression, neuronal structure, and hippocampal memory. Using in vitro and in vivo approaches, we assessed the role of neuroinflammation in hippocampal neuron degradation and the therapeutic potential of CFTR correction as an intervention.FINDINGS: Hippocampal dendrite length and spine density are reduced after MI, effects that associate with decreased neuronal CFTR expression and concomitant microglia activation and inflammatory cytokine expression. Conditioned medium from lipopolysaccharide-stimulated microglia (LCM) reduces neuronal cell CFTR protein expression and the mRNA expression of the synaptic regulator post-synaptic density protein 95 (PSD-95) in vitro. Blocking CFTR activity also down-regulates PSD-95 in neurons, indicating a relationship between CFTR expression and neuronal health. Pharmacologically correcting CFTR expression in vitro rescues the LCM-mediated down-regulation of PSD-95. In vivo, pharmacologically increasing hippocampal neuron CFTR expression improves MI-associated alterations in neuronal arborisation, spine density, and memory function, with a wide therapeutic time window.INTERPRETATION: Our results indicate that CFTR therapeutics improve inflammation-induced alterations in hippocampal neuronal structure and attenuate memory dysfunction following MI.
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