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Moskal J, Michalak S. Tight junction proteins in glial tumors development and progression. Front Cell Neurosci 2025; 19:1541885. [PMID: 39963115 PMCID: PMC11830821 DOI: 10.3389/fncel.2025.1541885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 01/09/2025] [Indexed: 02/20/2025] Open
Abstract
Tight junctions form a paracellular barrier in epithelial and endothelial cells, and they regulate the diffusion of fluids, molecules, and the penetration of cells across tissue compartments. Tight junctions are composed of a group of integral membrane proteins, which include the claudin family, tight junction-associated Marvel protein family, junctional adhesion molecule family, and proteins that anchor the cytoskeleton, such as zonula occludens proteins and the cingulin family. Several factors, such as neurotransmitters or cytokines, and processes like ischemia/hypoxia, inflammation, tumorigenesis, phosphorylation/dephosphorylation, ubiquitination, and palmitoylation, regulate tight junction proteins. Claudins are involved in tumorigenesis processes that lead to glioma formation. In gliomas, there is a noticeable dysregulation of claudins, occludin, and zonula occludens-1 abundance, and their dislocation has been observed. The weakening of intercellular adhesion and cell detachment is responsible for glioma infiltration into surrounding tissues. Furthermore, the paracellular permeability of the blood-brain barrier, formed with the involvement of tight junction proteins, influences the development of peritumoral edema - and, simultaneously, the rate of drug delivery to the glial tumor. Understanding the junctional and paracellular environments in brain tumors is crucial to predicting glial tumor progression and the feasibility of chemotherapeutic drug delivery. This knowledge may also illuminate differences between high and low-grade gliomas.
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Affiliation(s)
- Jakub Moskal
- Department of Neurosurgery and Neurotraumatology, Poznan University of Medical Sciences, Poznan, Poland
| | - Slawomir Michalak
- Department of Neurosurgery and Neurotraumatology, Poznan University of Medical Sciences, Poznan, Poland
- Department of Neurochemistry and Neuropathology, Poznan University of Medical Sciences, Poznan, Poland
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Zhu Y, Verkhratsky A, Chen H, Yi C. Understanding glucose metabolism and insulin action at the blood-brain barrier: Implications for brain health and neurodegenerative diseases. Acta Physiol (Oxf) 2025; 241:e14283. [PMID: 39822067 PMCID: PMC11737474 DOI: 10.1111/apha.14283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/09/2024] [Accepted: 01/01/2025] [Indexed: 01/19/2025]
Abstract
The blood-brain barrier (BBB) is a highly selective, semipermeable barrier critical for maintaining brain homeostasis. The BBB regulates the transport of essential nutrients, hormones, and signaling molecules between the bloodstream and the central nervous system (CNS), while simultaneously protecting the brain from potentially harmful substances and pathogens. This selective permeability ensures that the brain is nourished and shielded from toxins. An exception to this are brain regions, such as the hypothalamus and circumventricular organs, which are irrigated by fenestrated capillaries, allowing rapid and direct response to various blood components. We overview the metabolic functions of the BBB, with an emphasis on the impact of altered glucose metabolism and insulin signaling on BBB in the pathogenesis of neurodegenerative diseases. Notably, endothelial cells constituting the BBB exhibit distinct metabolic characteristics, primarily generating ATP through aerobic glycolysis. This occurs despite their direct exposure to the abundant oxygen in the bloodstream, which typically supports oxidative phosphorylation. The effects of insulin on astrocytes, which form the glial limitans component of the BBB, show a marked sexual dimorphism. BBB nutrient sensing in the hypothalamus, along with insulin signaling, regulates systemic metabolism. Insulin modifies BBB permeability by regulating the expression of tight junction proteins, angiogenesis, and vascular remodeling, as well as modulating blood flow in the brain. The disruptions in glucose and insulin signaling are particularly evident in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, where BBB breakdown accelerates cognitive decline. This review highlights the critical role of normal glucose metabolism and insulin signaling in maintaining BBB functionality and investigates how disruptions in these pathways contribute to the onset and progression of neurodegenerative diseases.
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Affiliation(s)
- Yiyi Zhu
- Research CenterThe Seventh Affiliated Hospital of Sun Yat‐Sen UniversityShenzhenChina
| | - Alexei Verkhratsky
- Faculty of Biology, Medicine and HealthThe University of ManchesterManchesterUK
- Department of NeurosciencesUniversity of the Basque Country, CIBERNEDLeioaBizkaiaSpain
- IKERBASQUE Basque Foundation for ScienceBilbaoSpain
- Department of Forensic Analytical Toxicology, School of Forensic MedicineChina Medical UniversityShenyangChina
| | - Hui Chen
- School of Life Sciences, Faculty of ScienceUniversity of Technology SydneyUltimoNew South WalesAustralia
| | - Chenju Yi
- Research CenterThe Seventh Affiliated Hospital of Sun Yat‐Sen UniversityShenzhenChina
- Guangdong Provincial Key Laboratory of Brain Function and DiseaseGuangzhouChina
- Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational ResearchShenzhenChina
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Weber CM, Moiz B, Pena GS, Kheradmand M, Wunderler B, Kettula C, Sangha GS, Smith JC, Clyne AM. Impacts of APOE-ε4 and exercise training on brain microvascular endothelial cell barrier function and metabolism. EBioMedicine 2025; 111:105487. [PMID: 39647262 PMCID: PMC11667009 DOI: 10.1016/j.ebiom.2024.105487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 10/27/2024] [Accepted: 11/20/2024] [Indexed: 12/10/2024] Open
Abstract
BACKGROUND The APOE-ε4 genotype is the highest genetic risk factor for Alzheimer's disease (AD), and exercise training can reduce the risk of AD. Two early pathologies of AD are degradation of tight junctions between brain microvascular endothelial cells (BMEC) and brain glucose hypometabolism. Therefore, the objective of this work was to determine how the APOE-ε4 genotype and serum from exercise trained individuals impacts BMEC barrier function and metabolism. METHODS iPSC homozygous for the APOE-ε3 and APOE-ε4 alleles were differentiated to BMEC-like cells and used to measure barrier function and metabolism. To investigate exercise effects, serum was collected from older adults pre- and post- 6 months of exercise training (n = 9 participants per genotype). APOE-ε3 and APOE-ε4 BMEC were treated with genotype-matched serum, and then barrier function and metabolism were measured. FINDINGS APOE-ε4 genotype impaired BMEC barrier function and metabolism by reducing sirtuin 1 (SIRT1) levels by 27% (p = 0.0188) and baseline insulin signalling by 37% (p = 0.0186) compared to APOE-ε3 BMEC. Exercise-trained serum increased SIRT1 by 33% (p = 0.0043) in APOE-ε3 BMEC but decreased SIRT1 by 22% (p = 0.0004) in APOE ε4 BMEC. INTERPRETATION APOE-ε4 directly impairs glucose metabolism and barrier function. Serum from exercise trained individuals alters SIRT1 in a genotype-dependent manner but may require additional cues from exercise to decrease AD pathologies. FUNDING Brain and Behaviour Initiative at the University of Maryland through the Seed Grant Program, NSF-GRFP DGE 1840340, Fischell Fellowship in Biomedical Engineering, NSF CBET-2211966 and DGE-1632976, National Niemann-Pick Disease Foundation, University of Maryland ASPIRE Program, NIH R01HL165193, R01HL140239-01, and R01AG057552.
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Affiliation(s)
- Callie M Weber
- Department of Bioengineering, University of Maryland; College Park, MD, 20742, United States
| | - Bilal Moiz
- Department of Bioengineering, University of Maryland; College Park, MD, 20742, United States
| | - Gabriel S Pena
- Department of Kinesiology, University of Maryland, College Park, MD, 20742, United States
| | - Marzyeh Kheradmand
- Department of Bioengineering, University of Maryland; College Park, MD, 20742, United States
| | - Brooke Wunderler
- Department of Bioengineering, University of Maryland; College Park, MD, 20742, United States
| | - Claire Kettula
- Department of Bioengineering, University of Maryland; College Park, MD, 20742, United States
| | - Gurneet S Sangha
- Department of Bioengineering, University of Maryland; College Park, MD, 20742, United States
| | - J Carson Smith
- Department of Kinesiology, University of Maryland, College Park, MD, 20742, United States
| | - Alisa Morss Clyne
- Department of Bioengineering, University of Maryland; College Park, MD, 20742, United States.
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Chang YC, Chan MH, Yang YF, Li CH, Hsiao M. Glucose transporter 4: Insulin response mastermind, glycolysis catalyst and treatment direction for cancer progression. Cancer Lett 2023; 563:216179. [PMID: 37061122 DOI: 10.1016/j.canlet.2023.216179] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/27/2023] [Accepted: 04/07/2023] [Indexed: 04/17/2023]
Abstract
The glucose transporter family (GLUT) consists of fourteen members. It is responsible for glucose homeostasis and glucose transport from the extracellular space to the cell cytoplasm to further cascade catalysis. GLUT proteins are encoded by the solute carrier family 2 (SLC2) genes and are members of the major facilitator superfamily of membrane transporters. Moreover, different GLUTs also have their transporter kinetics and distribution, so each GLUT member has its uniqueness and importance to play essential roles in human physiology. Evidence from many studies in the field of diabetes showed that GLUT4 travels between the plasma membrane and intracellular vesicles (GLUT4-storage vesicles, GSVs) and that the PI3K/Akt pathway regulates this activity in an insulin-dependent manner or by the AMPK pathway in response to muscle contraction. Moreover, some published results also pointed out that GLUT4 mediates insulin-dependent glucose uptake. Thus, dysfunction of GLUT4 can induce insulin resistance, metabolic reprogramming in diverse chronic diseases, inflammation, and cancer. In addition to the relationship between GLUT4 and insulin response, recent studies also referred to the potential upstream transcription factors that can bind to the promoter region of GLUT4 to regulating downstream signals. Combined all of the evidence, we conclude that GLUT4 has shown valuable unknown functions and is of clinical significance in cancers, which deserves our in-depth discussion and design compounds by structure basis to achieve therapeutic effects. Thus, we intend to write up a most updated review manuscript to include the most recent and critical research findings elucidating how and why GLUT4 plays an essential role in carcinogenesis, which may have broad interests and impacts on this field.
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Affiliation(s)
- Yu-Chan Chang
- Department of Biomedical Imaging and Radiological Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ming-Hsien Chan
- Department of Biomedical Imaging and Radiological Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-Fang Yang
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Chien-Hsiu Li
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Michael Hsiao
- Genomics Research Center, Academia Sinica, Taipei, Taiwan; Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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5
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Loss of brain energy metabolism control as a driver for memory impairment upon insulin resistance. Biochem Soc Trans 2023; 51:287-301. [PMID: 36606696 DOI: 10.1042/bst20220789] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/10/2022] [Accepted: 12/12/2022] [Indexed: 01/07/2023]
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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Pervaiz I, Zahra FT, Mikelis C, Al-Ahmad AJ. An in vitro model of glucose transporter 1 deficiency syndrome at the blood-brain barrier using induced pluripotent stem cells. J Neurochem 2022; 162:483-500. [PMID: 35943296 DOI: 10.1111/jnc.15684] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 07/08/2022] [Accepted: 08/03/2022] [Indexed: 11/28/2022]
Abstract
Glucose is an important source of energy for the central nervous system. Its uptake at the blood-brain barrier (BBB) is mostly mediated via glucose transporter 1 (GLUT1), a facilitated transporter encoded by the SLC2A1 gene. GLUT1 Deficiency Syndrome (GLUT1DS) is a haploinsufficiency characterized by mutations in the SLC2A1 gene, resulting in impaired glucose uptake at the BBB and clinically characterized by epileptic seizures and movement disorder. A major limitation is an absence of in vitro models of the BBB reproducing the disease. This study aimed to characterize an in vitro model of GLUT1DS using human pluripotent stem cells (iPSCs). Two GLUT1DS clones were generated (GLUT1-iPSC) from their original parental clone iPS(IMR90)-c4 by CRISPR/Cas9 and differentiated into brain microvascular endothelial cells (iBMECs). Cells were characterized in terms of SLC2A1 expression, changes in the barrier function, glucose uptake and metabolism, and angiogenesis. GLUT1DS iPSCs and iBMECs showed comparable phenotype to their parental control, with exception of reduced GLUT1 expression at the protein level. Although no major disruption in the barrier function was reported in the two clones, a significant reduction in glucose uptake accompanied by an increase in glycolysis and mitochondrial respiration was reported in both GLUT1DS-iBMECs. Finally, impaired angiogenic features were reported in such clones compared to the parental clone. Our study provides the first documented characterization of GLUT1DS-iBMECs generated by CRISPR-Cas9, suggesting that GLUT1 truncation appears detrimental to brain angiogenesis and brain endothelial bioenergetics, but maybe not be detrimental to iBMECs differentiation and barriergenesis. Our future direction is to further characterize the functional outcome of such truncated product, as well as its impact on other cells of the neurovascular unit.
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Affiliation(s)
- Iqra Pervaiz
- Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy, Department of Pharmaceutical Sciences, Amarillo, Texas, United States of America
| | - Fatema Tuz Zahra
- Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy, Department of Pharmaceutical Sciences, Amarillo, Texas, United States of America
| | - Constantinos Mikelis
- Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy, Department of Pharmaceutical Sciences, Amarillo, Texas, United States of America
| | - Abraham Jacob Al-Ahmad
- Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy, Department of Pharmaceutical Sciences, Amarillo, Texas, United States of America
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González A, Calfío C, Churruca M, Maccioni RB. Glucose metabolism and AD: evidence for a potential diabetes type 3. Alzheimers Res Ther 2022; 14:56. [PMID: 35443732 PMCID: PMC9022265 DOI: 10.1186/s13195-022-00996-8] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/27/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Alzheimer's disease is the most prevalent cause of dementia in the elderly. Neuronal death and synaptic dysfunctions are considered the main hallmarks of this disease. The latter could be directly associated to an impaired metabolism. In particular, glucose metabolism impairment has demonstrated to be a key regulatory element in the onset and progression of AD, which is why nowadays AD is considered the type 3 diabetes. METHODS We provide a thread regarding the influence of glucose metabolism in AD from three different perspectives: (i) as a regulator of the energy source, (ii) through several metabolic alterations, such as insulin resistance, that modify peripheral signaling pathways that influence activation of the immune system (e.g., insulin resistance, diabetes, etc.), and (iii) as modulators of various key post-translational modifications for protein aggregation, for example, influence on tau hyperphosphorylation and other important modifications, which determine its self-aggregating behavior and hence Alzheimer's pathogenesis. CONCLUSIONS In this revision, we observed a 3 edge-action in which glucose metabolism impairment is acting in the progression of AD: as blockade of energy source (e.g., mitochondrial dysfunction), through metabolic dysregulation and post-translational modifications in key proteins, such as tau. Therefore, the latter would sustain the current hypothesis that AD is, in fact, the novel diabetes type 3.
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Affiliation(s)
- Andrea González
- Laboratory of Neurosciences and Functional Medicine, International Center for Biomedicine (ICC), Avda. Vitacura 3568, D 511-512, Vitacura, Santiago, Chile
- Faculty of Sciences, University of Chile, Las Encinas 3370, Ñuñoa, Santiago, Chile
| | - Camila Calfío
- Laboratory of Neurosciences and Functional Medicine, International Center for Biomedicine (ICC), Avda. Vitacura 3568, D 511-512, Vitacura, Santiago, Chile
- Faculty of Sciences, University of Chile, Las Encinas 3370, Ñuñoa, Santiago, Chile
| | - Macarena Churruca
- Laboratory of Neurosciences and Functional Medicine, International Center for Biomedicine (ICC), Avda. Vitacura 3568, D 511-512, Vitacura, Santiago, Chile
| | - Ricardo B Maccioni
- Laboratory of Neurosciences and Functional Medicine, International Center for Biomedicine (ICC), Avda. Vitacura 3568, D 511-512, Vitacura, Santiago, Chile.
- Faculty of Sciences, University of Chile, Las Encinas 3370, Ñuñoa, Santiago, Chile.
- Department of Neurology, Faculty of Medicine East Campus Hospital Salvador, University of Chile, Salvador 486, Providencia, Santiago, Chile.
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8
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Leung SWS, Shi Y. The glycolytic process in endothelial cells and its implications. Acta Pharmacol Sin 2022; 43:251-259. [PMID: 33850277 PMCID: PMC8791959 DOI: 10.1038/s41401-021-00647-y] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 02/22/2021] [Indexed: 02/06/2023]
Abstract
Endothelial cells play an obligatory role in regulating local vascular tone and maintaining homeostasis in vascular biology. Cell metabolism, converting food to energy in organisms, is the primary self-sustaining mechanism for cell proliferation and reproduction, structure maintenance, and fight-or-flight responses to stimuli. Four major metabolic processes take place in the energy-producing process, including glycolysis, oxidative phosphorylation, glutamine metabolism, and fatty acid oxidation. Among them, glycolysis is the primary energy-producing mechanism in endothelial cells. The present review focused on glycolysis in endothelial cells under both physiological and pathological conditions. Since the switches among metabolic processes precede the functional changes and disease developments, some prophylactic and/or therapeutic strategies concerning the role of glycolysis in cardiovascular disease are discussed.
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Affiliation(s)
- Susan, Wai Sum Leung
- grid.194645.b0000000121742757Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Yi Shi
- grid.8547.e0000 0001 0125 2443Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200032 China ,grid.8547.e0000 0001 0125 2443Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
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Li Y, Faiz A, Moshage H, Schubert R, Schilling L, Kamps JA. Comparative transcriptome analysis of inner blood-retinal barrier and blood-brain barrier in rats. Sci Rep 2021; 11:12151. [PMID: 34108511 PMCID: PMC8190099 DOI: 10.1038/s41598-021-91584-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 05/13/2021] [Indexed: 11/15/2022] Open
Abstract
Although retinal microvessels (RMVs) and brain microvessels (BMVs) are closely related in their developmental and share similar blood-neural barriers, studies have reported markedly different responses to stressors such as diabetes. Therefore, we hypothesized that RMVs and BMVs will display substantial differences in gene expression levels even though they are of the same embryological origin. In this study, both RMVs and BMVs were mechanically isolated from rats. Full retinal and brain tissue samples (RT, BT) were collected for comparisons. Total RNA extracted from these four groups were processed on Affymetrix rat 2.0 microarray Chips. The transcriptional profiles of these tissues were then analyzed. In the present paper we looked at differentially expressed genes (DEGs) in RMVs (against RT) and BMVs (against BT) using a rather conservative threshold value of ≥ ± twofold change and a false discovery rate corrected for multiple comparisons (p < 0.05). In RMVs a total of 1559 DEGs were found, of which 1004 genes were higher expressed in RMVs than in RT. Moreover, 4244 DEGs between BMVs and BT were identified, of which 1956 genes were ≥ twofold enriched in BMVs. Using these DEGs, we comprehensively analyzed the actual expression levels and highlighted their involvement in critical functional structures in RMVs and BMVs, such as junctional complex, transporters and signaling pathways. Our work provides for the first time the transcriptional profiles of rat RMVs and BMVs. These results may help to understand why retina and brain microvasculature show different susceptibilities to stressors, and they might even provide new insight for pharmacological interventions.
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Affiliation(s)
- Y Li
- Division of Neurosurgical Research, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Department of Pathology and Medical Biology, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - A Faiz
- Department of Pathology and Medical Biology, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - H Moshage
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - R Schubert
- European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Physiology, Institute of Theoretical Medicine, Medical Faculty, Augsburg University, Augsburg, Germany
| | - L Schilling
- Division of Neurosurgical Research, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. .,European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
| | - J A Kamps
- Department of Pathology and Medical Biology, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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Shen W, Lee SR, Mathai AE, Zhang R, Du J, Yam MX, Pye V, Barnett NL, Rayner CL, Zhu L, Hurley JB, Seth P, Hirabayashi Y, Furuya S, Gillies MC. Effect of selectively knocking down key metabolic genes in Müller glia on photoreceptor health. Glia 2021; 69:1966-1986. [PMID: 33835598 DOI: 10.1002/glia.24005] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 03/24/2021] [Accepted: 03/25/2021] [Indexed: 01/05/2023]
Abstract
The importance of Müller glia for retinal homeostasis suggests that they may have vulnerabilities that lead to retinal disease. Here, we studied the effect of selectively knocking down key metabolic genes in Müller glia on photoreceptor health. Immunostaining indicated that murine Müller glia expressed insulin receptor (IR), hexokinase 2 (HK2) and phosphoglycerate dehydrogenase (PHGDH) but very little pyruvate dehydrogenase E1 alpha 1 (PDH-E1α) and lactate dehydrogenase A (LDH-A). We crossed Müller glial cell-CreER (MC-CreER) mice with transgenic mice carrying a floxed IR, HK2, PDH-E1α, LDH-A, or PHGDH gene to study the effect of selectively knocking down key metabolic genes in Müller glia cells on retinal health. Selectively knocking down IR, HK2, or PHGDH led to photoreceptor degeneration and reduced electroretinographic responses. Supplementing exogenous l-serine prevented photoreceptor degeneration and improved retinal function in MC-PHGDH knockdown mice. We unexpectedly found that the levels of retinal serine and glycine were not reduced but, on the contrary, highly increased in MC-PHGDH knockdown mice. Moreover, dietary serine supplementation, while rescuing the retinal phenotypes caused by genetic deletion of PHGDH in Müller glial cells, restored retinal serine and glycine homeostasis probably through regulation of serine transport. No retinal abnormalities were observed in MC-CreER mice crossed with PDH-E1α- or LDH-A-floxed mice despite Cre expression. Our findings suggest that Müller glia do not complete glycolysis but use glucose to produce serine to support photoreceptors. Supplementation with exogenous serine is effective in preventing photoreceptor degeneration caused by PHGDH deficiency in Müller glia.
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Affiliation(s)
- Weiyong Shen
- Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, Save Sight Institute, Sydney, New South Wales, Australia
| | - So-Ra Lee
- Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, Save Sight Institute, Sydney, New South Wales, Australia
| | - Ashish Easow Mathai
- Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, Save Sight Institute, Sydney, New South Wales, Australia
| | - Rui Zhang
- Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, Save Sight Institute, Sydney, New South Wales, Australia
| | - Jianhai Du
- Department of Ophthalmology and Biochemistry, West Virginia University, Morgantown, West Virginia, USA
| | - Michelle X Yam
- Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, Save Sight Institute, Sydney, New South Wales, Australia
| | - Victoria Pye
- Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, Save Sight Institute, Sydney, New South Wales, Australia
| | - Nigel L Barnett
- Clem Jones Centre for Regenerative Medicine, Faculty of Health Science & Medicine, Bond University, Gold Coast, Queensland, Australia
| | - Cassie L Rayner
- Clem Jones Centre for Regenerative Medicine, Faculty of Health Science & Medicine, Bond University, Gold Coast, Queensland, Australia
| | - Ling Zhu
- Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, Save Sight Institute, Sydney, New South Wales, Australia
| | - James B Hurley
- Department of Biochemistry, University of Washington, Seattle, Washington, USA
| | - Pankaj Seth
- Division of Interdisciplinary Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Yoshio Hirabayashi
- Sako Cellular Informatics Laboratory, RIKEN Cluster for Pioneering Research, Wako, Japan
| | - Shigeki Furuya
- Department of Bioscience and Biotechnology, Kyushu University, Fukuoka, Japan
| | - Mark C Gillies
- Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, Save Sight Institute, Sydney, New South Wales, Australia
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11
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Zhao ZH, Du KJ, Wang T, Wang JY, Cao ZP, Chen XM, Song H, Zheng G, Shen XF. Maternal Lead Exposure Impairs Offspring Learning and Memory via Decreased GLUT4 Membrane Translocation. Front Cell Dev Biol 2021; 9:648261. [PMID: 33718391 PMCID: PMC7947239 DOI: 10.3389/fcell.2021.648261] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 02/08/2021] [Indexed: 11/13/2022] Open
Abstract
Lead (Pb) can cause a significant neurotoxicity in both adults and children, leading to the impairment to brain function. Pb exposure plays a key role in the impairment of learning and memory through synaptic neurotoxicity, resulting in the cognitive function. Researches have demonstrated that Pb exposure plays an important role in the etiology and pathogenesis of neurodegenerative diseases, such as Alzheimer's disease. However, the underlying mechanisms remain unclear. In the current study, a gestational Pb exposure (GLE) rat model was established to investigate the underlying mechanisms of Pb-induced cognitive impairment. We demonstrated that low-level gestational Pb exposure impaired spatial learning and memory as well as hippocampal synaptic plasticity at postnatal day 30 (PND 30) when the blood concentration of Pb had already recovered to normal levels. Pb exposure induced a decrease in hippocampal glucose metabolism by reducing glucose transporter 4 (GLUT4) levels in the cell membrane through the phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt) pathway. In vivo and in vitro GLUT4 over-expression increased the membrane translocation of GLUT4 and glucose uptake, and reversed the Pb-induced impairment to synaptic plasticity and cognition. These findings indicate that Pb exposure impairs synaptic plasticity by reducing the level of GLUT4 in the cell membrane as well as glucose uptake via the PI3K-Akt signaling pathway, demonstrating a novel mechanism for Pb exposure-induced neurotoxicity.
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Affiliation(s)
- Zai-Hua Zhao
- Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, China
| | - Ke-Jun Du
- Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, China
| | - Tao Wang
- Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, China
| | - Ji-Ye Wang
- Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, China
| | - Zi-Peng Cao
- Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, China
| | - Xiao-Ming Chen
- Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, China
| | - Han Song
- Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, China.,Department of Health Service, Chinese PLA General Hospital, Beijing, China
| | - Gang Zheng
- Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, China
| | - Xue-Feng Shen
- Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, China
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12
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Wang T, Wang J, Hu X, Huang XJ, Chen GX. Current understanding of glucose transporter 4 expression and functional mechanisms. World J Biol Chem 2020; 11:76-98. [PMID: 33274014 PMCID: PMC7672939 DOI: 10.4331/wjbc.v11.i3.76] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/22/2020] [Accepted: 09/22/2020] [Indexed: 02/05/2023] Open
Abstract
Glucose is used aerobically and anaerobically to generate energy for cells. Glucose transporters (GLUTs) are transmembrane proteins that transport glucose across the cell membrane. Insulin promotes glucose utilization in part through promoting glucose entry into the skeletal and adipose tissues. This has been thought to be achieved through insulin-induced GLUT4 translocation from intracellular compartments to the cell membrane, which increases the overall rate of glucose flux into a cell. The insulin-induced GLUT4 translocation has been investigated extensively. Recently, significant progress has been made in our understanding of GLUT4 expression and translocation. Here, we summarized the methods and reagents used to determine the expression levels of Slc2a4 mRNA and GLUT4 protein, and GLUT4 translocation in the skeletal muscle, adipose tissues, heart and brain. Overall, a variety of methods such real-time polymerase chain reaction, immunohistochemistry, fluorescence microscopy, fusion proteins, stable cell line and transgenic animals have been used to answer particular questions related to GLUT4 system and insulin action. It seems that insulin-induced GLUT4 translocation can be observed in the heart and brain in addition to the skeletal muscle and adipocytes. Hormones other than insulin can induce GLUT4 translocation. Clearly, more studies of GLUT4 are warranted in the future to advance of our understanding of glucose homeostasis.
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Affiliation(s)
- Tiannan Wang
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, United States
| | - Jing Wang
- College of Pharmacy, South-Central University for Nationalities, Wuhan 430074, Hubei Province, China
| | - Xinge Hu
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, United States
| | - Xian-Ju Huang
- College of Pharmacy, South-Central University for Nationalities, Wuhan 430074, Hubei Province, China
| | - Guo-Xun Chen
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, United States
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13
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Abstract
The glucose transporter GLUT4 is critical for skeletal muscle glucose uptake in response to insulin and muscle contraction/exercise. Exercise increases GLUT4 translocation to the sarcolemma and t-tubule and, over the longer term, total GLUT4 protein content. Here, we review key aspects of GLUT4 biology in relation to exercise, with a focus on exercise-induced GLUT4 translocation, postexercise metabolism and muscle insulin sensitivity, and exercise effects on GLUT4 expression.
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Affiliation(s)
- Marcelo Flores-Opazo
- Laboratory of Exercise and Physical Activity Sciences, Department of Physiotherapy, University Finis Terrae, Santiago, Chile
| | - Sean L McGee
- Metabolic Research Unit, School of Medicine and Institute for Mental and Physical Health and Clinical Translation (IMPACT), Deakin University, Waurn Ponds
| | - Mark Hargreaves
- Department of Physiology, The University of Melbourne, Melbourne, Australia
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14
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Sohn JW, Ho WK. Cellular and systemic mechanisms for glucose sensing and homeostasis. Pflugers Arch 2020; 472:1547-1561. [PMID: 32960363 DOI: 10.1007/s00424-020-02466-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 08/14/2020] [Accepted: 09/14/2020] [Indexed: 12/25/2022]
Abstract
Glucose is a major source of energy in animals. Maintaining blood glucose levels within a physiological range is important for facilitating glucose uptake by cells, as required for optimal functioning. Glucose homeostasis relies on multiple glucose-sensing cells in the body that constantly monitor blood glucose levels and respond accordingly to adjust its glycemia. These include not only pancreatic β-cells and α-cells that secrete insulin and glucagon, but also central and peripheral neurons regulating pancreatic endocrine function. Different types of cells respond distinctively to changes in blood glucose levels, and the mechanisms involved in glucose sensing are diverse. Notably, recent studies have challenged the currently held views regarding glucose-sensing mechanisms. Furthermore, peripheral and central glucose-sensing cells appear to work in concert to control blood glucose level and maintain glucose and energy homeostasis in organisms. In this review, we summarize the established concepts and recent advances in the understanding of cellular and systemic mechanisms that regulate glucose sensing and its homeostasis.
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Affiliation(s)
- Jong-Woo Sohn
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, South Korea.
| | - Won-Kyung Ho
- Department of Physiology, Seoul National University College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul, 03080, South Korea.
- Department of Brain and Cognitive Sciences, Seoul National University College of Natural Sciences, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, South Korea.
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15
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Glucose transporters in brain in health and disease. Pflugers Arch 2020; 472:1299-1343. [PMID: 32789766 PMCID: PMC7462931 DOI: 10.1007/s00424-020-02441-x] [Citation(s) in RCA: 306] [Impact Index Per Article: 61.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/20/2020] [Accepted: 07/24/2020] [Indexed: 12/15/2022]
Abstract
Energy demand of neurons in brain that is covered by glucose supply from the blood is ensured by glucose transporters in capillaries and brain cells. In brain, the facilitative diffusion glucose transporters GLUT1-6 and GLUT8, and the Na+-d-glucose cotransporters SGLT1 are expressed. The glucose transporters mediate uptake of d-glucose across the blood-brain barrier and delivery of d-glucose to astrocytes and neurons. They are critically involved in regulatory adaptations to varying energy demands in response to differing neuronal activities and glucose supply. In this review, a comprehensive overview about verified and proposed roles of cerebral glucose transporters during health and diseases is presented. Our current knowledge is mainly based on experiments performed in rodents. First, the functional properties of human glucose transporters expressed in brain and their cerebral locations are described. Thereafter, proposed physiological functions of GLUT1, GLUT2, GLUT3, GLUT4, and SGLT1 for energy supply to neurons, glucose sensing, central regulation of glucohomeostasis, and feeding behavior are compiled, and their roles in learning and memory formation are discussed. In addition, diseases are described in which functional changes of cerebral glucose transporters are relevant. These are GLUT1 deficiency syndrome (GLUT1-SD), diabetes mellitus, Alzheimer’s disease (AD), stroke, and traumatic brain injury (TBI). GLUT1-SD is caused by defect mutations in GLUT1. Diabetes and AD are associated with changed expression of glucose transporters in brain, and transporter-related energy deficiency of neurons may contribute to pathogenesis of AD. Stroke and TBI are associated with changes of glucose transporter expression that influence clinical outcome.
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16
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Obafemi TO, Olasehinde OR, Olaoye OA, Jaiyesimi KF, Adewumi FD, Adewale OB, Afolabi BA. Metformin/Donepezil combination modulates brain antioxidant status and hippocampal endoplasmic reticulum stress in type 2 diabetic rats. J Diabetes Metab Disord 2020; 19:499-510. [PMID: 32550202 DOI: 10.1007/s40200-020-00541-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 04/26/2020] [Accepted: 05/06/2020] [Indexed: 02/07/2023]
Abstract
Purpose Diabetes mellitus is associated with perturbations in brain biochemical parameters associated with dementia. This study aimed at comparing the effect of metformin and metformin/donepezil combination on oxidative stress, endoplasmic reticulum stress and inflammation in the brain of diabetic Wistar rats. Methods Diabetes was induced by single intraperitoneal injection of 40 mg/kg streptozotocin after administration of 10% fructose for 14 days. Animals were randomly assigned to four groups of five animals each. Group 1 was the normal control and received only distilled water. Groups 2 and 3 were diabetic rats treated with metformin/donepezil combination and metformin only respectively, while group 4 was diabetic control. Treatment lasted for 21 days after confirmation of diabetes. Activities of acetylcholinesterase (AchE), butyrylcholinesterase (BchE), superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase were evaluated in the brain of diabetic rats. Enzyme-linked immunosorbent assay was used to estimate brain levels of tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) malondialdehyde and glucose transporter-4 (GLUT4), while expression of endoplasmic reticulum stress markers - glucose regulated protein-78 (GRP78), activating transcription factor-4 (ATF4) and C/EBP homologous protein (CHOP) was determined using real-time PCR in the hippocampus of diabetic rats. Results Treatment with metformin/donepezil combination significantly reduced the activities of AchE, BchE as well as levels of malondialdehyde, TNF-α and IL-6, while the activities of SOD, GPx and catalase were significantly increased in the brain. Moreover, expression of ER stress markers was attenuated in the hippocampus. Conclusion Metformin/donepezil combination appeared more efficacious than metformin only and could be considered for managing diabetes-associated dementia.
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Affiliation(s)
- Tajudeen Olabisi Obafemi
- Biochemistry Programme, Department of Chemical Sciences, Afe Babalola University, Ado-Ekiti, PMB 5454 Nigeria
| | - Oluwaseun R Olasehinde
- Medical Biochemistry Unit, College of Health Sciences, Afe Babalola University, PMB 5454, Ado-Ekiti, Nigeria
| | - Oyindamola A Olaoye
- Biochemistry Programme, Department of Chemical Sciences, Afe Babalola University, Ado-Ekiti, PMB 5454 Nigeria
| | - Kikelomo F Jaiyesimi
- Biochemistry Programme, Department of Chemical Sciences, Afe Babalola University, Ado-Ekiti, PMB 5454 Nigeria
| | - Funmilayo D Adewumi
- Industrial Chemistry Programme, Department of Chemical Sciences, Afe Babalola University, Ado-Ekiti, PMB 5454 Nigeria
| | - Olusola B Adewale
- Biochemistry Programme, Department of Chemical Sciences, Afe Babalola University, Ado-Ekiti, PMB 5454 Nigeria
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17
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Zhang C, Chen Z, Li W, Liu X, Tang S, Jiang L, Li M, Peng H, Lian M. Influences of different sugar ligands on targeted delivery of liposomes. J Drug Target 2020; 28:789-801. [PMID: 32242754 DOI: 10.1080/1061186x.2020.1744156] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Ligands are an important part of targeted drug delivery systems. Optimised lignads not only improve the target efficiency, but also enhance therapeutical effect of drugs. In our research, five sugar molecules (Mannose, Galactose, Glucose, Malt disaccharide, and Maltotriose) conjugated PEG600-DSPE were synthesised, of which polysaccharides were first discovered by us as sugar ligands to modify liposomes, which interacts with over expressive GLUT on cancer cells. DiO was encapsulated as fluorescent probe to evaluate their cellular uptake abilities of targeting C6 glioma cells, and the distribution in different visceral organs of rats. The results demonstrated that Malt disaccharide and Glucose-PEG600-DSPE had the strong efficiency of cellular uptake by C6 glioma cells. The distribution and accumulation of liposomes showed that different sugars modified liposomes could target different visceral organs in rats. It has provided a novel idea for ligand selectivity and optimisation of nanocarriers for tumour targeted therapy.
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Affiliation(s)
- Changmei Zhang
- Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Harbin, China
| | - Zhong Chen
- Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Harbin, China
| | - Wenhua Li
- Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Harbin, China
| | - Xiaoying Liu
- Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Harbin, China
| | - Shukun Tang
- Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Harbin, China
| | - Lei Jiang
- Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Harbin, China
| | - Minghui Li
- Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Harbin, China
| | - Haisheng Peng
- Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Harbin, China
| | - Mingming Lian
- Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Harbin, China
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18
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Leão LL, Tangen G, Barca ML, Engedal K, Santos SHS, Machado FSM, de Paula AMB, Monteiro-Junior RS. Does hyperglycemia downregulate glucose transporters in the brain? Med Hypotheses 2020; 139:109614. [PMID: 32087490 DOI: 10.1016/j.mehy.2020.109614] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 01/30/2020] [Accepted: 02/05/2020] [Indexed: 12/11/2022]
Abstract
Diabetes is a metabolic condition associated with hyperglycemia manifested by the elevation of blood glucose levels occurring when the pancreas decreases or stops the production of insulin, in case of insulin resistance or both. The current literature supports that insulin resistance may be responsible for the memory decline associated with diabetes. Glucose transporters (GLUTs) are a family of proteins involved in glucose transport across biological membranes. GLUT-1 and GLUT-3 are involved in glucose delivery to the brain. Evidence suggests that both transporters are downregulated in chronic peripheral hyperglycemia. Here we show the mechanisms of glucose transport and its influence on cognitive function, including a hypothesis of how peripheral hyperglycemia related genes network interactions may lead to glucose transporters downregulation and its possible consequences.
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Affiliation(s)
- Luana Lemos Leão
- Post-graduate Program of Health Sciences, State University of Montes Claros, Montes Claros, Minas Gerais, Brazil
| | - Gro Tangen
- Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway
| | - Maria Lage Barca
- Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway
| | - Knut Engedal
- Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway
| | - Sérgio Henrique S Santos
- Post-graduate Program of Health Sciences, State University of Montes Claros, Montes Claros, Minas Gerais, Brazil; Institute of Agricultural Sciences, Universidade Federal de Minas Gerais, Brazil
| | - Frederico Sander M Machado
- Post-graduate Program of Health Sciences, State University of Montes Claros, Montes Claros, Minas Gerais, Brazil
| | - Alfredo Maurício B de Paula
- Post-graduate Program of Health Sciences, State University of Montes Claros, Montes Claros, Minas Gerais, Brazil
| | - Renato Sobral Monteiro-Junior
- Post-graduate Program of Health Sciences, State University of Montes Claros, Montes Claros, Minas Gerais, Brazil; Post-Graduate Program of Medicine (Neurology/Neuroscience), Federal Fluminense University, Niterói, Rio de Janeiro, Brazil; Neuroscience of Exercise Institute, Aroldo Tourinho Hospital, Montes Claros, MG, Brazil.
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19
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The median eminence as the hypothalamic area involved in rapid transfer of glucose to the brain: functional and cellular mechanisms. J Mol Med (Berl) 2019; 97:1085-1097. [PMID: 31129757 DOI: 10.1007/s00109-019-01799-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 05/03/2019] [Accepted: 05/13/2019] [Indexed: 12/15/2022]
Abstract
Our data proposes that glucose is transferred directly to the cerebrospinal fluid (CSF) of the hypothalamic ventricular cavity through a rapid "fast-track-type mechanism" that would efficiently stimulate the glucosensing areas. This mechanism would occur at the level of the median eminence (ME), a periventricular hypothalamic zone with no blood-brain barrier. This "fast-track" mechanism would involve specific glial cells of the ME known as β2 tanycytes that could function as "inverted enterocytes," expressing low-affinity glucose transporters GLUT2 and GLUT6 in order to rapidly transfer glucose to the CSF. Due to the large size of tanycytes, the presence of a high concentration of mitochondria and the expression of low-affinity glucose transporters, it would be expected that these cells accumulate glucose in the endoplasmic reticulum (ER) by sequestering glucose-6-phosphate (G-6-P), in a similar way to that recently demonstrated in astrocytes. Glucose could diffuse through the cells by micrometric distances to be released in the apical region of β2 tanycytes, towards the CSF. Through this mechanism, levels of glucose would increase inside the hypothalamus, stimulating glucosensing mechanisms quickly and efficiently. KEY MESSAGES: • Glucose diffuses through the median eminence cells (β2 tanycytes), towards the hypothalamic CSF. • Glucose is transferred through a rapid "fast-track-type mechanism" via GLUT2 and GLUT6. • Through this mechanism, hypothalamic glucose levels increase, stimulating glucosensing.
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20
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Dakic T, Jevdjovic T, Lakic I, Djurasevic SF, Djordjevic J, Vujovic P. Food For Thought: Short-Term Fasting Upregulates Glucose Transporters in Neurons and Endothelial Cells, But Not in Astrocytes. Neurochem Res 2018; 44:388-399. [PMID: 30460639 DOI: 10.1007/s11064-018-2685-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 10/30/2018] [Accepted: 11/15/2018] [Indexed: 12/22/2022]
Abstract
Our group previously reported that 6-h fasting increased both insulin II mRNA expression and insulin level in rat hypothalamus. Given that insulin effects on central glucose metabolism are insufficiently understood, we wanted to examine if the centrally produced insulin affects expression and/or regional distribution of glucose transporters, and glycogen stores in the hypothalamus during short-term fasting. In addition to determining the amount of total and activated insulin receptor, glucose transporters, and glycogen, we also studied distribution of insulin receptors and glucose transporters within the hypothalamus. We found that short-term fasting did not affect the astrocytic 45 kDa GLUT1 isoform, but it significantly increased the amount of endothelial 55 kDa GLUT1, and neuronal GLUT3 in the membrane fractions of hypothalamic proteins. The level of GLUT2 whose presence was detected in neurons, ependymocytes and tanycytes was also elevated. Unlike hepatic glycogen which was decreased, hypothalamic glycogen content was not changed after 6-h fasting. Our findings suggest that neurons may be given a priority over astrocytes in terms of glucose supply even during the initial phase of metabolic response to fasting. Namely, increase in glucose influx into the brain extracellular fluid and neurons by increasing the translocation of GLUT1, and GLUT3 in the cell membrane may represent the first line of defense in times of scarcity. The absence of co-localization of these membrane transporters with the activated insulin receptor suggests this process takes place in an insulin-independent manner.
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Affiliation(s)
- Tamara Dakic
- Department for Comparative Physiology and Ecophysiology, Institute for Physiology and Biochemistry, Faculty of Biology, University of Belgrade, Belgrade, Serbia.
| | - Tanja Jevdjovic
- Department for Comparative Physiology and Ecophysiology, Institute for Physiology and Biochemistry, Faculty of Biology, University of Belgrade, Belgrade, Serbia
| | - Iva Lakic
- Department for Comparative Physiology and Ecophysiology, Institute for Physiology and Biochemistry, Faculty of Biology, University of Belgrade, Belgrade, Serbia
| | - Sinisa F Djurasevic
- Department for Comparative Physiology and Ecophysiology, Institute for Physiology and Biochemistry, Faculty of Biology, University of Belgrade, Belgrade, Serbia
| | - Jelena Djordjevic
- Department for Comparative Physiology and Ecophysiology, Institute for Physiology and Biochemistry, Faculty of Biology, University of Belgrade, Belgrade, Serbia
| | - Predrag Vujovic
- Department for Comparative Physiology and Ecophysiology, Institute for Physiology and Biochemistry, Faculty of Biology, University of Belgrade, Belgrade, Serbia
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21
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Castro V, Skowronska M, Lombardi J, He J, Seth N, Velichkovska M, Toborek M. Occludin regulates glucose uptake and ATP production in pericytes by influencing AMP-activated protein kinase activity. J Cereb Blood Flow Metab 2018; 38:317-332. [PMID: 28718701 PMCID: PMC5951017 DOI: 10.1177/0271678x17720816] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Energetic regulation at the blood-brain barrier is critical for maintaining its integrity, transport capabilities, and brain demands for glucose. However, the underlying mechanisms that regulate these processes are still poorly explored. We recently characterized the protein occludin as a NADH oxidase and demonstrated its influence on the expression and activation of the histone deacetylase SIRT-1. Because SIRT-1 works in concert with AMP-activated protein kinase (AMPK) (AMPK), we investigated the impact of occludin on this metabolic switch. Here we show that in blood-brain barrier pericytes, occludin promotes AMPK expression and activation, influencing the expression of glucose transporters GLUT-1 and GLUT-4, glucose uptake, and ATP content. Furthermore, occludin expression, AMP-dependent protein kinase activity, and glucose uptake were altered under inflammatory (TNFα) and infectious (HIV) conditions. We also show that pericytes share glucose and mitochondria with astrocytes, and that occludin levels modify the ability of pericytes to share those energetic resources. In addition, we demonstrate that murine mitochondria can be transferred from live brain microvessels to energetically impaired human astrocytes, promoting their survival. Our findings demonstrate that occludin plays an important role in blood-brain barrier pericyte metabolism by influencing AMPK protein kinase activity, glucose uptake, ATP production, and by regulating the ability of pericytes to interact metabolically with astrocytes.
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Affiliation(s)
- Victor Castro
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Marta Skowronska
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Jorge Lombardi
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Jane He
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Neil Seth
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Martina Velichkovska
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Michal Toborek
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA
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22
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Rojas-Gutierrez E, Muñoz-Arenas G, Treviño S, Espinosa B, Chavez R, Rojas K, Flores G, Díaz A, Guevara J. Alzheimer's disease and metabolic syndrome: A link from oxidative stress and inflammation to neurodegeneration. Synapse 2017; 71:e21990. [PMID: 28650104 DOI: 10.1002/syn.21990] [Citation(s) in RCA: 136] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 06/20/2017] [Accepted: 06/21/2017] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is the most common cause of dementia and one of the most important causes of morbidity and mortality among the aging population. AD diagnosis is made post-mortem, and the two pathologic hallmarks, particularly evident in the end stages of the illness, are amyloid plaques and neurofibrillary tangles. Currently, there is no curative treatment for AD. Additionally, there is a strong relation between oxidative stress, metabolic syndrome, and AD. The high levels of circulating lipids and glucose imbalances amplify lipid peroxidation that gradually diminishes the antioxidant systems, causing high levels of oxidative metabolism that affects cell structure, leading to neuronal damage. Accumulating evidence suggests that AD is closely related to a dysfunction of both insulin signaling and glucose metabolism in the brain, leading to an insulin-resistant brain state. Four drugs are currently used for this pathology: Three FDA-approved cholinesterase inhibitors and one NMDA receptor antagonist. However, wide varieties of antioxidants are promissory to delay or prevent the symptoms of AD and may help in treating the disease. Therefore, therapeutic efforts to achieve attenuation of oxidative stress could be beneficial in AD treatment, attenuating Aβ-induced neurotoxicity and improve neurological outcomes in AD. The term inflammaging characterizes a widely accepted paradigm that aging is accompanied by a low-grade chronic up-regulation of certain pro-inflammatory responses in the absence of overt infection, and is a highly significant risk factor for both morbidity and mortality in the elderly.
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Affiliation(s)
- Eduardo Rojas-Gutierrez
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Guadalupe Muñoz-Arenas
- Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Puebla, Pue, Mexico
| | - Samuel Treviño
- Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Puebla, Pue, Mexico
| | - Blanca Espinosa
- Departamento de Bioquímica, Instituto Nacional de Enfermedades Respiratorias-INER, Ciudad de México, Mexico
| | - Raúl Chavez
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Karla Rojas
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Gonzalo Flores
- Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, Puebla, Pue, Mexico
| | - Alfonso Díaz
- Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Puebla, Pue, Mexico
| | - Jorge Guevara
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
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23
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Al-Ahmad AJ. Comparative study of expression and activity of glucose transporters between stem cell-derived brain microvascular endothelial cells and hCMEC/D3 cells. Am J Physiol Cell Physiol 2017; 313:C421-C429. [PMID: 28993322 DOI: 10.1152/ajpcell.00116.2017] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 07/28/2017] [Accepted: 07/28/2017] [Indexed: 12/22/2022]
Abstract
Glucose constitutes a major source of energy of mammalian brains. Glucose uptake at the blood-brain barrier (BBB) occurs through a facilitated glucose transport, through glucose transporter 1 (GLUT1), although other isoforms have been described at the BBB. Mutations in GLUT1 are associated with the GLUT1 deficiency syndrome, yet none of the current in vitro models of the human BBB maybe suited for modeling such a disorder. In this study, we investigated the expression of glucose transporters and glucose diffusion across brain microvascular endothelial cells (BMECs) derived from healthy patient-derived induced pluripotent stem cells (iPSCs). We investigated the expression of different glucose transporters at the BBB using immunocytochemistry and flow cytometry and measured glucose uptake and diffusion across BMEC monolayers obtained from two iPSC lines and from hCMEC/D3 cells. BMEC monolayers showed expression of several glucose transporters, in particular GLUT1, GLUT3, and GLUT4. Diffusion of glucose across the monolayers was mediated via a saturable transcellular mechanism and partially inhibited by pharmacological inhibitors. Taken together, our study suggests the presence of several glucose transporters isoforms at the human BBB and demonstrates the feasibility of modeling glucose across the BBB using patient-derived stem cells.
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Affiliation(s)
- Abraham J Al-Ahmad
- Texas Tech University Health Sciences Center, School of Pharmacy, Department of Pharmaceutical Sciences, Amarillo, Texas
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24
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Kokavec A. Migraine: A disorder of metabolism? Med Hypotheses 2016; 97:117-130. [PMID: 27876120 DOI: 10.1016/j.mehy.2016.10.029] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 10/23/2016] [Accepted: 10/31/2016] [Indexed: 02/08/2023]
Abstract
The treatment and prevention of migraine within the last decade has become largely pharmacological. While there is little doubt that the advent of drugs (e.g. triptans) has helped many migraine sufferers to lead a normal life, there is still little knowledge with respect to the factors responsible for precipitating a migraine attack. Evidence from biochemical and behavioural studies from a number of disciplines is integrated to put forward the proposal that migraine is part of a cascade of events, which together act to protect the organism when confronted by a metabolic challenge.
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Affiliation(s)
- Anna Kokavec
- University of New England, School of Health, Armidale, NSW 2350, United States.
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25
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De Backer I, Hussain SS, Bloom SR, Gardiner JV. Insights into the role of neuronal glucokinase. Am J Physiol Endocrinol Metab 2016; 311:E42-55. [PMID: 27189932 PMCID: PMC4967152 DOI: 10.1152/ajpendo.00034.2016] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 05/13/2016] [Indexed: 12/17/2022]
Abstract
Glucokinase is a key component of the neuronal glucose-sensing mechanism and is expressed in brain regions that control a range of homeostatic processes. In this review, we detail recently identified roles for neuronal glucokinase in glucose homeostasis and counterregulatory responses to hypoglycemia and in regulating appetite. We describe clinical implications from these advances in our knowledge, especially for developing novel treatments for diabetes and obesity. Further research required to extend our knowledge and help our efforts to tackle the diabetes and obesity epidemics is suggested.
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Affiliation(s)
- Ivan De Backer
- Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom
| | - Sufyan S Hussain
- Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom
| | - Stephen R Bloom
- Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom
| | - James V Gardiner
- Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom
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26
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Sanguinetti E, Liistro T, Mainardi M, Pardini S, Salvadori PA, Vannucci A, Burchielli S, Iozzo P. Maternal high-fat feeding leads to alterations of brain glucose metabolism in the offspring: positron emission tomography study in a porcine model. Diabetologia 2016; 59:813-21. [PMID: 26733004 DOI: 10.1007/s00125-015-3848-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 11/10/2015] [Indexed: 11/28/2022]
Abstract
AIMS/HYPOTHESIS Maternal obesity negatively affects fetal development. Abnormalities in brain glucose metabolism are predictive of metabolic-cognitive disorders. METHODS We studied the offspring (aged 0, 1, 6, 12 months) of minipigs fed a normal vs high-fat diet (HFD), by positron emission tomography (PET) to measure brain glucose metabolism, and ex vivo assessments of brain insulin receptors (IRβ) and GLUT4. RESULTS At birth, brain glucose metabolism and IRβ were twice as high in the offspring of HFD-fed than control mothers. During infancy and youth, brain glucose uptake, GLUT4 and IRβ increased in the offspring of control mothers and decreased in those of HFD-fed mothers, leading to a 40-85% difference (p < 0.05), and severe glycogen depletion, lasting until adulthood. CONCLUSIONS/INTERPRETATION Maternal high-fat feeding leads to brain glucose overexposure during fetal development, followed by long-lasting depression in brain glucose metabolism in minipigs. These features may predispose the offspring to develop metabolic-neurodegenerative diseases.
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Affiliation(s)
- Elena Sanguinetti
- Institute of Clinical Physiology, National Research Council (CNR), via Moruzzi 1, Pisa, 56124, Italy
- Scuola Superiore di Studi Universitari Sant'Anna, Pisa, Italy
| | - Tiziana Liistro
- Institute of Clinical Physiology, National Research Council (CNR), via Moruzzi 1, Pisa, 56124, Italy
| | - Marco Mainardi
- Institute of Neuroscience, National Research Council (CNR), Pisa, Italy
- Institute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Silvia Pardini
- Institute of Clinical Physiology, National Research Council (CNR), via Moruzzi 1, Pisa, 56124, Italy
| | - Piero A Salvadori
- Institute of Clinical Physiology, National Research Council (CNR), via Moruzzi 1, Pisa, 56124, Italy
| | | | | | - Patricia Iozzo
- Institute of Clinical Physiology, National Research Council (CNR), via Moruzzi 1, Pisa, 56124, Italy.
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27
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Glucose Transporters at the Blood-Brain Barrier: Function, Regulation and Gateways for Drug Delivery. Mol Neurobiol 2016; 54:1046-1077. [PMID: 26801191 DOI: 10.1007/s12035-015-9672-6] [Citation(s) in RCA: 221] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 12/17/2015] [Indexed: 12/31/2022]
Abstract
Glucose transporters (GLUTs) at the blood-brain barrier maintain the continuous high glucose and energy demands of the brain. They also act as therapeutic targets and provide routes of entry for drug delivery to the brain and central nervous system for treatment of neurological and neurovascular conditions and brain tumours. This article first describes the distribution, function and regulation of glucose transporters at the blood-brain barrier, the major ones being the sodium-independent facilitative transporters GLUT1 and GLUT3. Other GLUTs and sodium-dependent transporters (SGLTs) have also been identified at lower levels and under various physiological conditions. It then considers the effects on glucose transporter expression and distribution of hypoglycemia and hyperglycemia associated with diabetes and oxygen/glucose deprivation associated with cerebral ischemia. A reduction in glucose transporters at the blood-brain barrier that occurs before the onset of the main pathophysiological changes and symptoms of Alzheimer's disease is a potential causative effect in the vascular hypothesis of the disease. Mutations in glucose transporters, notably those identified in GLUT1 deficiency syndrome, and some recreational drug compounds also alter the expression and/or activity of glucose transporters at the blood-brain barrier. Approaches for drug delivery across the blood-brain barrier include the pro-drug strategy whereby drug molecules are conjugated to glucose transporter substrates or encapsulated in nano-enabled delivery systems (e.g. liposomes, micelles, nanoparticles) that are functionalised to target glucose transporters. Finally, the continuous development of blood-brain barrier in vitro models is important for studying glucose transporter function, effects of disease conditions and interactions with drugs and xenobiotics.
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28
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Determination of the Best Concentration of Streptozotocin to Create a Diabetic Brain Using Histological Techniques. J Mol Neurosci 2016; 59:24-35. [DOI: 10.1007/s12031-015-0702-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Accepted: 12/11/2015] [Indexed: 11/25/2022]
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29
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Elizondo-Vega R, Cortes-Campos C, Barahona MJ, Oyarce KA, Carril CA, García-Robles MA. The role of tanycytes in hypothalamic glucosensing. J Cell Mol Med 2015; 19:1471-82. [PMID: 26081217 PMCID: PMC4511346 DOI: 10.1111/jcmm.12590] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Accepted: 03/03/2015] [Indexed: 12/23/2022] Open
Abstract
Tanycytes are elongated hypothalamic glial cells that cover the basal walls of the third ventricle; their apical regions contact the cerebrospinal fluid (CSF), and their processes reach hypothalamic neuronal nuclei that control the energy status of an organism. These nuclei maintain the balance between energy expenditure and intake, integrating several peripheral signals and triggering cellular responses that modify the feeding behaviour and peripheral glucose homeostasis. One of the most important and well-studied signals that control this process is glucose; however, the mechanism by which this molecule is sensed remains unknown. We along with others have proposed that tanycytes play a key role in this process, transducing changes in CSF glucose concentration to the neurons that control energy status. Recent studies have demonstrated the expression and function of monocarboxylate transporters and canonical pancreatic β cell glucose sensing molecules, including glucose transporter 2 and glucokinase, in tanycytes. These and other data, which will be discussed in this review, suggest that hypothalamic glucosensing is mediated through a metabolic interaction between tanycytes and neurons through lactate. This article will summarize the recent evidence that supports the importance of tanycytes in hypothalamic glucosensing, and discuss the possible mechanisms involved in this process. Finally, it is important to highlight that a detailed analysis of this mechanism could represent an opportunity to understand the evolution of associated pathologies, including diabetes and obesity, and identify new candidates for therapeutic intervention.
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Affiliation(s)
- Roberto Elizondo-Vega
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | | | - Maria J Barahona
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Karina A Oyarce
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Claudio A Carril
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Maria A García-Robles
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
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30
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Ebling FJP. Hypothalamic control of seasonal changes in food intake and body weight. Front Neuroendocrinol 2015; 37:97-107. [PMID: 25449796 DOI: 10.1016/j.yfrne.2014.10.003] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 10/15/2014] [Accepted: 10/17/2014] [Indexed: 12/22/2022]
Abstract
Seasonal cycles of fattening and body weight reflecting changes in both food intake and energy expenditure are a core aspect of the biology of mammals that have evolved in temperate and arctic latitudes. Identifying the neuroendocrine mechanisms that underlie these cycles has provided new insights into the hypothalamic control of appetite and fuel oxidation. Surprisingly, seasonal cycles do not result from changes in the leptin-responsive and homeostatic pathways located in the mediobasal and lateral hypothalamus that regulate meal timing and compensatory responses to starvation or caloric restriction. Rather, they result from changes in tanycyte function, which locally regulates transport and metabolism of thyroid hormone and retinoic acid. These signals are crucial for the initial development of the brain, so it is hypothesized that seasonal neuroendocrine cycles reflect developmental mechanisms in the adult hypothalamus, manifest as changes in neurogenesis and plasticity of connections.
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Affiliation(s)
- Francis J P Ebling
- School of Life Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
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31
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Muhič M, Vardjan N, Chowdhury HH, Zorec R, Kreft M. Insulin and Insulin-like Growth Factor 1 (IGF-1) Modulate Cytoplasmic Glucose and Glycogen Levels but Not Glucose Transport across the Membrane in Astrocytes. J Biol Chem 2015; 290:11167-76. [PMID: 25792745 DOI: 10.1074/jbc.m114.629063] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Indexed: 01/21/2023] Open
Abstract
Astrocytes contain glycogen, an energy buffer, which can bridge local short term energy requirements in the brain. Glycogen levels reflect a dynamic equilibrium between glycogen synthesis and glycogenolysis. Many factors that include hormones and neuropeptides, such as insulin and insulin-like growth factor 1 (IGF-1) likely modulate glycogen stores in astrocytes, but detailed mechanisms at the cellular level are sparse. We used a glucose nanosensor based on Förster resonance energy transfer to monitor cytosolic glucose concentration with high temporal resolution and a cytochemical approach to determine glycogen stores in single cells. The results show that after glucose depletion, glycogen stores are replenished. Insulin and IGF-1 boost the process of glycogen formation. Although astrocytes appear to express glucose transporter GLUT4, glucose entry across the astrocyte plasma membrane is not affected by insulin. Stimulation of cells with insulin and IGF-1 decreased cytosolic glucose concentration, likely because of elevated glucose utilization for glycogen synthesis.
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Affiliation(s)
- Marko Muhič
- From the Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia
| | - Nina Vardjan
- From the Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia, Celica Biomedical, 1000 Ljubljana, Slovenia, and
| | - Helena H Chowdhury
- From the Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia, Celica Biomedical, 1000 Ljubljana, Slovenia, and
| | - Robert Zorec
- From the Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia, Celica Biomedical, 1000 Ljubljana, Slovenia, and
| | - Marko Kreft
- From the Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia, Celica Biomedical, 1000 Ljubljana, Slovenia, and the Department of Biology, Biotechnical Faculty, University of Ljubljana, Večna pot 111, 1000 Ljubljana, Slovenia
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32
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Takezawa Y, Baba O, Kohsaka S, Nakajima K. Accumulation of glycogen in axotomized adult rat facial motoneurons. J Neurosci Res 2015; 93:913-21. [DOI: 10.1002/jnr.23546] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Revised: 11/25/2014] [Accepted: 11/30/2014] [Indexed: 11/11/2022]
Affiliation(s)
- Yosuke Takezawa
- Department of Bioinformatics; Faculty of Engineering, Soka University; Tokyo Japan
| | - Otto Baba
- Department of Oral Function and Molecular Biology; School of Dentistry, Ohu University; Koriyamashi Japan
| | - Shinichi Kohsaka
- Department of Neurochemistry; National Institute of Neuroscience; Tokyo Japan
| | - Kazuyuki Nakajima
- Department of Bioinformatics; Faculty of Engineering, Soka University; Tokyo Japan
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33
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Takezawa Y, Kohsaka S, Nakajima K. Transient down-regulation and restoration of glycogen synthase levels in axotomized rat facial motoneurons. Brain Res 2014; 1586:34-45. [PMID: 25152465 DOI: 10.1016/j.brainres.2014.08.049] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Revised: 08/15/2014] [Accepted: 08/16/2014] [Indexed: 11/19/2022]
Abstract
In adult rats, transection of the facial nerve causes a functional down-regulation of motoneurons and glial activation/proliferation. It has not been clear how energy-supplying systems are regulated in an axotomized facial nucleus. Here we investigated the regulation of molecules involved in glycogen degradation/synthesis in axotomized facial nuclei in rats. Immunoblotting revealed that the amounts of glycogen phosphorylase in the contralateral and ipsilateral nuclei were unchanged for the first 14 days, whereas the amount of glycogen synthase in the axotomized facial nuclei was significantly decreased from days 7-14 post-insult. A quantitative analysis estimated that the glycogen synthase levels in the transected nucleus were reduced to approx. 50% at 14 days post-injury. An immunohistochemical study showed that the injured motoneurons had decreased expressions of glycogen synthase proteins. The glycogen synthase levels in the axotomized facial nucleus had returned to control levels by 5 weeks post-insult, as had the cholinergic markers. The immunohistochemical study also revealed the recovery of glycogen synthase levels at the later stage. The glycogen phosphorylase levels in the injured nucleus were not significantly changed during weeks 3-5 post-insult. Taken together, these results demonstrated that the injured facial motoneurons transiently reduced glycogen synthase levels at around 1-2 weeks post-insult, but restored the levels at 4-5 weeks post-insult.
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Affiliation(s)
- Yosuke Takezawa
- Department of Bioinformatics, Faculty of Engineering, Soka University, Tokyo 192-8577, Japan
| | - Shinichi Kohsaka
- Department of Neurochemistry, National Institute of Neuroscience, Tokyo 187-8502, Japan
| | - Kazuyuki Nakajima
- Department of Bioinformatics, Faculty of Engineering, Soka University, Tokyo 192-8577, Japan.
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34
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Rdzak GM, Abdelghany O. Does insulin therapy for type 1 diabetes mellitus protect against Alzheimer's disease? Pharmacotherapy 2014; 34:1317-23. [PMID: 25280207 DOI: 10.1002/phar.1494] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Alzheimer's disease is the most common cause of dementia in the United States. A better understanding of the disease's underlying pathways may provide novel treatment and/or prevention strategies for this progressive chronic neurodegenerative disorder. In recent years, there has been a growing interest in the possible links between insulin and Alzheimer's disease. Insulin-induced hypoglycemia causes adaptive changes in the brain, including an improved ability to use alternative fuels. Insulin has been shown to facilitate reduction of intracellular amyloid plaque and downregulation of amyloid-β-derived diffusible ligand-binding sites. Insulin also promotes tau hypophosphorylation, which stabilizes microtubules and promotes tubulin polymerization. Excess exogenous insulin may also play a role in overcoming the decreased utilization and transport of glucose in patients with Alzheimer's disease. Intranasal insulin therapy may have beneficial effects on cognition and function in patients with Alzheimer's disease, as well as having only minor adverse effects, and this route of administration been the focus in clinical trials. These data support the mechanistic pathways that might link excess exogenous insulin administered to patients with type 1 diabetes mellitus to possible protection from Alzheimer's disease and provide a rationale for using insulin to prevent the disease in high-risk patients.
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Affiliation(s)
- Grzegorz M Rdzak
- Pharmacy Department, Yale-New Haven Hospital, New Haven, Connecticut
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35
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Sajja RK, Prasad S, Cucullo L. Impact of altered glycaemia on blood-brain barrier endothelium: an in vitro study using the hCMEC/D3 cell line. Fluids Barriers CNS 2014; 11:8. [PMID: 24708805 PMCID: PMC3985548 DOI: 10.1186/2045-8118-11-8] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 03/17/2014] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Cerebrovascular complications involving endothelial dysfunction at the blood-brain barrier (BBB) are central to the pathogenesis of diabetes-related CNS disorders. However, clinical and experimental studies have reported contrasting evidence in relation to the effects of hyperglycemia on BBB permeability and function. Similarly the effect of hypoglycemia on BBB integrity is not well understood. Therefore, we assessed the differential impact of hypo and hyperglycemic conditions on BBB integrity and endothelial function in vitro using hCMEC/D3, a well characterized human brain microvascular endothelial cell line. METHODS Parallel monolayers of hCMEC/D3 were exposed to normal, hypo- or hyperglycemic media, containing 5.5, 2.2 or 35 mM D-glucose, respectively. Following 3-24h exposure, the expression and distribution of BBB tight junction (ZO-1 and claudin-5) adherence junction (VE-cadherin) proteins, and glucose transporters as well as inflammatory (VCAM-1) and oxidative stress (Nrf-2) markers were analyzed by immunofluorescence and western blotting. Endothelial release of growth factors and pro-inflammatory cytokines were determined by ELISA. Further, the impact of altered glycemia on BBB permeability was assessed in hCMEC/D3 - astrocyte co-cultures on Transwell supports using fluorescent dextrans (4-70 kDa). RESULTS Compared to controls, exposure to hypoglycemia (3 and 24h) down-regulated the expression of claudin-5 and disrupted the ZO-1 localization at cell-cell contacts, while hyperglycemia marginally reduced claudin-5 expression without affecting ZO-1 distribution. Permeability to dextrans (4-10 kDa) and VEGF release at 24h were significantly increased by hypo- and hyperglycemia, although 70 kDa dextran permeability was increased only under hypoglycemic conditions. The expression of SGLT-1 was up-regulated at 24h hypoglycemic exposure while only a modest increase of GLUT-1 expression was observed. In addition, the expression of Nrf-2 and release of interleukin-6 and PDGF-BB, were down-regulated by hypoglycemia (but not hyperglycemia), while both conditions induced a marginal and transient increase in VCAM-1 expression from 3 to 24h, including a significant increase in VE-cadherin expression at 3 h following hyperglycemia. CONCLUSIONS In summary, our findings demonstrate a potential impairment of BBB integrity and function by hypo or hyperglycemia, through altered expression/distribution of TJ proteins and nutrient transporters. In addition, hypoglycemic exposure severely affects the expression of oxidative and inflammatory stress markers of BBB endothelium.
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Affiliation(s)
| | | | - Luca Cucullo
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S, Coulter Street, Amarillo, TX 79106, USA.
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Harrell CS, Burgado J, Kelly SD, Neigh GN. Ovarian steroids influence cerebral glucose transporter expression in a region- and isoform-specific pattern. J Neuroendocrinol 2014; 26:217-25. [PMID: 24612045 PMCID: PMC5688845 DOI: 10.1111/jne.12139] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Revised: 01/15/2014] [Accepted: 02/22/2014] [Indexed: 02/05/2023]
Abstract
Cerebral glucose uptake is mediated by several members of the family of facilitated glucose transporters (protein nomenclature GLUT; gene nomenclature solute carrier family 2 Slc2a). Glucose uptake differs between the sexes and also varies with menstrual status in women and across the rodent oestrous cycle. The present study demonstrates the extent to which hormonal variation across the four stages of the rat oestrous cycle affects the mRNA abundance of four members of the GLUT family, including the most well characterised cerebral transporters Slc2a1 and Slc2a3, as well as the insulin-sensitive transporters Slc2a4 and Slc2a8 in the hypothalamus, hippocampus and prefrontal cortex. Slc2a1 varied significantly across the cycle in the hippocampus and prefrontal cortex, and Slc2a3 and Slc2a4 also showed significant fluctuation in the hippocampus. Transporter expression significantly increased during pro-oestrus in both the hippocampus and prefrontal cortex. Furthermore, ovarian hormones are critical for normal expression of GLUT mRNA, as demonstrated by reduced expression of Slc2a1, Slc2a3 and Sl2a8 in the hippocampus after ovariectomy. Collectively, the data reported in the present study demonstrate that glucose transporters are highly sensitive to hormonal variation and that this sensitivity is regionally distinct; thereby fluctuations likely have specific phenotypic implications.
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Affiliation(s)
- C S Harrell
- Department of Physiology, Emory University, Atlanta, GA, USA
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37
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Nijland PG, Michailidou I, Witte ME, Mizee MR, van der Pol SMA, van Het Hof B, Reijerkerk A, Pellerin L, van der Valk P, de Vries HE, van Horssen J. Cellular distribution of glucose and monocarboxylate transporters in human brain white matter and multiple sclerosis lesions. Glia 2014; 62:1125-41. [PMID: 24692237 DOI: 10.1002/glia.22667] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Revised: 03/12/2014] [Accepted: 03/14/2014] [Indexed: 12/12/2022]
Abstract
To ensure efficient energy supply to the high demanding brain, nutrients are transported into brain cells via specific glucose (GLUT) and monocarboxylate transporters (MCT). Mitochondrial dysfunction and altered glucose metabolism are thought to play an important role in the progression of neurodegenerative diseases, including multiple sclerosis (MS). Here, we investigated the cellular localization of key GLUT and MCT proteins in human brain tissue of non-neurological controls and MS patients. We show that in control brain tissue GLUT and MCT proteins were abundantly expressed in a variety of central nervous system cells, particularly in microglia and endothelial cells. In active MS lesions, GLUTs and MCTs were highly expressed in infiltrating leukocytes and reactive astrocytes. Astrocytes manifest increased MCT1 staining and maintain GLUT expression in inactive lesions, whereas demyelinated axons exhibit significantly reduced GLUT3 and MCT2 immunoreactivity in inactive lesions. Finally, we demonstrated that the co-transcription factor peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), an important protein involved in energy metabolism, is highly expressed in reactive astrocytes in active MS lesions. Overexpression of PGC-1α in astrocyte-like cells resulted in increased production of several GLUT and MCT proteins. In conclusion, we provide for the first time a comprehensive overview of key nutrient transporters in white matter brain samples. Moreover, our data demonstrate an altered expression of these nutrient transporters in MS brain tissue, including a marked reduction of axonal GLUT3 and MCT2 expression in chronic lesions, which may impede efficient nutrient supply to the hypoxic demyelinated axons thereby contributing to the ongoing neurodegeneration in MS.
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Affiliation(s)
- Philip G Nijland
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
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38
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Jensen VFH, Bøgh IB, Lykkesfeldt J. Effect of insulin-induced hypoglycaemia on the central nervous system: evidence from experimental studies. J Neuroendocrinol 2014; 26:123-50. [PMID: 24428753 DOI: 10.1111/jne.12133] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Revised: 12/13/2013] [Accepted: 01/08/2014] [Indexed: 12/12/2022]
Abstract
Insulin-induced hypoglycaemia (IIH) is a major acute complication in type 1 as well as in type 2 diabetes, particularly during intensive insulin therapy. The brain plays a central role in the counter-regulatory response by eliciting parasympathetic and sympathetic hormone responses to restore normoglycaemia. Brain glucose concentrations, being approximately 15-20% of the blood glucose concentration in humans, are rigorously maintained during hypoglycaemia through adaptions such as increased cerebral glucose transport, decreased cerebral glucose utilisation and, possibly, by using central nervous system glycogen as a glucose reserve. However, during sustained hypoglycaemia, the brain cannot maintain a sufficient glucose influx and, as the cerebral hypoglycaemia becomes severe, electroencephalogram changes, oxidative stress and regional neuronal death ensues. With particular focus on evidence from experimental studies on nondiabetic IIH, this review outlines the central mechanisms behind the counter-regulatory response to IIH, as well as cerebral adaption to avoid sequelae of cerebral neuroglycopaenia, including seizures and coma.
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Affiliation(s)
- V F H Jensen
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Diabetes Toxicology and Safety Pharmacology, Novo Nordisk A/S, Maaloev, Denmark
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39
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El Khoury NB, Gratuze M, Papon MA, Bretteville A, Planel E. Insulin dysfunction and Tau pathology. Front Cell Neurosci 2014; 8:22. [PMID: 24574966 PMCID: PMC3920186 DOI: 10.3389/fncel.2014.00022] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Accepted: 01/16/2014] [Indexed: 01/26/2023] Open
Abstract
The neuropathological hallmarks of Alzheimer's disease (AD) include senile plaques of β-amyloid (Aβ) peptides (a cleavage product of the Amyloid Precursor Protein, or APP) and neurofibrillary tangles (NFT) of hyperphosphorylated Tau protein assembled in paired helical filaments (PHF). NFT pathology is important since it correlates with the degree of cognitive impairment in AD. Only a small proportion of AD is due to genetic variants, whereas the large majority of cases (~99%) is late onset and sporadic in origin. The cause of sporadic AD is likely to be multifactorial, with external factors interacting with biological or genetic susceptibilities to accelerate the manifestation of the disease. Insulin dysfunction, manifested by diabetes mellitus (DM) might be such factor, as there is extensive data from epidemiological studies suggesting that DM is associated with an increased relative risk for AD. Type 1 diabetes (T1DM) and type 2 diabetes (T2DM) are known to affect multiple cognitive functions in patients. In this context, understanding the effects of diabetes on Tau pathogenesis is important since Tau pathology show a strong relationship to dementia in AD, and to memory loss in normal aging and mild cognitive impairment. Here, we reviewed preclinical studies that link insulin dysfunction to Tau protein pathogenesis, one of the major pathological hallmarks of AD. We found more than 30 studies reporting Tau phosphorylation in a mouse or rat model of insulin dysfunction. We also payed attention to potential sources of artifacts, such as hypothermia and anesthesia, that were demonstrated to results in Tau hyperphosphorylation and could major confounding experimental factors. We found that very few studies reported the temperature of the animals, and only a handful did not use anesthesia. Overall, most published studies showed that insulin dysfunction can promote Tau hyperphosphorylation and pathology, both directly and indirectly, through hypothermia.
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Affiliation(s)
- Noura B El Khoury
- Département de Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval Québec, QC, Canada ; Axe Neurosciences, Centre Hospitalier de l'Université Laval Québec, QC, Canada
| | - Maud Gratuze
- Département de Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval Québec, QC, Canada ; Axe Neurosciences, Centre Hospitalier de l'Université Laval Québec, QC, Canada
| | - Marie-Amélie Papon
- Axe Neurosciences, Centre Hospitalier de l'Université Laval Québec, QC, Canada
| | - Alexis Bretteville
- Axe Neurosciences, Centre Hospitalier de l'Université Laval Québec, QC, Canada
| | - Emmanuel Planel
- Département de Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval Québec, QC, Canada ; Axe Neurosciences, Centre Hospitalier de l'Université Laval Québec, QC, Canada
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Morelli A, Sarchielli E, Comeglio P, Filippi S, Vignozzi L, Marini M, Rastrelli G, Maneschi E, Cellai I, Persani L, Adorini L, Vannelli GB, Maggi M. Metabolic syndrome induces inflammation and impairs gonadotropin-releasing hormone neurons in the preoptic area of the hypothalamus in rabbits. Mol Cell Endocrinol 2014; 382:107-119. [PMID: 24064031 DOI: 10.1016/j.mce.2013.09.017] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2013] [Revised: 09/16/2013] [Accepted: 09/16/2013] [Indexed: 12/16/2022]
Abstract
Rabbits with high fat diet (HFD)-induced metabolic syndrome (MetS) developed hypogonadotropic hypogonadism (HH) and showed a reduced gonadotropin-releasing hormone (GnRH) immunopositivity in the hypothalamus. This study investigated the relationship between MetS and hypothalamic alterations in HFD-rabbits. Gonadotropin levels decreased as a function of MetS severity, hypothalamic gene expression of glucose transporter 4 (GLUT4) and interleukin-6 (IL-6). HFD determined a low-grade inflammation in the hypothalamus, significantly inducing microglial activation, expression and immunopositivity of IL-6, as well as GLUT4 and reduced immunopositivity for KISS1 receptor, whose mRNA expression was negatively correlated to glucose intolerance. Correcting glucose metabolism with obetcholic acid improved hypothalamic alterations, reducing GLUT4 and IL-6 immunopositivity and significantly increasing GnRH mRNA, without, however, preventing HFD-related HH. No significant effects at the hypothalamic level were observed after systemic anti-inflammatory treatment (infliximab). Our results suggest that HFD-induced metabolic derangements negatively affect GnRH neuron function through an inflammatory injury at the hypothalamic level.
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Affiliation(s)
- Annamaria Morelli
- Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Erica Sarchielli
- Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Paolo Comeglio
- Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Sandra Filippi
- Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Department of Experimental and Clinical Biomedical Sciences and Department of NEUROFARBA, University of Florence, 50139 Florence, Italy
| | - Linda Vignozzi
- Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Mirca Marini
- Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Giulia Rastrelli
- Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Elena Maneschi
- Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Ilaria Cellai
- Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Luca Persani
- Department of Clinical Sciences and Community Health, University of Milan, Division of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano, 20149-Milan, Italy; CIRMAR (Centro Interuniversitario di Ricerca sulle basi molecolari della Malattie della Riproduzione), 20122 Milan, Italy
| | | | - Gabriella B Vannelli
- Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Mario Maggi
- Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy; CIRMAR (Centro Interuniversitario di Ricerca sulle basi molecolari della Malattie della Riproduzione), 20122 Milan, Italy; I.N.B.B. - Istituto Nazionale Biostrutture e Biosistemi, 00136 Rome, Italy.
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Tarussio D, Metref S, Seyer P, Mounien L, Vallois D, Magnan C, Foretz M, Thorens B. Nervous glucose sensing regulates postnatal β cell proliferation and glucose homeostasis. J Clin Invest 2014; 124:413-24. [PMID: 24334455 PMCID: PMC3871223 DOI: 10.1172/jci69154] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Accepted: 10/11/2013] [Indexed: 01/19/2023] Open
Abstract
How glucose sensing by the nervous system impacts the regulation of β cell mass and function during postnatal development and throughout adulthood is incompletely understood. Here, we studied mice with inactivation of glucose transporter 2 (Glut2) in the nervous system (NG2KO mice). These mice displayed normal energy homeostasis but developed late-onset glucose intolerance due to reduced insulin secretion, which was precipitated by high-fat diet feeding. The β cell mass of adult NG2KO mice was reduced compared with that of WT mice due to lower β cell proliferation rates in NG2KO mice during the early postnatal period. The difference in proliferation between NG2KO and control islets was abolished by ganglionic blockade or by weaning the mice on a carbohydrate-free diet. In adult NG2KO mice, first-phase insulin secretion was lost, and these glucose-intolerant mice developed impaired glucagon secretion when fed a high-fat diet. Electrophysiological recordings showed reduced parasympathetic nerve activity in the basal state and no stimulation by glucose. Furthermore, sympathetic activity was also insensitive to glucose. Collectively, our data show that GLUT2-dependent control of parasympathetic activity defines a nervous system/endocrine pancreas axis that is critical for β cell mass establishment in the postnatal period and for long-term maintenance of β cell function.
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Affiliation(s)
- David Tarussio
- Center for Integrative Genomics, University of Lausanne (UNIL), Lausanne, Switzerland.
Institut de Génomique Fonctionnelle, Montpellier, France.
Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, Université EA4674 Aix-Marseille — Faculté Saint Jérôme, Marseille, France.
CNRS-University Paris Diderot, Paris, France.
Institut Cochin — INSERM U1016 — CNRS UMR8104 — Université Paris Descartes, Paris, France
| | - Salima Metref
- Center for Integrative Genomics, University of Lausanne (UNIL), Lausanne, Switzerland.
Institut de Génomique Fonctionnelle, Montpellier, France.
Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, Université EA4674 Aix-Marseille — Faculté Saint Jérôme, Marseille, France.
CNRS-University Paris Diderot, Paris, France.
Institut Cochin — INSERM U1016 — CNRS UMR8104 — Université Paris Descartes, Paris, France
| | - Pascal Seyer
- Center for Integrative Genomics, University of Lausanne (UNIL), Lausanne, Switzerland.
Institut de Génomique Fonctionnelle, Montpellier, France.
Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, Université EA4674 Aix-Marseille — Faculté Saint Jérôme, Marseille, France.
CNRS-University Paris Diderot, Paris, France.
Institut Cochin — INSERM U1016 — CNRS UMR8104 — Université Paris Descartes, Paris, France
| | - Lourdes Mounien
- Center for Integrative Genomics, University of Lausanne (UNIL), Lausanne, Switzerland.
Institut de Génomique Fonctionnelle, Montpellier, France.
Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, Université EA4674 Aix-Marseille — Faculté Saint Jérôme, Marseille, France.
CNRS-University Paris Diderot, Paris, France.
Institut Cochin — INSERM U1016 — CNRS UMR8104 — Université Paris Descartes, Paris, France
| | - David Vallois
- Center for Integrative Genomics, University of Lausanne (UNIL), Lausanne, Switzerland.
Institut de Génomique Fonctionnelle, Montpellier, France.
Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, Université EA4674 Aix-Marseille — Faculté Saint Jérôme, Marseille, France.
CNRS-University Paris Diderot, Paris, France.
Institut Cochin — INSERM U1016 — CNRS UMR8104 — Université Paris Descartes, Paris, France
| | - Christophe Magnan
- Center for Integrative Genomics, University of Lausanne (UNIL), Lausanne, Switzerland.
Institut de Génomique Fonctionnelle, Montpellier, France.
Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, Université EA4674 Aix-Marseille — Faculté Saint Jérôme, Marseille, France.
CNRS-University Paris Diderot, Paris, France.
Institut Cochin — INSERM U1016 — CNRS UMR8104 — Université Paris Descartes, Paris, France
| | - Marc Foretz
- Center for Integrative Genomics, University of Lausanne (UNIL), Lausanne, Switzerland.
Institut de Génomique Fonctionnelle, Montpellier, France.
Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, Université EA4674 Aix-Marseille — Faculté Saint Jérôme, Marseille, France.
CNRS-University Paris Diderot, Paris, France.
Institut Cochin — INSERM U1016 — CNRS UMR8104 — Université Paris Descartes, Paris, France
| | - Bernard Thorens
- Center for Integrative Genomics, University of Lausanne (UNIL), Lausanne, Switzerland.
Institut de Génomique Fonctionnelle, Montpellier, France.
Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, Université EA4674 Aix-Marseille — Faculté Saint Jérôme, Marseille, France.
CNRS-University Paris Diderot, Paris, France.
Institut Cochin — INSERM U1016 — CNRS UMR8104 — Université Paris Descartes, Paris, France
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p-Hydroxybenzoic acid (p-HA) modified polymeric micelles for brain-targeted docetaxel delivery. ACTA ACUST UNITED AC 2013. [DOI: 10.1007/s11434-013-5760-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Deracinois B, Duban-Deweer S, Pottiez G, Cecchelli R, Karamanos Y, Flahaut C. TNAP and EHD1 are over-expressed in bovine brain capillary endothelial cells after the re-induction of blood-brain barrier properties. PLoS One 2012; 7:e48428. [PMID: 23119012 PMCID: PMC3485243 DOI: 10.1371/journal.pone.0048428] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2012] [Accepted: 09/25/2012] [Indexed: 12/31/2022] Open
Abstract
Although the physiological properties of the blood-brain barrier (BBB) are relatively well known, the phenotype of the component brain capillary endothelial cells (BCECs) has yet to be described in detail. Likewise, the molecular mechanisms that govern the establishment and maintenance of the BBB are largely unknown. Proteomics can be used to assess quantitative changes in protein levels and identify proteins involved in the molecular pathways responsible for cellular differentiation. Using the well-established in vitro BBB model developed in our laboratory, we performed a differential nano-LC MALDI-TOF/TOF-MS study of Triton X-100-soluble protein species from bovine BCECs displaying either limited BBB functions or BBB functions re-induced by glial cells. Due to the heterogeneity of the crude extract, we increased identification yields by applying a repeatable, reproducible fractionation process based on the proteins' relative hydrophobicity. We present proteomic and biochemical evidence to show that tissue non-specific alkaline phosphatase (TNAP) and Eps15 homology domain-containing protein 1(EDH1) are over-expressed by bovine BCECs after the re-induction of BBB properties. We discuss the impact of these findings on current knowledge of endothelial and BBB permeability.
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Affiliation(s)
- Barbara Deracinois
- Université Lille Nord de France, Lille, France
- Université d’Artois, LBHE, Lens, France
- IMPRT-IFR114, Lille, France
| | - Sophie Duban-Deweer
- Université Lille Nord de France, Lille, France
- Université d’Artois, LBHE, Lens, France
- IMPRT-IFR114, Lille, France
| | - Gwënaël Pottiez
- Université Lille Nord de France, Lille, France
- Université d’Artois, LBHE, Lens, France
- IMPRT-IFR114, Lille, France
| | - Roméo Cecchelli
- Université Lille Nord de France, Lille, France
- Université d’Artois, LBHE, Lens, France
- IMPRT-IFR114, Lille, France
| | - Yannis Karamanos
- Université Lille Nord de France, Lille, France
- Université d’Artois, LBHE, Lens, France
- IMPRT-IFR114, Lille, France
| | - Christophe Flahaut
- Université Lille Nord de France, Lille, France
- Université d’Artois, LBHE, Lens, France
- IMPRT-IFR114, Lille, France
- * E-mail:
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Abstract
The occurrence of altered brain glucose metabolism has long been suggested in both diabetes and Alzheimer’s diseases. However, the preceding mechanism to altered glucose metabolism has not been well understood. Glucose enters the brain via glucose transporters primarily present at the blood-brain barrier. Any changes in glucose transporter function and expression dramatically affects brain glucose homeostasis and function. In the brains of both diabetic and Alzheimer’s disease patients, changes in glucose transporter function and expression have been observed, but a possible link between the altered glucose transporter function and disease progress is missing. Future recognition of the role of new glucose transporter isoforms in the brain may provide a better understanding of brain glucose metabolism in normal and disease states. Elucidation of clinical pathological mechanisms related to glucose transport and metabolism may provide common links to the etiology of these two diseases. Considering these facts, in this review we provide a current understanding of the vital roles of a variety of glucose transporters in the normal, diabetic and Alzheimer’s disease brain.
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Affiliation(s)
- Kaushik Shah
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S. Coulter Street, Amarillo, TX 79106, USA.
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García-Cáceres C, Fuente-Martín E, Argente J, Chowen JA. Emerging role of glial cells in the control of body weight. Mol Metab 2012; 1:37-46. [PMID: 24024117 DOI: 10.1016/j.molmet.2012.07.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Revised: 07/09/2012] [Accepted: 07/09/2012] [Indexed: 12/18/2022] Open
Abstract
Glia are the most abundant cell type in the brain and are indispensible for the normal execution of neuronal actions. They protect neurons from noxious insults and modulate synaptic transmission through affectation of synaptic inputs, release of glial transmitters and uptake of neurotransmitters from the synaptic cleft. They also transport nutrients and other circulating factors into the brain thus controlling the energy sources and signals reaching neurons. Moreover, glia express receptors for metabolic hormones, such as leptin and insulin, and can be activated in response to increased weight gain and dietary challenges. However, chronic glial activation can be detrimental to neurons, with hypothalamic astrocyte activation or gliosis suggested to be involved in the perpetuation of obesity and the onset of secondary complications. It is now accepted that glia may be a very important participant in metabolic control and a possible therapeutical target. Here we briefly review this rapidly advancing field.
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Affiliation(s)
- Cristina García-Cáceres
- Institute of Diabetes and Obesity, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), Munich, Germany ; CIBER de Fisiopatología de Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
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Liu Y, Lu W. Recent advances in brain tumor-targeted nano-drug delivery systems. Expert Opin Drug Deliv 2012; 9:671-86. [DOI: 10.1517/17425247.2012.682726] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Shingo AS, Kanabayashi T, Murase T, Kito S. Cognitive decline in STZ-3V rats is largely due to dysfunctional insulin signalling through the dentate gyrus. Behav Brain Res 2012; 229:378-83. [PMID: 22289199 DOI: 10.1016/j.bbr.2012.01.034] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2011] [Revised: 01/12/2012] [Accepted: 01/15/2012] [Indexed: 11/19/2022]
Abstract
Recent epidemiological studies have associated type 2 diabetes mellitus with an increased risk of developing Alzheimer's disease (AD). A dramatic decrease in glucose utilisation has been observed in the brains of AD patients, and this decrease has led to the hypothesis that the cognitive dysfunction in AD is associated with decreased central glucose metabolism [1], in addition to cholinergic deficit and elevated amyloid accumulation in the brain [2]. The aims of the present study were to examine the effects of intracerebral administration of streptozotocin (STZ) on cognitive performance in rats as observed by Morris water maze (MWM) task and to clarify the successive insulin-related neurochemical changes through immunohistochemical analysis of the hippocampus. Significant differences were observed in all the parameters of the MWM task (escape latency, path efficiency, average swimming speed and swim path) between STZ-3V-treated and control rats. Immunohistochemical analysis using hippocampal formations revealed significant decreases in phospho-cyclic AMP binding protein, Akt and insulin-degrading enzyme immunoreactivities and a significant increase in amyloid beta immunoreactivity. Our behavioural experiments confirmed that intraventricular administration of STZ led to cognitive impairment, which was ascertained by the changes in hippocampal immunohistochemical markers. In conclusion, we demonstrated that cognitive decline in diabetes was primarily due to impaired intracerebral insulin signalling in addition to arteriosclerotic cerebrovascular changes, which hitherto have been advocated as the main cause of diabetic dementia.
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Jordan SD, Könner AC, Brüning JC. Sensing the fuels: glucose and lipid signaling in the CNS controlling energy homeostasis. Cell Mol Life Sci 2010; 67:3255-73. [PMID: 20549539 PMCID: PMC2933848 DOI: 10.1007/s00018-010-0414-7] [Citation(s) in RCA: 113] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2010] [Revised: 05/18/2010] [Accepted: 05/19/2010] [Indexed: 12/15/2022]
Abstract
The central nervous system (CNS) is capable of gathering information on the body's nutritional state and it implements appropriate behavioral and metabolic responses to changes in fuel availability. This feedback signaling of peripheral tissues ensures the maintenance of energy homeostasis. The hypothalamus is a primary site of convergence and integration for these nutrient-related feedback signals, which include central and peripheral neuronal inputs as well as hormonal signals. Increasing evidence indicates that glucose and lipids are detected by specialized fuel-sensing neurons that are integrated in these hypothalamic neuronal circuits. The purpose of this review is to outline the current understanding of fuel-sensing mechanisms in the hypothalamus, to integrate the recent findings in this field, and to address the potential role of dysregulation in these pathways in the development of obesity and type 2 diabetes mellitus.
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Affiliation(s)
- Sabine D. Jordan
- Department of Mouse Genetics and Metabolism, Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, Zülpicher Straße 47, 50674 Cologne, Germany
- Center of Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - A. Christine Könner
- Department of Mouse Genetics and Metabolism, Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, Zülpicher Straße 47, 50674 Cologne, Germany
- Center of Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
- 2nd Department for Internal Medicine, University Hospital Cologne, Cologne, Germany
| | - Jens C. Brüning
- Department of Mouse Genetics and Metabolism, Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, Zülpicher Straße 47, 50674 Cologne, Germany
- Center of Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
- 2nd Department for Internal Medicine, University Hospital Cologne, Cologne, Germany
- Max Planck Institute for the Biology of Aging, Cologne, Germany
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Harada S, Fujita-Hamabe W, Tokuyama S. RETRACTED: The importance of regulation of blood glucose levels through activation of peripheral 5′-AMP-activated protein kinase on ischemic neuronal damage. Brain Res 2010; 1351:254-263. [DOI: 10.1016/j.brainres.2010.06.052] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2010] [Revised: 06/17/2010] [Accepted: 06/21/2010] [Indexed: 01/17/2023]
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Kumari U, Heese K. Cardiovascular dementia - a different perspective. Open Biochem J 2010; 4:29-52. [PMID: 20448820 PMCID: PMC2864432 DOI: 10.2174/1874091x01004010029] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2009] [Revised: 01/12/2010] [Accepted: 01/22/2010] [Indexed: 02/08/2023] Open
Abstract
The number of dementia patients has been growing in recent years and dementia represents a significant threat to aging people all over the world. Recent research has shown that the number of people affected by Alzheimer's disease (AD) and dementia is growing at an epidemic pace. The rapidly increasing financial and personal costs will affect the world's economies, health care systems, and many families. Researchers are now exploring a possible connection among AD, vascular dementia (VD), diabetes mellitus (type 2, T2DM) and cardiovascular diseases (CD). This correlation may be due to a strong association of cardiovascular risk factors with AD and VD, suggesting that these diseases share some biologic pathways. Since heart failure is associated with an increased risk of AD and VD, keeping the heart healthy may prove to keep the brain healthy as well. The risk for dementia is especially high when diabetes mellitus is comorbid with severe systolic hypertension or heart disease. In addition, the degree of coronary artery disease (CAD) is independently associated with cardinal neuropathological lesions of AD. Thus, the contribution of T2DM and CD to AD and VD implies that cardiovascular therapies may prove useful in preventing AD and dementia.
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Affiliation(s)
- Udhaya Kumari
- Division of Cell and Molecular Biology, School of Biological Sciences, College of Science, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551
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