Deletion of Glucose Transporter GLUT8 in Mice Increases Locomotor Activity
Stefan SchmidtVerena GawlikSabine M. HölterRobert AugustinAndrea ScheepersMaik BehrensWolfgang WurstValérie Gailus‐DurnerHelmut FuchsMartin Hrabé de AngelisReinhart KlugeHans‐Georg JoostAnnette Schürmann
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Transport of glucose into neuronal cells is predominantly mediated by the glucose transporters GLUT1 and GLUT3. In addition, GLUT8 is expressed in some regions of the brain. By in situ hybridization we detected GLUT8-mRNA in hippocampus, thalamus, and cortex. However, its cellular and physiological function is still unknown. Thus, GLUT8 knockout (Slc2a8 -/-) mice were used for a screening approach in the modified hole board (mHB) behavioral test to analyze the role of GLUT8 in the central nervous system. Slc2a8 -/- mice showed increased mean velocity, total distance traveled and performed more turns in the mHB test. This hyperactivity of Slc2a8 -/- mice was confirmed by monitoring locomotor activity in the home cage and voluntary activity in a running wheel. In addition, Slc2a8 -/- mice showed increased arousal as indicated by elevated defecation, reduced latency to the first defecation and a tendency to altered grooming. Furthermore, the mHB test gave evidence that Slc2a8 -/- mice exhibit a reduced risk assessment because they performed less rearings in an unprotected area and showed significantly reduced latency to stretched body posture. Our data suggest that behavioral alterations of Slc2a8 -/- mice are due to dysfunctions in neuronal processes presumably as a consequence of defects in the glucose metabolism.Keywords:
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Cerebral hypoxia-ischemia produces major alterations in energy metabolism and glucose utilization in brain. The facilitative glucose transporter proteins mediate the transport of glucose across the blood–brain barrier (BBB) (55 kDa GLUT1) and into the neurons and glia (GLUT3 and 45 kDa GLUT1). Glucose uptake and utilization are low in the immature rat brain, as are the levels of the glucose transporter proteins. This study investigated the effect of cerebral hypoxia-ischemia in a model of unilateral brain damage on the expression of GLUT 1 and GLUT3 in the ipsilateral (damaged, hypoxic-ischemic) and contralateral (undamaged, hypoxic) hemispheres of perinatal rat brain. Early in the recovery period, both hemispheres exhibited increased expression of BBB GLUT1 and GLUT3, consistent with increased glucose transport and utilization. Further into recovery, BBB GLUT1 increased and neuronal GLUT3 decreased in the damaged hemisphere only, commensurate with neuronal loss.
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Hypoxia
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Traumatic brain injury results in an increased brain energy demand that is associated with profound changes in brain glycolysis and energy metabolism. Increased glycolysis must be met by increasing glucose supply that, in brain, is primarily mediated by two members of the facilitative glucose transporter family, Glut1 and Glut3. Glut1 is expressed in endothelial cells of the blood-brain barrier (BBB) and also in glia, while Glut3 is the primary glucose transporter expressed in neurons. However, few studies have investigated the changes in glucose transporter expression following traumatic brain injury, and in particular, the neuronal and glial glucose transporter responses to injury. This study has therefore focussed on investigating the expression of the glial specific 45-kDa isoform of Glut1 and neuronal specific Glut3 following severe diffuse traumatic brain injury in rats. Following impact-acceleration injury, Glut3 expression was found to increase by at least 300% as early as 4 h after induction of injury and remained elevated for at least 48 h postinjury. The increase in Glut3 expression was clearly evident in both the cerebral cortex and cerebellum. In contrast, expression of the glial specific 45-kDa isoform of Glut1 did not significantly change in either the cerebral cortex or cerebellum following traumatic injury. We conclude that increased glucose uptake after traumatic brain injury is primarily accounted for by increased neuronal Glut 3 glucose transporter expression and that this increased expression after trauma is part of a neuronal stress response that may be involved in increasing neuronal glycolysis and associated energy metabolism to fuel repair processes.
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L6 muscle cells survive long-term (18 h) disruption of oxidative phosphorylation by the mitochondrial uncoupler 2,4-dinitrophenol (DNP) because, in response to this metabolic stress, they increase their rate of glucose transport. This response is associated with an elevation of the protein content of glucose transporter isoforms GLUT3 and GLUT1, but not GLUT4. Previously we have reported that the rise in GLUT1 expression is likely to be a result of de novo biosynthesis of the transporter, since the uncoupler increases GLUT1 mRNA levels. Unlike GLUT1, very little is known about how interfering with mitochondrial ATP production regulates GLUT3 protein expression. Here we examine the mechanisms employed by DNP to increase GLUT3 protein content and glucose uptake in L6 muscle cells. We report that, in contrast with GLUT1, continuous exposure to DNP had no effect on GLUT3 mRNA levels. DNP-stimulated glucose transport was unaffected by the protein-synthesis inhibitor cycloheximide. The increase in GLUT3 protein mediated by DNP was also insensitive to cycloheximide, paralleling the response of glucose uptake, whereas the rise in GLUT1 protein levels was blocked by the inhibitor. The GLUT3 glucose transporter may therefore provide the majority of the glucose transport stimulation by DNP, despite elevated levels of GLUT1 protein. The half-lives of GLUT3 and GLUT1 proteins in L6 myotubes were determined to be about 15 h and 6 h respectively. DNP prolonged the half-life of both proteins. After 24 h of DNP treatment, 88% of GLUT3 protein and 57% of GLUT1 protein had not turned over, compared with 25% in untreated cells. We conclude that the long-term stimulation of glucose transport by DNP arises from an elevation of GLUT3 protein content associated with an increase in GLUT3 protein half-life. These findings suggest that disruption of the oxidative chain of L6 muscle cells leads to an adaptive response of glucose transport that is distinct from the insulin response, involving specific glucose transporter isoforms that are regulated by different mechanisms.
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Pentylenetetrazole and kainic acid, seizure-inducing agents that are known to increase glucose utilization in brain, were used to produce chronic seizures in mature rats. To test the hypothesis that increased brain glucose utilization associated with seizures may alter glucose transporter expression, polyclonal carboxyl-terminal antisera to glucose transporters (GLUT1 and GLUT3) were employed with a quantitative immunocytochemical method and immunoblots to detect changes in the regional abundances of these proteins. GLUT3 abundances in control rats were found to be correlated with published values for regional glucose utilization in normal brain. Following treatment with kainic acid and pentylenetetrazole, both GLUT3 and GLUT1 increased in abundance in a region and isoform-specific manner. GLUT3 was maximal at eight hours, whereas GLUT1 was maximal at three days. Immunoblots indicated that most of the GLUT3 increase was accounted for by the higher molecular weight component of the GLUT3 doublet. The rapid response time for GLUT3 relative to GLUT1 may be related to the rapid increase in neuronal metabolic energy demands during seizure. These observations support the hypothesis that glucose transporters may be upregulated in brain under conditions when brain glucose metabolism is elevated.
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Abstract The expression of facilitative glucose transporter (GLUT) isoforms in human astrocytic tumors was examined. Reverse transcriptase‐polymerase chain reaction of a surgically biopsied glioblastoma was carried out using the degenerative oligonucleotide primers corresponding to the sequences of the human facilitative glucose transporter family, and polymerase chain reaction products were hybridized with human GLUT1, GLUT2, GLUT3, GLUT4, and GLUT5 cDNA probes. The results showed that a biopsied glioblastoma expressed GLUT1, GLUT3, and GLUT4 glucose transporter genes. Northern blot analysis of total RNA (10 μg) from a biopsied glioblastoma showed the transcripts of only GLUT1 and GLUT3, suggesting that the expression of insulin‐responsive glucose transporter GLUT4 mRNA is relatively low. Immunoblot analysis of biopsied glioblastoma tissues by polyclonal antibodies against the C‐terminal synthetic peptides of GLUT1, GLUT3, and GLUT4 showed a single band of each polypeptide. However, elevated expression of GLUT1 and GLUT3 glucose transporters was not observed in the glioblastoma. Astrocytic tumor tissues (n = 14) were also examined immunohistochemically. Reactive products for GLUT1 were observed in the luminal surface of capillaries in all cases, whereas tumor cells were positive for GLUT1 in only two of 14 cases. GLUT3 was positive in astrocytic tumor cells in all cases. Three of 14 cases expressed the GLUT4 protein, which was localized in the cytoplasm of tumor cells. These results suggest that the facilitative glucose transport may be altered in astrocytic tumor cells and thus display a significant change in glucose metabolism.
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In the brain, glucose is transported by GLUT1 across the blood–brain barrier and into astrocytes, and by GLUT3 into neurons. In the present study, the expression of GLUT1 and GLUT3 mRNA and protein was determined in adult neural stem cells cultured from the subventricular zone of rats. Both mRNAs and proteins were coexpressed, GLUT1 protein being 5‐fold higher than GLUT3. Stress induced by hypoxia and/or hyperglycemia increased the expression of GLUT1 and GLUT3 mRNA and of GLUT3 protein. It is concluded that adult neural stem cells can transport glucose by GLUT1 and GLUT3 and can regulate their glucose transporter densities.
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Neurosphere
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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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The supply of glucose to neurons of the brain and retina is carried out by a specific, facilitated transport with the participation of sodium-independent glucose transporters of the GLUT family. Studying the mechanisms of glucose transport with pharmacological or genetic inhibition of transporters is considered as a promising way to reduce glucose-toxic damage to the retina to prevent diabetic retinopathy. We studied the content of GLUT1, GLUT3, GLUT4 and Hypoxia inducible factor 1 alpha (HIF-1α) in the plasma of patients with different stages of proliferative diabetic retinopathy (PDR), duration of type 2 diabetes (T2D) was up to 20 and over 20 years, and control group. Research on the level of transporters in the blood plasma was carried out by the method of immuno-enzymatic analysis using Elabscience kits (USA). No significant difference in the GLUT1 and GLUT4 blood plasma content was found between patients with PDR and control individuals, and the GLUT3 content was 2-fold higher. Also, the content of HIF-1α was 25% higher. No significant fluctuations in the content of transporters GLUT1, GLUT3, GLUT4, HIF-1α were found depending on the duration of T2DM, the degree of deepening of PDR and the level of hyperglycemia. Correlation analysis revealed a significant two-way correlation of the GLUT3 index with blood glucose level (r = 0.581), HbA1C (r = 0.553), GLUT1 (r = 0.440) and GLUT4 (r = 0.372). The conservatism of GLUT1 transporter content in the studied groups gives a reason to consider protein expression as genetically determined for the basic maintenance of homeostasis. The GLUT3 content increase in patients with PDR, which does not depend on the retinal damage degree, duration of T2D and glucose concentration, defines this mechanism of transport as the main pathogenetic link of glucose toxicity in neurons against the background of chronic hyperglycemia. Insulin-dependent transporter GLUT4 is probably not involved in the occurrence of PDR under of T2D.
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