Neurons Have an Active Glycogen Metabolism that Contributes to Tolerance to Hypoxia

Sáez, Isabel; Durán, Jordi; Sinadinos, Christopher; Beltran, Antoni; Yanes, Óscar; Tevy, María Florencia; Martínez-Pons, Carlos; Milán, Marco; Guinovart, Joan J.

doi:10.1038/jcbfm.2014.33

Cited by 178 publications

(181 citation statements)

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“…For instance, tissue-specific functions of glycogen have been observed in adipocytes, where it provides glycerol for triacylglycerol synthesis in the fasting to feeding transition [36] and modulates lipid metabolism after a switch from a high-fat to a standard chow diet [37]. Likewise, in neurons, glycogen has been shown to contribute to tolerance to hypoxia [38].…”

Section: Discussionmentioning

confidence: 99%

Genetic models rule out a major role of beta cell glycogen in the control of glucose homeostasis

et al. 2016

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Aims/hypothesis Glycogen accumulation occurs in beta cells of diabetic patients and has been proposed to partly mediate glucotoxicity-induced beta cell dysfunction. However, the role of glycogen metabolism in beta cell function and its contribution to diabetes pathophysiology remain poorly understood. We investigated the function of beta cell glycogen by studying glucose homeostasis in mice with (1) defective glycogen synthesis in the pancreas; and (2) excessive glycogen accumulation in beta cells. Methods Conditional deletion of the Gys1 gene and overexpression of protein targeting to glycogen (PTG) was accomplished by Cre-lox recombination using pancreasspecific Cre lines. Glucose homeostasis was assessed by determining fasting glycaemia, insulinaemia and glucose tolerance. Beta cell mass was determined by morphometry. Glycogen was detected histologically by periodic acidSchiff's reagent staining. Isolated islets were used for the determination of glycogen and insulin content, insulin secretion, immunoblots and gene expression assays. Results Gys1 knockout (Gys1 KO ) mice did not exhibit differences in glucose tolerance or basal glycaemia and insulinaemia relative to controls. Insulin secretion and gene expression in isolated islets was also indistinguishable between Gys1 KO and controls. Conversely, despite effective glycogen overaccumulation in islets, mice with PTG overexpression (PTG OE ) presented similar glucose tolerance to controls. However, under fasting conditions they exhibited lower glycaemia and higher insulinaemia. Importantly, neither young nor aged PTG OE mice showed differences in beta cell mass relative to age-matched controls. Finally, a high-fat diet did not reveal a beta cell-autonomous phenotype in either model. Conclusions/interpretation Glycogen metabolism is not required for the maintenance of beta cell function. Glycogen accumulation in beta cells alone is not sufficient to trigger the dysfunction or loss of these cells, or progression to diabetes.

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Section: Discussionmentioning

confidence: 99%

Genetic models rule out a major role of beta cell glycogen in the control of glucose homeostasis

et al. 2016

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“…Moreover, it is now accepted that the accumulation of glycogen in neurons leads to their rapid degeneration and is implicated in aging, as well as promoting several pathological conditions of the brain such as Lafora disease. The activity of bGP is critical for the controlled degradation of glycogen in neurons because they only express the brain isoform of GP (17). A reduction of bGP activity would lead to the uncontrolled accumulation of glycogen in neurons and contribute to the pathogenesis of several brain diseases (18,35,36).…”

Section: Discussionmentioning

confidence: 99%

“…Astrocytic glycogen breakdown and subsequent astrocyte-neuron lactate transport have also been proposed to support high cognitive processes such as learning and memory consolidation (10 -16). In addition, glycogen metabolism in neurons participates in neuronal tolerance to hypoxic stress (17). Glycogen itself is also important for brain function.…”

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confidence: 99%

Insights into Brain Glycogen Metabolism

Mathieu

Sierra-Gallay

Duval

et al. 2016

Journal of Biological Chemistry

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Brain glycogen metabolism plays a critical role in major brain functions such as learning or memory consolidation. However, alteration of glycogen metabolism and glycogen accumulation in the brain contributes to neurodegeneration as observed in Lafora disease. Glycogen phosphorylase (GP), a key enzyme in glycogen metabolism, catalyzes the rate-limiting step of glycogen mobilization. Moreover, the allosteric regulation of the three GP isozymes (muscle, liver, and brain) by metabolites and phosphorylation, in response to hormonal signaling, fine-tunes glycogenolysis to fulfill energetic and metabolic requirements. Whereas the structures of muscle and liver GPs have been known for decades, the structure of brain GP (bGP) has remained elusive despite its critical role in brain glycogen metabolism. Here, we report the crystal structure of human bGP in complex with PEG 400 (2.5 Å ) and in complex with its allosteric activator AMP (3.4 Å ). These structures demonstrate that bGP has a closer structural relationship with muscle GP, which is also activated by AMP, contrary to liver GP, which is not. Importantly, despite the structural similarities between human bGP and the two other mammalian isozymes, the bGP structures reveal molecular features unique to the brain isozyme that provide a deeper understanding of the differences in the activation properties of these allosteric enzymes by the allosteric effector AMP. Overall, our study further supports that the distinct structural and regulatory properties of GP isozymes contribute to the different functions of muscle, liver, and brain glycogen.

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“…Although the neuronal utilization of glucose for glycogen synthesis has been suggested for years (64), neurons have only recently been shown to use glucose to generate glycogen. Neuronal glycogen may be important for promoting neuronal survival under pathological conditions, such as oxidative stress and hypoxia (65). However, the neurons could be able to use but not accumulate glycogen because this process has been related with neuronal death in some pathologies (66,67).…”

Section: Wnt Signaling Stimulates Glucose Utilization In Neuronsmentioning

confidence: 99%

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

Cisternas

Salazar

Silva-Álvarez

et al. 2016

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinThe Wnt signaling pathway is critical for a number of functions in the central nervous system, including regulation of the synaptic cleft structure and neuroprotection against injury. Deregulation of Wnt signaling has been associated with several brain pathologies, including Alzheimer's disease. In recent years, it has been suggested that the Wnt pathway might act as a central integrator of metabolic signals from peripheral organs to the brain, which would represent a new role for Wnt signaling in cell metabolism. Energy metabolism is critical for normal neuronal function, which mainly depends on glucose utilization. Brain energy metabolism is important in almost all neurological disorders, to which a decrease in the capacity of the brain to utilize glucose has been linked. However, little is known about the relationship between Wnt signaling and neuronal glucose metabolism in the cellular context. In the present study, we found that acute treatment with the Wnt3a ligand induced a large increase in glucose uptake, without changes in the expression or localization of glucose transporter type 3. In addition, we observed that Wnt3a treatment increased the activation of the metabolic sensor Akt. Moreover, we observed an increase in the activity of hexokinase and in the glycolytic rate, and both processes were dependent on activation of the Akt pathway. Furthermore, we did not observe changes in the activity of glucose-6-phosphate dehydrogenase or in the pentose phosphate pathway. The effect of Wnt3a was independent of both the transcription of Wnt target genes and synaptic effects of Wnt3a. Together, our results suggest that Wnt signaling stimulates glucose utilization in cortical neurons through glycolysis to satisfy the high energy demand of these cells.

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Neurons Have an Active Glycogen Metabolism that Contributes to Tolerance to Hypoxia

Cited by 178 publications

References 50 publications

Genetic models rule out a major role of beta cell glycogen in the control of glucose homeostasis

Genetic models rule out a major role of beta cell glycogen in the control of glucose homeostasis

Insights into Brain Glycogen Metabolism

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

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