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Activity-dependent neuronal Klotho enhances astrocytic aerobic glycolysis

ABSTRACT: Mutations of the β-glucuronidase protein α-Klotho have been associated with premature aging, and altered cognitive function. Although highly expressed in specific areas of the brain, Klotho functions in the central nervous system remain unknow. Here, we show that cultured hippocampal neurons respond to insulin and glutamate stimulation by elevating Klotho protein levels. Conversely, AMPA and NMDA antagonism suppress neuronal Klotho expression. We also provide evidence that soluble Klotho enhances astrocytic aerobic glycolysis by hindering pyruvate metabolism through the mitochondria, and stimulating its processing by lactate dehydrogenase. Pharmacological inhibition of FGFR1, Erk phosphorylation, and monocarboxylic acid transporters prevents Klotho-induced lactate release from astrocytes. Taken together these data suggest Klotho is a potential new player in the metabolic coupling between neurons and astrocytes. Neuronal glutamatergic activity and insulin modulation elicit Klotho release, which in turn stimulates astrocytic lactate formation and release. Lactate can then be used by neurons as a metabolic substrate contributing to fulfill their elevated energy requirements.

ORGANISM(S): Mus musculus

PROVIDER: GSE100046 | GEO | 2018/03/08

REPOSITORIES: GEO

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Project description:Aubert2005 - Interaction between astrocytes and neurons on energy metabolism Enocded non-curated model. Issues: - Confusing equations A.41 and A.42 - Missing values for parameters Vv,0 and dHb,0 This model is described in the article: Interaction between astrocytes and neurons studied using a mathematical model of compartmentalized energy metabolism. Aubert A, Costalat R. J. Cereb. Blood Flow Metab. 2005 Nov; 25(11): 1476-1490 Abstract: Understanding cerebral energy metabolism in neurons and astrocytes is necessary for the interpretation of functional brain imaging data. It has been suggested that astrocytes can provide lactate as an energy fuel to neurons, a process referred to as astrocyte-neuron lactate shuttle (ANLS). Some authors challenged this hypothesis, defending the classical view that glucose is the major energy substrate of neurons, at rest as well as in response to a stimulation. To test the ANLS hypothesis from a theoretical point of view, we developed a mathematical model of compartmentalized energy metabolism between neurons and astrocytes, adopting hypotheses highly unfavorable to ANLS. Simulation results can be divided between two groups, depending on the relative neuron versus astrocyte stimulation. If this ratio is low, ANLS is observed during all the stimulus and poststimulus periods (continuous ANLS), but a high ratio induces ANLS only at the beginning of the stimulus and during the poststimulus period (triphasic behavior). Finally, our results show that current experimental data on lactate kinetics are compatible with the ANLS hypothesis, and that it is essential to assess the neuronal and astrocytic NADH/NAD+ ratio changes to test the ANLS hypothesis. This model is hosted on BioModels Database and identified by: MODEL1411210000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Activity-dependent neuronal Klotho enhances astrocytic aerobic glycolysis

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