Cell Reports
Volume 23, Issue 7, 15 May 2018, Pages 1922-1931.e4
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GSK3β Regulates Brain Energy Metabolism

https://doi.org/10.1016/j.celrep.2018.04.045Get rights and content
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Highlights

  • GSK3β regulates mitochondrial energy metabolism in neurons and in glia

  • Metabolic regulation by GSK3β extends to cellular NAD metabolism

  • Inhibition of GSK3β alters PGC-1α protein stability, localization, and activity

  • GSK3β inhibition alters hippocampal energy metabolism

Summary

GSK3β is a serine threonine kinase implicated in the progression of Alzheimer’s disease. Although the role of GSK3β in growth and pathology has been extensively studied, little is known about the metabolic consequences of GSK3β manipulation, particularly in the brain. Here, we show that GSK3β regulates mitochondrial energy metabolism in human H4 neuroglioma cells and rat PC12-derived neuronal cells and that inhibition of GSK3β in mice in vivo alters metabolism in the hippocampus in a region-specific manner. We demonstrate that GSK3β inhibition increases mitochondrial respiration and membrane potential and alters NAD(P)H metabolism. These metabolic effects are associated with increased PGC-1α protein stabilization, enhanced nuclear localization, and increased transcriptional co-activation. In mice treated with the GSK3β inhibitor lithium carbonate, changes in hippocampal energy metabolism are linked to increased PGC-1α. These data highlight a metabolic role for brain GSK3β and suggest that the GSK3β/PGC-1α axis may be important in neuronal metabolic integrity.

Keywords

GSK3β
energy metabolism
brain
lithium
PGC-1α
neuron
glia
hippocampus

Cited by (0)

6

These authors contributed equally

7

Present address: Oregon State University, Corvallis, OR, USA

8

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