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The Journal of Neuroscience, July 4, 2007, 27(27):7094-7104; doi:10.1523/JNEUROSCI.0174-07.2007

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Development/Plasticity/Repair
Activation of Astrocytes by CNTF Induces Metabolic Plasticity and Increases Resistance to Metabolic Insults

Carole Escartin,^1,2,3 Karin Pierre,³ Angélique Colin,^1,2 Emmanuel Brouillet,^1,2 Thierry Delzescaux,² Martine Guillermier,^1,2 Marc Dhenain,^1,2 Nicole Déglon,^1,2 Philippe Hantraye,^1,2 Luc Pellerin,³ and Gilles Bonvento^1,2

¹Commissariat à l'Energie Atomique-Direction des Sciences du Vivant, Institut d'Imagerie Biomédicale, Service Hospitalier Frederic Joliot, Centre National de la Recherche Scientifique, Unité de Recherche Associée 2210, 91401 Orsay, France, ²Commissariat à l'Energie Atomique-Direction des Sciences du Vivant, Institut d'Imagerie Biomédicale, Molecular Imaging Research Center, 92265 Fontenay-aux-roses, France, and ³Département de Physiologie, Université de Lausanne, Lausanne 1005, Switzerland

Correspondence should be addressed to Dr. Gilles Bonvento, Service Hospitalier Frédéric Joliot, Commissariat à l'Energie Atomique, Centre National de la Recherche Scientifique, Unité de Recherche Associée 2210, 4 place du Général Leclerc, 91401 Orsay, France. Email: gilles.bonvento{at}cea.fr

High energy demands of neurons make them vulnerable to adverse effects of energy impairment. Recently, astrocytes were shown to regulate the flux of energy substrates to neurons. In pathological situations, astrocytes are activated but the consequences on brain energy metabolism are still poorly characterized. We found that local lentiviral-mediated gene transfer of ciliary neurotrophic factor (CNTF), a cytokine known to activate astrocytes, induced a stable decrease in the glycolytic flux in the rat striatum in vivo as measured by 2-[¹⁸F]-2-deoxy-D-glucose autoradiography and micro-positron emission tomography imaging. The activity of the mitochondrial complex IV enzyme cytochrome oxidase was not modified, suggesting maintenance of downstream oxidative steps of energy production. CNTF significantly increased the phosphorylation level of the intracellular energy sensor AMP-activated protein kinase (AMPK), supporting a specific reorganization of brain energy pathways. Indeed, we found that different key enzymes/transporters of fatty acids β-oxidation and ketolysis were overexpressed by CNTF-activated astrocytes within the striatum. In primary striatal neuron/astrocyte mixed cultures exposed to CNTF, the AMPK pathway was also activated, and the rate of oxidation of fatty acids and ketone bodies was significantly enhanced. This metabolic plasticity conferred partial glial and neuronal protection against prolonged palmitate exposure and glycolysis inhibition. We conclude that CNTF-activated astrocytes may have a strong protective potential to face severe metabolic insults.

Key words: astrocytes; CNTF; ketone bodies; glucose uptake; fatty acid; neuroprotection

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Received Jan. 16, 2007; revised May 9, 2007; accepted May 14, 2007.

Correspondence should be addressed to Dr. Gilles Bonvento, Service Hospitalier Frédéric Joliot, Commissariat à l'Energie Atomique, Centre National de la Recherche Scientifique, Unité de Recherche Associée 2210, 4 place du Général Leclerc, 91401 Orsay, France. Email: gilles.bonvento{at}cea.fr

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