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

Abstract

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-[18 F]-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 ␤-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.

The Neuroprotective Agent CNTF Decreases Neuronal Metabolites in the Rat Striatum: An in Vivo Multimodal Magnetic Resonance Imaging Study

“…2,7 Ciliary neurotrophic factor neuroprotective effects were reproduced in nonhuman primates, opening the path to clinical trials for amyotrophic lateral sclerosis, 4 diseases of the retina 5 and Huntington's disease. 3 Therefore, it is rather unexpected that CNTF reduces neuronal metabolite levels in the rat striatum.…”

“…We previously reported that astrocyte activation by CNTF alters their metabolic profile, leading to protective effects on neurons exposed to glycolytic inhibition. 7 Here, we aimed to further delineate CNTF metabolic effects on the intact brain. We performed a multimodal imaging study combining proton magnetic resonance spectroscopy ( 1 H-MRS), high-performance liquid chromatography (HPLC) analysis and brain mapping of glutamate (Glu) with Chemical Exchange Saturation Transfer (gluCEST) on rats injected with a lentiviral vector encoding CNTF.…”

Astrocytes: new targets of melanocortin 4 receptor actions

“…Indeed, MC4R stimulation by a-MSH induces inhibition of AMPK in GT1-7 hypothalamic cells (Damm et al 2012). In another study, Escartin et al (2007) showed that in ciliary neurotropic factor-activated astrocytes in the striatum, AMPK is activated and these cells were more resistant to glycolysis inhibition and less affected by palmitate toxicity. Also, AMPK was detected in spinal astrocytes and was activated by ADP treatment resulting in ATP production in these cells (Cui et al 2011).…”

Astrocytes in the damaged brain: Molecular and cellular insights into their reactive response and healing potential

“…Moreover, IL1, IL2, IFN , TNF TGF and others have been found to give rise to massive astrogliosis when injected directly into the brain or overexpressed in transgenic animals [37,38,39]. Similarly, ciliary neurotrophic factor (CNTF), a member of the IL6 family of cytokines with growth factor properties, can promote astrogliosis both in vitro [40] and after administration to the intact brain in vivo [41]. Some reactive traits together with progenitor features are also induced by the mitogen TGF [42,43].…”

“…For example, astrocytes convert stored glycogen to glucose or lactate to obtain energetic substrates, thereby sustaining their own metabolisms or possibly passing these substrates to neighbouring neurons for energy production [132]. Moreover, CNTFactivated astrocytes also increase fatty acid beta-oxidation and ketolysis to produce energy, while decreasing glycolytic pathways [40]. This metabolic plasticity confers a remarkable ability to resist to metabolic insults and support the survival of surrounding neurons [40].…”