Activation of astrocytes by CNTF induces metabolic plasticity and increases resistance to metabolic insults
Activation of astrocytes by CNTF induces metabolic plasticity and increases resistance to metabolic insults
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DOI：
10.1523/jneurosci.0174-07.2007
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发表时间：
2007-07-04
影响因子：
5.3
通讯作者：
Bonvento, Gilles
中科院分区：
文献类型：
--
作者：
Escartin, Carole;Pierre, Karin;Bonvento, Gilles
神经元的高能量需求使它们容易受到能量损害的不利影响。最近，星形胶质细胞被证明可以调节能量基质到神经元的通量。在病理情况下，星形胶质细胞被激活，但对大脑能量代谢的影响仍不清楚。我们发现，睫状神经营养因子（CNTF）是一种已知能激活星形胶质细胞的细胞因子，通过2-[F-18]2-脱氧-d -葡萄糖放射自显像和微正电子发射断层成像，在体内诱导了大鼠纹状体糖溶酶通量的稳定下降。线粒体复合体IV酶细胞色素氧化酶的活性没有改变，表明下游氧化步骤的能量生产维持。CNTF显著增加细胞内能量传感器amp活化蛋白激酶（AMPK）的磷酸化水平，支持大脑能量通路的特异性重组。事实上，我们发现不同的脂肪酸-氧化和酮解的关键酶/转运体在纹状体中被cntf激活的星形胶质细胞过度表达。在原代纹状体神经元/星形胶质细胞混合培养中，暴露于CNTF的AMPK通路也被激活，脂肪酸和酮体的氧化速率显著提高。这种代谢可塑性赋予部分胶质细胞和神经元对长时间棕榈酸盐暴露和糖酵解抑制的保护作用。我们得出结论，cntf激活的星形胶质细胞可能具有强大的保护潜力，以面对严重的代谢损伤。
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-[F-18]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 beta-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.