Peroxisome proliferator-activated receptor γ thiazolidinedione agonists increase glucose metabolism in astrocytes
Peroxisome proliferator-activated receptor γ thiazolidinedione agonists increase glucose metabolism in astrocytes
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DOI：
10.1074/jbc.m208132200
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发表时间：
2003-02-21
影响因子：
4.8
通讯作者：
Feinstein, DL
中科院分区：
文献类型：
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作者：
Dello Russo, C;Gavrilyuk, V;Feinstein, DL
过氧化物酶体增殖物激活受体（PPARs）的激活可以调节脑生理学并在神经系统疾病模型中提供保护;然而，它们在脑中的确切靶点和作用机制都不清楚。在许多细胞中，PPARgamma激动剂增加葡萄糖摄取和代谢。由于星形胶质细胞储存葡萄糖并根据需要向神经元提供乳酸，我们测试了PPARgamma激动剂对星形胶质细胞葡萄糖代谢的影响。用PPARgamma噻唑烷二酮（TZD）激动剂吡格列酮（Pio）孵育皮质星形胶质细胞以时间和剂量依赖性方式显著增加葡萄糖消耗，在30 μ m Pio中4小时后观察到最大增加36%。Pio增加2-脱氧葡萄糖摄取，因为增加了通过1型葡萄糖转运蛋白的通量。然而，在这个时间点，Pio没有增加1型葡萄糖转运蛋白的表达，也没有被转录或翻译抑制剂阻断其作用。PIO也增加星形胶质细胞乳酸的产生，只要3小时后孵育。这些作用被其他TZD复制;然而，疗效顺序（曲格列酮>吡格列酮>罗格列酮）表明，这些作用不是通过PPAR γ激活介导的。TZDs增加星形胶质细胞cAMP水平，其葡萄糖修饰作用被蛋白激酶A抑制剂降低。TZDs抑制状态III呼吸在孤立的脑线粒体，而在星形胶质细胞中，它们引起线粒体膜超极化。Pio保护星形胶质细胞免受低血糖诱导的细胞死亡。最后，葡萄糖摄取的修改，从PIO喂养大鼠制备的脑切片。这些结果表明，TZD改变星形胶质细胞代谢和线粒体功能，这可能对葡萄糖可用性降低的神经系统疾病有益。
Activation of peroxisome proliferator-activated receptors (PPARs) can regulate brain physiology and provide protection in models of neurological disease; however, neither their exact targets nor mechanisms of action in brain are known. In many cells, PPARgamma agonists increase glucose uptake and metabolism. Because astrocytes store glucose and provide lactate to neurons on demand, we tested effects of PPARgamma agonists on astroglial glucose metabolism. Incubation of cortical astrocytes with the PPARgamma thiazolidinedione (TZD) agonist pioglitazone (Pio) significantly increased glucose consumption in a time- and dose-dependent manner, with maximal increase of 36% observed after 4 h in 30 mum Pio. Pio increased 2-deoxy-glucose uptake because of increased flux through the type 1 glucose transporter. However, at this time point Pio did not increase type 1 glucose transporter expression, nor were its effects blocked by transcriptional or translational inhibitors. Pio also increased astrocyte lactate production as soon as 3 h after incubation. These effects were replicated by other TZDs; however, the order of efficacy (troglitazone > pioglitazone > rosiglitazone) suggests that effects were not mediated via PPARgamma activation. TZDs increased astrocyte cAMP levels, and their glucose modifying effects were reduced by protein kinase A inhibitors. TZDs inhibited state III respiration in isolated brain mitochondria, whereas in astrocytes they caused mitochondrial membrane hyperpolarization. Pio protected astrocytes against hypoglycemia-induced cell death. Finally, glucose uptake was modified in brain sections prepared from Pio-fed rats. These results demonstrate that TZDs modify astrocyte metabolism and mitochondrial function, which could be beneficial in neurological conditions where glucose availability is reduced.