Astrocytes provide neurons with structural support and energy in form of lactate, modulate synaptic transmission, are insulin sensitive and act as gatekeeper for water, ions, glutamate and second messengers. Furthermore, astrocytes are important for glucose sensing, possess neuroendocrine functions and also play an important role in cerebral lipid metabolism. To answer the question, if there is a connection between lipid metabolism and insulin action in human astrocytes, we investigated if storage of ectopic lipids in human astrocytes has an impact on insulin signalling in those cells. Human astrocytes were cultured in the presence of a lipid emulsion, consisting of fatty acids and triglycerides, to induce ectopic lipid storage. After several days, cells were stimulated with insulin and gene expression profiling was performed. In addition, phosphorylation of Akt as well as glycogen synthesis and cell proliferation was assessed. Ectopic lipid storage was detected in human astrocytes after lipid exposure and lipid storage was persistent even when the fat emulsion was removed from the cell culture medium. Chronic exposure to lipids induced profound changes in the gene expression profile, whereby some genes showed a reversible gene expression profile upon removal of fat, and some did not. This included FOXO-dependent expression patterns. Furthermore, insulin-induced phosphorylation of Akt was diminished and also insulin-induced glycogen synthesis and proliferation was impaired in lipid-laden astrocytes. Chronic lipid exposure induces lipid storage in human astrocytes accompanied by insulin resistance. Analyses of the gene expression pattern indicated the potential of a partially reversible gene expression profile. Targeting astrocytic insulin resistance by reducing ectopic lipid load might represent a promising treatment target for insulin resistance of the brain in obesity, diabetes and neurodegeneration.

星形胶质细胞以乳酸的形式为神经元提供结构支持和能量，调节突触传递，对胰岛素敏感，并充当水，离子，谷氨酸和第二信使的守门员。此外，星形胶质细胞对于葡萄糖感测很重要，具有神经内分泌功能，并且在脑脂质代谢中也起重要作用。为了回答这个问题，人类星形胶质细胞中脂质代谢与胰岛素作用之间是否存在联系，我们研究了人类星形胶质细胞中异位脂质的储存是否对这些细胞中的胰岛素信号传导有影响。在由脂肪酸和甘油三酸酯组成的脂质乳液的存在下培养人星形胶质细胞，以诱导异位脂质的储存。几天后，用胰岛素刺激细胞并进行基因表达谱分析。此外，评估了Akt的磷酸化以及糖原合成和细胞增殖。暴露于脂质后，在人星形胶质细胞中检测到异位脂质存储，并且即使从细胞培养基中除去脂肪乳剂，脂质存储仍持续存在。长期暴露于脂质会引起基因表达谱的深刻变化，其中一些基因在去除脂肪后显示出可逆的基因表达谱，而另一些则没有。这包括FOXO依赖性表达模式。此外，在脂质负载的星形胶质细胞中，胰岛素诱导的Akt磷酸化减少，并且胰岛素诱导的糖原合成和增殖也受到损害。慢性脂质暴露会在人星形胶质细胞中诱导脂质存储，并伴有胰岛素抵抗。基因表达模式的分析表明了部分可逆的基因表达谱的潜力。通过减少异位脂质负荷来靶向星形细胞胰岛素抵抗可能代表肥胖，糖尿病和神经变性中脑胰岛素抵抗的有希望的治疗目标。