Fuente-Martín Esther, García-Cáceres Cristina, Argente-Arizón Pilar, Díaz Francisca, Granado Miriam, Freire-Regatillo Alejandra, Castro-González David, Ceballos María L, Frago Laura M, Dickson Suzanne L, Argente Jesús, Chowen Julie A
Hospital Infantil Universitario Niño Jesús, Department of Endocrinology, Instituto de Investigación La Princesa, University Autónoma of Madrid and Centro de Investigación Biomédica en Red (CIBER) de la Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain.
Instituto Cajal, Dept. of Cellular, Molecular and Developmental Neurobiology, and CIBERNED, CSIC, Madrid, Spain.
Sci Rep. 2016 Mar 30;6:23673. doi: 10.1038/srep23673.
Hypothalamic astrocytes can respond to metabolic signals, such as leptin and insulin, to modulate adjacent neuronal circuits and systemic metabolism. Ghrelin regulates appetite, adiposity and glucose metabolism, but little is known regarding the response of astrocytes to this orexigenic hormone. We have used both in vivo and in vitro approaches to demonstrate that acylated ghrelin (acyl-ghrelin) rapidly stimulates glutamate transporter expression and glutamate uptake by astrocytes. Moreover, acyl-ghrelin rapidly reduces glucose transporter (GLUT) 2 levels and glucose uptake by these glial cells. Glutamine synthetase and lactate dehydrogenase decrease, while glycogen phosphorylase and lactate transporters increase in response to acyl-ghrelin, suggesting a change in glutamate and glucose metabolism, as well as glycogen storage by astrocytes. These effects are partially mediated through ghrelin receptor 1A (GHSR-1A) as astrocytes do not respond equally to desacyl-ghrelin, an isoform that does not activate GHSR-1A. Moreover, primary astrocyte cultures from GHSR-1A knock-out mice do not change glutamate transporter or GLUT2 levels in response to acyl-ghrelin. Our results indicate that acyl-ghrelin may mediate part of its metabolic actions through modulation of hypothalamic astrocytes and that this effect could involve astrocyte mediated changes in local glucose and glutamate metabolism that alter the signals/nutrients reaching neighboring neurons.
下丘脑星形胶质细胞能够对代谢信号作出反应，如瘦素和胰岛素，从而调节相邻的神经回路和全身代谢。胃饥饿素调节食欲、肥胖和葡萄糖代谢，但关于星形胶质细胞对这种促食欲激素的反应却知之甚少。我们使用体内和体外方法均证明，酰化胃饥饿素（acyl-ghrelin）能迅速刺激星形胶质细胞中谷氨酸转运体的表达并促进其对谷氨酸的摄取。此外，酰化胃饥饿素能迅速降低这些神经胶质细胞中葡萄糖转运体2（GLUT2）的水平以及葡萄糖摄取量。谷氨酰胺合成酶和乳酸脱氢酶减少，而糖原磷酸化酶和乳酸转运体则因酰化胃饥饿素而增加，这表明星形胶质细胞的谷氨酸和葡萄糖代谢以及糖原储存发生了变化。这些效应部分是通过胃饥饿素受体1A（GHSR-1A）介导的，因为星形胶质细胞对去酰化胃饥饿素（一种不激活GHSR-1A的异构体）的反应并不相同。此外，来自GHSR-1A基因敲除小鼠的原代星形胶质细胞培养物对酰化胃饥饿素不发生谷氨酸转运体或GLUT2水平的变化。我们的结果表明，酰化胃饥饿素可能通过调节下丘脑星形胶质细胞来介导其部分代谢作用，并且这种效应可能涉及星形胶质细胞介导的局部葡萄糖和谷氨酸代谢变化，从而改变到达相邻神经元的信号/营养物质。
