Ghrelin Regulates Glucose and Glutamate Transporters in Hypothalamic Astrocytes.

Esther Fuente-Martín,Julie A Chowen,Miriam Granado,Suzanne L Dickson,María L Ceballos,Jesús Argente,Laura M Frago,Alejandra Freire-Regatillo,David Castro-González,Pilar Argente-Arizón,Francisca Díaz,Cristina García-Cáceres

doi:10.1038/srep23673

Abstract

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.

Highlights

The coordination of energy intake and expenditure is a complex process that is influenced by both peripheral and central signals that regulate body weight and glucose homeostasis
We have recently demonstrated that chronic intracerebroventricular administration of acyl-ghrelin to rats (i) decreases the astrocytic markers, glial fibrillary acidic protein (GFAP) and vimentin, in the hypothalamus; this occurs despite ghrelin’s effects to increase weight gain, and (ii) modulates cytokine production by astrocytes in vitro[10], suggesting a direct effect of this hormone on these glial cells
Glial cell function is substantially affected by metabolic status[4,5]; we investigated whether acyl-ghrelin, a metabolic hormone, plays a role in this phenomenon through modification of glucose and glutamate transporters highly expressed in astrocytes

Summary

Introduction

The coordination of energy intake and expenditure is a complex process that is influenced by both peripheral and central signals that regulate body weight and glucose homeostasis. Activation of hypothalamic microglia and astrocytes in response to high fat diet (HFD)-induced weight gain is accompanied by increased glial production of cytokines and activation of inflammatory signaling pathways in the hypothalamus[1,2,3,4,5,6] which is suggested to promote central insulin/leptin resistance and metabolic disequilibrium[7] This inflammatory process can be directly triggered by nutrients such as free fatty acids[8], while circulating metabolic factors such as the anti-obesity hormone, leptin, can activate glial cells[2,3,4,5,9]. What remains completely unexplored is whether ghrelin has an acute effect on hypothalamic astrocyte morphology and glucose/ glutamate transport

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Conclusion