Ghrelin Regulates Glucose and Glutamate Transporters in Hypothalamic Astrocytes

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.

Ghrelin Facilitates GLUT2-, SGLT1- and SGLT2-mediated Intestinal Glucose Transport in Goldfish (Carassius auratus)

“…To the best of our knowledge, no studies have previously reported a role for ghrelin in the modulation of glucose transporters in the intestine of any vertebrate. A role for ghrelin in this function has been shown, however, in other tissues, such as the hypothalamic astrocytes30, the white adipocytes31, and the cardiomyocytes32 of mammals, and the hypothalamus and hindbrain of fish34. Using both in vivo and in vitro approaches, here we demonstrated an important stimulatory role for ghrelin in the gene expression of the three transporters in the intestine of goldfish.…”

“…In terms of glucose transport, ghrelin has been reported to reduce both GLUT2 levels and the glucose uptake in primary astrocytes from rat hypothalamus30, to increase insulin-induced glucose uptake in isolated rat white adipocytes31, and to enhance GLUT4 mRNA expression in rat cultured myocytes32. In fish, the involvement of ghrelin in the regulation of glucose metabolism has been less explored, but it is suggested that this peptide regulates carbohydrate metabolism via insulin inhibition and glucagon stimulation in zebrafish33.…”

Glia: silent partners in energy homeostasis and obesity pathogenesis

“…Accordingly, deletion of the leptin receptor in astrocytes results in remodelling of the hypothalamic neuronal circuitry and diminished leptin-induced anorexia [67–70], highlighting how interactions between the glial and neuronal network may affect the response to satiety cues. Other hormonal signals such as ghrelin and GLP-1 can also activate astrocytes, but more work is needed to firmly establish the in vivo significance of these findings [71, 72]. Finally, using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), a pharmacogenetic approach to modulate the activity of specific cells, Yang et al demonstrated that hypothalamic astrocytes suppress food intake via adenosine-mediated inhibition of the orexigenic Agouti-regulated protein (AgRP) neurons (Fig.…”

Astrocyte IKKβ/NF-κB signaling is required for diet-induced obesity and hypothalamic inflammation

“…Thus, astrocytes have the potential to impact energy homeostasis regulation in health and disease. Indeed, MBH astrocytes modulate feeding behavior when pharmacologically activated [23], [24] and show dynamic responses to circulating signals of nutrient availability such as insulin and leptin [25], [26], [27], [28]. In addition, MBH astrocytes become activated with obesity and HFD feeding in rodents and humans [10], [29], raising the possibility that astrocyte inflammation disrupts hypothalamic regulation of energy balance and promotes DIO.…”