Differential effects of GH and GH-releasing peptide-6 on astrocytes

Abstract

GH and GH secretagogues (GHSs) are involved in many cellular activities such as stimulation of mitosis, proliferation and differentiation. As astrocytes are involved in developmental and protective functions, our aim was to analyse the effects of GH and GH-releasing hexapeptide on astrocyte proliferation and differentiation in the hypothalamus and hippocampus. Treatment of adult male Wistar rats with GH (i.v., 100 mg/day) for 1 week increased the levels of glial fibrillary acidic protein (GFAP) and decreased the levels of vimentin in the hypothalamus and hippocampus. These changes were not accompanied by increased proliferation. By contrast, GH-releasing hexapeptide (i.v., 150 mg/day) did not affect GFAP levels but increased proliferation in the areas studied. To further study the intracellular mechanisms involved in these effects, we treated C6 astrocytoma cells with GH or GH-releasing hexapeptide and the phosphatidylinositol 3 0 -kinase (PI3K) inhibitor, LY294002, and observed that the presence of this inhibitor reverted the increase in GFAP levels induced by GH and the proliferation induced by GH-releasing hexapeptide. We conclude that although GH-releasing hexapeptide is a GHS, it may exert GH-independent effects centrally on astrocytes when administered i.v., although the effects of both substances appear to be mediated by the PI3K/Akt pathway.

Glial cells and energy balance

“…In addition to aiding in glucose and lipid sensing (Leloup et al 2016), astrocytes express receptors for and respond to hormones implicated in the control of food R61 Review p argente-arizón and others Glial cells and energy balance intake, such as leptin, ghrelin and insulin (Diano et al 1998a, Hsuchou et al 2009, Baquedano et al 2013. They are the only cells within the CNS able to beta-oxidize fatty acids (FAs) for the production of ketone bodies, which signals to the surrounding neurons.…”

“…Yang and coworkers suggest that glial cells alter feeding by modulating extracellular levels of adenosine, which affects the firing rate of AgRP neurons (Yang et al 2015). Ghrelin can also act directly on hypothalamic astrocytes, as not only do they express receptors for this orexigenic hormone (Baquedano et al 2013, Fuente-Martin et al 2016, but in vitro studies show that ghrelin modifies the ability of astrocytes to transport glutamate and glucose, as well as their expression of glutamine synthetase, lactate dehydrogenase, glycogen phosphorylase and lactate transporters (Fuente-Martin et al 2016). These observations suggest a possible direct effect of ghrelin on glutamate and carbohydrate metabolism by astrocytes.…”

“…However, hypothalamic glial cells not only participate in pathological events, such as the inflammatory response that occurs as a consequence of HFD consumption (Milanski et al 2009, Thaler et al 2012, Buckman et al 2014, Valdearcos et al 2014, Yan et al 2014), but they are also intricately involve in the physiological control of the surrounding neurons, including those dictating energy balance. The importance of this relationship is even further emphasized by the fact that these glial cells express receptors and systems of transport for numerous metabolic hormones and factors (Boyles et al 1985, Vielkind et al 1990, Zhu et al 1990, Vannucci et al 1997, Marty et al 2005, Pan et al 2008, Hsuchou et al 2009, Baquedano et al 2013, suggesting that at least part of the central effects of these metabolic signals are mediated through these non-neuronal cells. Thus, a deeper understanding of glial cell function will allow both a better understanding of their role in normal brain physiology, as well as their participation in pathological processes, and hopefully lead to the identification of new therapeutic targets for obesity treatment.…”

Involvement of Astrocytes in Mediating the Central Effects of Ghrelin

“…In addition to its expression in neurons, GHSR1a has been shown to be expressed in astrocytes of the hypothalamic arcuate nucleus [19,20] and of the dentate gyrus in the hippocampus [18,91], although a thorough mapping of the expression of this receptor in astrocytes is yet to be performed.…”

“…Indeed, these glial cells express receptors for numerous trophic factors and hormones, participating in and mediating the effects of these signals on the surrounding neurons. Astrocytes express the ghrelin receptor and respond to this hormone and its analogs [18,19,20], although there is little information to date regarding the physiological and/or pathophysiological function of these receptors in astrocytes. Here we have reviewed what is known to date regarding the response of astrocytes to ghrelin and how these glial cells might participate in mediating the effects of this hormone on appetite and neuroprotection.…”