Exendin (5-39), an antagonist of GLP-1 receptor, modulates synaptic transmission via glutamate uptake in the dentate gyrus

Astrocytes Regulate GLP-1 Receptor-Mediated Effects on Energy Balance

“…Increased cAMP levels have been linked to reduced expression of glutamate transporters (Lim et al, 2005). Our data demonstrating that astrocytic GLP-1R activation elevates cAMP hints at the intriguing possibility that astrocytic glutamate transporters (e.g., GLT-1, GLAST) may be downregulated as a result of GLP-1R activation, providing a potential mechanism by which GLP-1R signaling in astrocytes could increase glutamate levels in the NTS synapse and consequently reduce food intake (Ritter, 2004;Hisadome et al, 2011;. GLP-1R activation also increases interleukin signaling (Shirazi et al, 2013).…”

“…Astrocytes play a critical role in regulating glutamatergic neurotransmission, yet are surprisingly understudied as potential mediators of energy balance-relevant signals. Given that the food intake-and body weight-suppressive effects of central GLP-1R signaling are mediated in part by presynaptic modulation of glutamate signaling (Hisadome et al, 2011;, it is intriguing to consider the idea that GLP-1Rs expressed on astrocytes may influence glutamate signaling to affect energy balance. We focused our attention on astrocytes in the NTS because of the critical role this nucleus serves in processing vagally mediated glutamatergic satiation signals (Grill and Hayes, 2012), as well as the endogenous relevance of NTS GLP-1R signaling for the control of feeding (Hayes et al, 2009).…”

“…Within the NTS, the incretin hormone glucagon-like peptide-1 (GLP-1) acts to control food intake and body weight . Produced peripherally by intestinal L cells and centrally by preproglucagon (PPG) neurons within the caudal NTS, GLP-1 and GLP-1 receptor (GLP-1R) agonists suppress food intake and body weight through direct GLP-1R signaling in the NTS, as well as through action in other distributed nuclei in the brain (McMahon and Wellman, 1998;Grill and Hayes, 2009;Dossat et al, 2011;Alhadeff et al, 2012;Secher et al, 2014;Hsu et al, 2015). However, the cellular and molecular mechanisms mediating the energy balance effects of GLP-1R activation remain largely underinvestigated.…”

“…In particular, several studies demonstrate a role for the ionotropic AMPA/kainate glutamate receptors (Hisadome et al, 2011;Mietlicki-Baase et al, 2014) as downstream mediators of the food intake-and body weight-suppressive effects of GLP-1R signaling within midbrain and forebrain nuclei. Importantly, these reports also indicate that the relevant GLP-1Rs are located presynaptically to AMPA/kainate receptors and can influence presynaptic glutamate release (Acuna-Goycolea and van den Pol, 2004;Amato et al, 2010;Hisadome et al, 2011;. However, to date, the ability of GLP-1R activation to affect energy balance via non-neuronal modulation of synaptic glutamatergic signaling has not been systematically evaluated.…”

“…Indeed, glutamate is predominately cleared from the synapse by the following two subtypes of astrocytic glutamate reuptake transporters: glutamate transporter-1 (GLT-1) and glutamate aspartate transporter (GLAST;Perego et al, 2000;Danbolt, 2001). Intriguingly, a small body of literature suggests that astrocytes within the CNS express the GLP-1R (Chowen et al, 1999;Iwai et al, 2006;Kobayashi et al, 2013), yet no studies have systemically examined its expression or behavioral relevance for energy balance control. As the NTS expresses GLP-1R (Hayes et al, 2010; and is the first central site to receive and process within-meal vagally mediated glutamatergic signals arising from the GI tract (Moran, 2006;Grill and Hayes, 2009), a combination of in vitro, ex vivo, and in vivo techniques was used to test the hypothesis that GLP-1R signaling in NTS astrocytes is functionally relevant for energy balance control.…”