Distribution and ultrastructural localization of the glucagon-like peptide-1 receptor (GLP-1R) in the rat brain

Farkas, Erzsébet; Szilvásy‐Szabó, Anett; Ruska, Yvette; Sinkó, Richárd; Rasch, Morten Grønbech; Egebjerg, Thomas; Pyke, Charles; Gereben, Balázs; Knudsen, Lotte Bjerre; Fekete, Csaba

doi:10.1007/s00429-020-02189-1

Cited by 34 publications

(36 citation statements)

References 37 publications

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“…Other studies also indicated that GLP-1 directly stimulates the activity of POMC neurons [13]. As our recent ultrastructural studies [14] demonstrated that GLP-1R is present not only on the perikarya but also in a high number of axon terminals in the ARC, we raised the possibility that in addition to its direct effect on the POMC neurons, GLP-1 may also influence the POMC neurons indirectly by modulating the activity of the GLP-1-sensitive presynaptic terminals. To test this hypothesis, we performed ultrastructural studies to determine the relationship of the POMC neurons and the GLP-1R-IR structures and examined the effect of GLP-1 signaling on the inputs of the POMC neurons.…”

Section: Introductionmentioning

confidence: 76%

Glucagon-Like Peptide-1 Regulates the Proopiomelanocortin Neurons of the Arcuate Nucleus both Directly and Indirectly via Presynaptic Action

et al. 2020

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GLP-1 exerts its anorexigenic effect at least partly via the POMC neurons of the arcuate nucleus (ARC). These neurons are known to express GLP-1 receptor (GLP-1R). To determine whether in addition to its direct effect, GLP-1 also modulates, how neuronal inputs can regulate the POMC neurons by acting on presynaptic terminals, ultrastructural and electrophysiological studies were performed on tissues of adult male mice. GLP-1R-immunoreactivity was associated with the cell membrane of POMC neurons and with axon terminals forming synapses on these cells. The GLP-1 analog Exendin 4 (Ex4) markedly increased the firing rate of all examined POMC neurons and depolarized these cells. These effects of Ex4 were prevented by intracellular administration of the G-protein blocker GDP-β-S. Ex4 also influenced the miniature and evoked postsynaptic currents (PSCs) of POMC neurons. Ex4 increased the frequency of miniature excitatory PSCs and the amplitude of the evoked excitatory PSCs in half of the POMC neurons. Ex4 increased the frequency of miniature inhibitory PSCs and the amplitudes of the evoked inhibitory PSCs in one-third of neurons. These effects of Ex4 were not influenced by intracellular GDP-β-S, indicating that GLP-1-signaling directly stimulates a population of axon terminals innervating the POMC neurons. The different Ex4 responsiveness of their mPSCs indicates the heterogeneity of the POMC neurons of the ARC. In summary, our data demonstrate that in addition to its direct excitatory effect on the POMC neurons, GLP-1-signaling also facilitates the presynaptic input of these cells by acting on presynaptically localized GLP-1R.

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Section: Introductionmentioning

confidence: 76%

Glucagon-Like Peptide-1 Regulates the Proopiomelanocortin Neurons of the Arcuate Nucleus both Directly and Indirectly via Presynaptic Action

et al. 2020

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“…In the current study, we observed the following new findings. Previous studies have found that GLP-1Rs are expressed in various tissues, including the pancreatic islets, brain, dorsal root ganglia, and spinal cord [20,[40][41][42][43]. Regarding the cellular localization of GLP-1R in the CNS, there are controversial findings.…”

Section: Discussionmentioning

confidence: 99%

Activation of microglial GLP-1R in the trigeminal nucleus caudalis suppresses central sensitization of chronic migraine after recurrent nitroglycerin stimulation

Feng

Zhang²,

Wang³

et al. 2021

J Headache Pain

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Background Central sensitization is considered a critical pathogenic mechanism of chronic migraine (CM). Activation of microglia in the trigeminal nucleus caudalis (TNC) contributes to this progression. Microglial glucagon-like peptide-1 receptor (GLP-1R) activation can alleviate pain; however, whether it is involved in the mechanism of CM has not been determined. Thus, this study aims to investigate the precise role of GLP-1R in the central sensitization of CM. Methods Repeated nitroglycerin injection-treated mice were used as a CM animal model in the experiment. To identify the distribution and cell localization of GLP-1R in the TNC, we performed immunofluorescence staining. Changes in the expression of GLP-1R, Iba-1, PI3K and p-Akt in the TNC were examined by western blotting. To confirm the effect of GLP-1R and PI3K/Akt in CM, a GLP-1R selective agonist (liraglutide) and antagonist (exendin(9–39)) and a PI3K selective antagonist (LY294002) were administered. Mechanical hypersensitivity was measured through von Frey filaments. To investigate the role of GLP-1R in central sensitization, calcitonin gene-related peptide (CGRP) and c-fos were determined using western blotting and immunofluorescence. To determine the changes in microglial activation, IL-1β and TNF-α were examined by western blotting, and the number and morphology of microglia were measured by immunofluorescence. We also confirmed the effect of GLP-1R on microglial activation in lipopolysaccharide-treated BV-2 microglia. Results The protein expression of GLP-1R was increased in the TNC after nitroglycerin injection. GLP-1R was colocalized with microglia and astrocytes in the TNC and was fully expressed in BV-2 microglia. The GLP-1R agonist liraglutide alleviated basal allodynia and suppressed the upregulation of CGRP, c-fos and PI3K/p-Akt in the TNC. Similarly, the PI3K inhibitor LY294002 prevented nitroglycerin-induced hyperalgesia. In addition, activating GLP-1R reduced Iba-1, IL-1β and TNF-α release and inhibited TNC microglial number and morphological changes (process retraction) following nitroglycerin administration. In vitro, the protein levels of IL-1β and TNF-α in lipopolysaccharide-stimulated BV-2 microglia were also decreased by liraglutide. Conclusions These findings suggest that microglial GLP-1R activation in the TNC may suppress the central sensitization of CM by regulating TNC microglial activation via the PI3K/Akt pathway.

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“…In a very recent study by Farkas et al, 2020, localization of GLP-1R protein was determined in rat's brain. Immunoreactivity was seen in the circumventricular organs and areas around the arcuate nucleus and nucleus tractus solitarii (Farkas et al, 2020). Moreover, neuronal profiles of GLP-1R were distinguished in telencephalon, diencephalon, brainstem and cerebellum.…”

Section: Introductionmentioning

confidence: 97%

Investigating the Glucagon-like Peptide-1 and Its Receptor in Human Brain: Distribution of Expression, Functional Implications, Age-related Changes and Species Specific Characteristics

Gupta

Kaur

Shekhawat

et al. 2023

BCN

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Emerging evidence has shown that the Glucagon like peptide-1 (GLP-1) agonist can be used for treating Alzheimer’s disease, but knowledge of its neural targets is limited. To understand the neural substrates of GLP-1, we have done whole brain mapping for GLP-1 and its receptor (GLP-1R), in 30 human brains. GLP-1 expression was studied by immuno-histochemistry and confirmed by western blot method. GLP-1R gene expression was studied by RT-PCR. GLP-1 expression was seen in most of the cortical areas (maximum in frontal, prefrontal & parietal cortex), diencephalon and brainstem, but not in cerebellum. Protein expression studies validated these results. Highest expression of GLP-1R was found in the frontal cortex. The orbito-frontal cortex and cerebellum had negligible expression. Hippocampus demonstrated significant presence of GLP-1R but patchy immunoreactivity to GLP-1. GLP-1R presence in most of the human cortical regions and absence in cerebellum is the major deviation from the animal brain. Sites which might be of interest in Alzheimer’s have been identified. GLP-1 demonstrated age related decline in most of the areas after 5thdecade. At 60yrs GLP-1 was not found in any of the cortical areas except in the prefrontal cortex but it was present in the sub-cortical areas. Age related profiling of GLP-1 in various brain areas has been analysed, which can have important bearing on understanding the Alzheimer’s. This study provides detailed description of GLP-1 and GLP-1R locations by complete human brain mapping for the first time and may lead to novel treatment options targeting the GLP-1 receptors.

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Distribution and ultrastructural localization of the glucagon-like peptide-1 receptor (GLP-1R) in the rat brain

Cited by 34 publications

References 37 publications

Glucagon-Like Peptide-1 Regulates the Proopiomelanocortin Neurons of the Arcuate Nucleus both Directly and Indirectly via Presynaptic Action

Glucagon-Like Peptide-1 Regulates the Proopiomelanocortin Neurons of the Arcuate Nucleus both Directly and Indirectly via Presynaptic Action

Activation of microglial GLP-1R in the trigeminal nucleus caudalis suppresses central sensitization of chronic migraine after recurrent nitroglycerin stimulation

Investigating the Glucagon-like Peptide-1 and Its Receptor in Human Brain: Distribution of Expression, Functional Implications, Age-related Changes and Species Specific Characteristics

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