GLP-1 increases Kiss-1 mRNA expression in kisspeptin-expressing neuronal cells†

Abstract

Feeding-related metabolic factors exert regulatory influences on the hypothalamic-pituitary-gonadal axis. Glucagon-like peptide-1 (GLP-1) is an anorexigenic hormone synthesized from the ileum in response to food intake. The purpose of this study was to examine the direct effect of GLP-1 on hypothalamic kisspeptin and gonadotropin-releasing hormone (GnRH) expression using the rat clonal hypothalamic cell line rHypoE-8. GLP-1 significantly increased Kiss-1 mRNA expression in rHypoE-8 cells up to 1.94 ± 0.22-fold. This effect of GLP-1 on Kiss-1 gene expression was also observed in GT1-7 GnRH-producing neurons and in primary cultures of fetal rat brain. GLP-1 increased cAMP-mediated signaling, as determined by cAMP response element activity assays, but failed to activate extracellular signal-regulated kinase pathways. Another anorexigenic factor, leptin, similarly increased Kiss-1 mRNA levels up to 1.34 ± 0.08-fold in rHypoE-8 cells. However, combined treatment with GLP-1 and leptin failed to potentiate their individual effects on Kiss-1 mRNA expression. Gnrh mRNA expression was not significantly increased by GLP-1 stimulation in rHypoE-8, but kisspeptin significantly stimulated the expression of Gnrh mRNA in these cells. Our current observations suggest that the anorexigenic peptide GLP-1 directly regulates Kiss-1 mRNA expression in these hypothalamic cell lines and in neuronal cells of fetal rat brain and affects the expression of Gnrh mRNA.

Networking of glucagon-like peptide-1 axons with GnRH neurons in the basal forebrain of male mice revealed by 3DISCO-based immunocytochemistry and optogenetics

“…Earlier studies have shown that GLP-1 can control the HPG axis centrally via interaction with the GnRH system (Beak et al 1998;Farkas et al 2016). Furthermore, its key regulator, the hypothalamic kisspeptin neuron circuit is also influenced by GLP-1 (Oride et al 2017;Heppner et al 2017). In the present study, we have provided compelling evidence for the modulatory role of the brain-derived GLP-1 upon GnRH neurons.…”

The effects of kisspeptin on β‐cell function, serum metabolites and appetite in humans

“…33 The gut hormones, GLP-1, PYY and glucagon have key roles in glucose homeostasis. Additionally, in rodent studies, GLP-1 has been shown to alter hypothalamic kisspeptin expression and neuronal activity, 42,43 and in mice glucagon stimulates hepatic kisspeptin production to alter GSIS. 13 In our study, there was no difference in circulating GLP-1, PYY or glucagon levels following intravenous glucose during kisspeptin administration compared to vehicle ( Figure S1C-E).…”

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

“…The GLP-1R-immunoreactive areas were ranked into four categories based on the density of immunoreactive fibers from "+", meaning low level to "++++" meaning "very high" level, and based on the density of immunoreactive perikarya from *meaning low to ***meaning high level The presence of GLP-1R on axon terminals suggests that GLP-1 signaling may regulate the activity of presynaptic terminals and may modulate both GABA and glutamate release. Since the elevation of intracellular cAMP level is one of the main mediators of GLP-1R signaling (Rowlands et al 2018;Kawatani et al 2018;Oride et al 2017), and cAMP is known to increase the release probability in presynaptic terminals (Chen and Regehr 1997), it is likely that GLP-1 and/or GLP-1 agonists increase the activity of the GLP-1R-containing presynaptic terminals. This hypothesis is supported by the findings of Rebosio et al (2018) demonstrating that the GLP-1 agonist exendin-4 increases the GABA and aspartate release from hippocampal synaptosomal preparations, and also by our observation demonstrating facilitation of the synaptic input of POMC neurons by GLP-1 signaling (Péterfi 2020).…”