Glucagon-like peptide-1 of brainstem origin activates dorsomedial hypothalamic neurons in satiated rats

Renner, Éva; Puškaš, Nela; Dobolyi, Árpád; Palkovits, Miklós

doi:10.1016/j.peptides.2012.02.018

Cited by 37 publications

(33 citation statements)

References 67 publications

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“…GLP-1-IR fibers contacted subset of GnRH neurons in mouse samples showing the assumed role of brain-born GLP-1. Various hypothalamic loci are innervated by GLP-1-containing fibers (Renner et al, 2012; Katsurada et al, 2014) originating from the NST. In this view, it is not surprising that areas where GnRH neurons reside are also innervated by GLP-1-IR axons.…”

Section: Discussionmentioning

confidence: 99%

Glucagon-Like Peptide-1 Excites Firing and Increases GABAergic Miniature Postsynaptic Currents (mPSCs) in Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mice via Activation of Nitric Oxide (NO) and Suppression of Endocannabinoid Signaling Pathways

Farkas

Vastagh

Farkas

et al. 2016

Front. Cell. Neurosci.

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Glucagon-like peptide-1 (GLP-1), a metabolic signal molecule, regulates reproduction, although, the involved molecular mechanisms have not been elucidated, yet. Therefore, responsiveness of gonadotropin-releasing hormone (GnRH) neurons to the GLP-1 analog Exendin-4 and elucidation of molecular pathways acting downstream to the GLP-1 receptor (GLP-1R) have been challenged. Loose patch-clamp recordings revealed that Exendin-4 (100 nM–5 μM) elevated firing rate in hypothalamic GnRH-GFP neurons of male mice via activation of GLP-1R. Whole-cell patch-clamp measurements demonstrated increased excitatory GABAergic miniature postsynaptic currents (mPSCs) frequency after Exendin-4 administration, which was eliminated by the GLP-1R antagonist Exendin-3(9–39) (1 μM). Intracellular application of the G-protein inhibitor GDP-β-S (2 mM) impeded action of Exendin-4 on mPSCs, suggesting direct excitatory action of GLP-1 on GnRH neurons. Blockade of nitric-oxide (NO) synthesis by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME; 100 μM) or N5-[Imino(propylamino)methyl]-L-ornithine hydrochloride (NPLA; 1 μM) or intracellular scavenging of NO by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (CPTIO; 1 mM) partially attenuated the excitatory effect of Exendin-4. Similar partial inhibition was achieved by hindering endocannabinoid pathway using cannabinoid receptor type-1 (CB1) inverse-agonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl) pyrazole-3-carboxamide (AM251; 1 μM). Simultaneous blockade of NO and endocannabinoid signaling mechanisms eliminated action of Exendin-4 suggesting involvement of both retrograde machineries. Intracellular application of the transient receptor potential vanilloid 1 (TRPV1)-antagonist 2E-N-(2, 3-Dihydro-1,4-benzodioxin-6-yl)-3-[4-(1, 1-dimethylethyl)phenyl]-2-Propenamide (AMG9810; 10 μM) or the fatty acid amide hydrolase (FAAH)-inhibitor PF3845 (5 μM) impeded the GLP-1-triggered endocannabinoid pathway indicating an anandamide-TRPV1-sensitive control of 2-arachidonoylglycerol (2-AG) production. Furthermore, GLP-1 immunoreactive (IR) axons innervated GnRH neurons in the hypothalamus suggesting that GLP-1 of both peripheral and neuronal sources can modulate GnRH neurons. RT-qPCR study confirmed the expression of GLP-1R and neuronal NO synthase (nNOS) mRNAs in GnRH-GFP neurons. Immuno-electron microscopic analysis revealed the presence of nNOS protein in GnRH neurons. These results indicate that GLP-1 exerts direct facilitatory actions via GLP-1R on GnRH neurons and modulates NO and 2-AG retrograde signaling mechanisms that control the presynaptic excitatory GABAergic inputs to GnRH neurons.

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Section: Discussionmentioning

confidence: 99%

Glucagon-Like Peptide-1 Excites Firing and Increases GABAergic Miniature Postsynaptic Currents (mPSCs) in Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mice via Activation of Nitric Oxide (NO) and Suppression of Endocannabinoid Signaling Pathways

Farkas

Vastagh

Farkas

et al. 2016

Front. Cell. Neurosci.

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“…Meanwhile, the intracerebroventricular administration of GLP-1 results in a broad increase in the c-fos expression in the paraventricular nucleus, nucleus of the tractus solitaries and area postrema (25), resulting in a reduced caloric intake and weight loss in rodents (14,26,27). Although the precise role of GLP-1 neurons in the CNS has not been identified, it was recently demonstrated that GLP-1 neurons in the nucleus of the solitary tract process a satiety signal from an afferent input to the hypothalamus in rats (28), suggesting the anorexic properties of central GLP-1 signaling.…”

Section: Discussionmentioning

confidence: 99%

Liraglutide as a Potentially Useful Agent for Regulating Appetite in Diabetic Patients with Hypothalamic Hyperphagia and Obesity

et al. 2014

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Hypothalamic hyperphagia and obesity are characterized by a lack of satiety and an abnormally high appetite that is difficult to control. We herein report the cases of two patients with hypothalamic hyperphagia and obesity with MRI-detectable hypothalamic lesions. These patients suffered from diabetes mellitus associated with an abnormal eating behavior and weight gain. Liraglutide was successfully used to treat their diabetes mellitus and suppress their abnormal appetites. Glucagon-like peptide-1 analogues, including liraglutide, are promising treatment options in patients with hypothalamic hyperphagia and obesity, as these agents enhance the hypothalamic input of the satiety signal, which is lacking in such patients.

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“…SYSTEMS and nucleus accumbens, are thought to be involved in regulation of feeding and metabolism (Vrang et al, 2007;Alhadeff et al, 2012;Renner et al, 2010Renner et al, , 2012. This putative role is underscored by the expression of leptin receptors by many neurons in this same caudal area of the NTS Hayes, 2009, 2012;Rinaman, 2010;Ritter et al, 2011).…”

Section: Nucleus Of the Solitary Tract And Area Postremamentioning

confidence: 99%

Central Autonomic System

Saper

Stornetta

2015

The Rat Nervous System

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Glucagon-like peptide-1 of brainstem origin activates dorsomedial hypothalamic neurons in satiated rats

Cited by 37 publications

References 67 publications

Glucagon-Like Peptide-1 Excites Firing and Increases GABAergic Miniature Postsynaptic Currents (mPSCs) in Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mice via Activation of Nitric Oxide (NO) and Suppression of Endocannabinoid Signaling Pathways

Glucagon-Like Peptide-1 Excites Firing and Increases GABAergic Miniature Postsynaptic Currents (mPSCs) in Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mice via Activation of Nitric Oxide (NO) and Suppression of Endocannabinoid Signaling Pathways

Liraglutide as a Potentially Useful Agent for Regulating Appetite in Diabetic Patients with Hypothalamic Hyperphagia and Obesity

Central Autonomic System

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