Glucagon-Like Peptide-1-, but not Growth and Differentiation Factor 15-, Receptor Activation Increases the Number of Interleukin-6-Expressing Cells in the External Lateral Parabrachial Nucleus

2019 ◽  
Vol 109 (4) ◽  
pp. 310-321 ◽  
Author(s):  
Fredrik Anesten ◽  
Devesh Mishra ◽  
Adrià Dalmau Gasull ◽  
Linda Engström-Ruud ◽  
Jakob Bellman ◽  
...  
Keyword(s):  
Energy Balance ◽  
Mrna Level ◽  
Intraperitoneal Administration ◽  
Receptor Activation ◽  
Parabrachial Nucleus ◽  
Differentiation Factor ◽  
Lateral Parabrachial Nucleus ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Anorexigenic Peptide

Interleukin (IL)-6 in the hypothalamus and hindbrain is an important downstream mediator of suppression of body weight and food intake by glucagon-like peptide-1 (GLP-1) receptor stimulation. CNS GLP-1 is produced almost exclusively in prepro-glucagon neurons in the nucleus of the solitary tract. These neurons innervate energy balance-regulating areas, such as the external lateral parabrachial nucleus (PBNel); essential for induction of anorexia. Using a validated novel IL-6-reporter mouse strain, we investigated the interactions in PBNel between GLP-1, IL-6, and calcitonin gene-related peptide (CGRP, a well-known mediator of anorexia). We show that PBNel GLP-1R-containing cells highly (to about 80%) overlap with IL-6-containing cells on both protein and mRNA level. Intraperitoneal administration of a GLP-1 analogue exendin-4 to mice increased the proportion of IL-6-containing cells in PBNel 3-fold, while there was no effect in the rest of the lateral parabrachial nucleus. In contrast, injections of an anorexigenic peptide growth and differentiation factor 15 (GDF15) markedly increased the proportion of CGRP-containing cells, while IL-6-containing cells were not affected. In summary, GLP-1R are found on IL-6-producing cells in PBNel, and GLP-1R stimulation leads to an increase in the proportion of cells with IL-6-reporter fluorescence, supporting IL-6 mediation of GLP-1 effects on energy balance.

scholarly journals Residues within the Transmembrane Domain of the Glucagon-Like Peptide-1 Receptor Involved in Ligand Binding and Receptor Activation: Modelling the Ligand-Bound Receptor

2011 ◽  
Vol 25 (10) ◽  
pp. 1804-1818 ◽  
Author(s):  
K. Coopman ◽  
R. Wallis ◽  
G. Robb ◽  
A. J. H. Brown ◽  
G. F. Wilkinson ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Structural Model ◽  
Transmembrane Domain ◽  
Transmembrane Helix ◽  
Receptor Activation ◽  
Agonist Affinity ◽  
Camp Generation ◽  
N Terminus ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The C-terminal regions of glucagon-like peptide-1 (GLP-1) bind to the N terminus of the GLP-1 receptor (GLP-1R), facilitating interaction of the ligand N terminus with the receptor transmembrane domain. In contrast, the agonist exendin-4 relies less on the transmembrane domain, and truncated antagonist analogs (e.g. exendin 9–39) may interact solely with the receptor N terminus. Here we used mutagenesis to explore the role of residues highly conserved in the predicted transmembrane helices of mammalian GLP-1Rs and conserved in family B G protein coupled receptors in ligand binding and GLP-1R activation. By iteration using information from the mutagenesis, along with the available crystal structure of the receptor N terminus and a model of the active opsin transmembrane domain, we developed a structural receptor model with GLP-1 bound and used this to better understand consequences of mutations. Mutation at Y152 [transmembrane helix (TM) 1], R190 (TM2), Y235 (TM3), H363 (TM6), and E364 (TM6) produced similar reductions in affinity for GLP-1 and exendin 9–39. In contrast, other mutations either preferentially [K197 (TM2), Q234 (TM3), and W284 (extracellular loop 2)] or solely [D198 (TM2) and R310 (TM5)] reduced GLP-1 affinity. Reduced agonist affinity was always associated with reduced potency. However, reductions in potency exceeded reductions in agonist affinity for K197A, W284A, and R310A, while H363A was uncoupled from cAMP generation, highlighting critical roles of these residues in translating binding to activation. Data show important roles in ligand binding and receptor activation of conserved residues within the transmembrane domain of the GLP-1R. The receptor structural model provides insight into the roles of these residues.

scholarly journals GLP-1 Receptor Stimulation of the Lateral Parabrachial Nucleus Reduces Food Intake: Neuroanatomical, Electrophysiological, and Behavioral Evidence

Endocrinology ◽  
2014 ◽  
Vol 155 (11) ◽  
pp. 4356-4367 ◽  
Author(s):  
Jennifer E. Richard ◽  
Imre Farkas ◽  
Fredrik Anesten ◽  
Rozita H. Anderberg ◽  
Suzanne L. Dickson ◽  
...  
Keyword(s):  
Feeding Behavior ◽  
Fluorescent Protein ◽  
Yellow Fluorescent Protein ◽  
Parabrachial Nucleus ◽  
Lateral Parabrachial Nucleus ◽  
Electrophysiological Studies ◽  
Glucagon Like Peptide 1 ◽  
Behavioral Evidence ◽  
Stimulation Of

Abstract The parabrachial nucleus (PBN) is a key nucleus for the regulation of feeding behavior. Inhibitory inputs from the hypothalamus to the PBN play a crucial role in the normal maintenance of feeding behavior, because their loss leads to starvation. Viscerosensory stimuli result in neuronal activation of the PBN. However, the origin and neurochemical identity of the excitatory neuronal input to the PBN remain largely unexplored. Here, we hypothesize that hindbrain glucagon-like peptide 1 (GLP-1) neurons provide excitatory inputs to the PBN, activation of which may lead to a reduction in feeding behavior. Our data, obtained from mice expressing the yellow fluorescent protein in GLP-1-producing neurons, revealed that hindbrain GLP-1-producing neurons project to the lateral PBN (lPBN). Stimulation of lPBN GLP-1 receptors (GLP-1Rs) reduced the intake of chow and palatable food and decreased body weight in rats. It also activated lPBN neurons, reflected by an increase in the number of c-Fos-positive cells in this region. Further support for an excitatory role of GLP-1 in the PBN is provided by electrophysiological studies showing a remarkable increase in firing of lPBN neurons after Exendin-4 application. We show that within the PBN, GLP-1R activation increased gene expression of 2 energy balance regulating peptides, calcitonin gene-related peptide (CGRP) and IL-6. Moreover, nearly 70% of the lPBN GLP-1 fibers innervated lPBN CGRP neurons. Direct intra-lPBN CGRP application resulted in anorexia. Collectively, our molecular, anatomical, electrophysiological, pharmacological, and behavioral data provide evidence for a functional role of the GLP-1R for feeding control in the PBN.

Feeding and glucagon-like peptide-1 receptor activation stabilise β-catenin in specific hypothalamic nuclei in male rats

2018 ◽  
Vol 30 (6) ◽  
pp. e12607 ◽  
Author(s):  
H. J. L. McEwen ◽  
E. Cognard ◽  
S. R. Ladyman ◽  
Z. Khant-Aung ◽  
A. Tups ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Male Rats ◽  
Hypothalamic Nuclei ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Second Extracellular Loop of Human Glucagon-like Peptide-1 Receptor (GLP-1R) Has a Critical Role in GLP-1 Peptide Binding and Receptor Activation

2011 ◽  
Vol 287 (6) ◽  
pp. 3642-3658 ◽  
Author(s):  
Cassandra Koole ◽  
Denise Wootten ◽  
John Simms ◽  
Laurence J. Miller ◽  
Arthur Christopoulos ◽  
...  
Keyword(s):  
Critical Role ◽  
Peptide Binding ◽  
Receptor Activation ◽  
Extracellular Loop ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Basal Receptor Activation by Locally Produced Glucagon-Like Peptide-1 Contributes to Maintaining β-Cell Function

2005 ◽  
Vol 19 (5) ◽  
pp. 1373-1382 ◽  
Author(s):  
Kai Masur ◽  
Elmi C. Tibaduiza ◽  
Ci Chen ◽  
Brooke Ligon ◽  
Martin Beinborn
Keyword(s):  
Cell Function ◽  
Receptor Activation ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Glucagon-Like Peptide 1 Receptor Activation Attenuates Platelet Aggregation and Thrombosis

Diabetes ◽  
2016 ◽  
Vol 65 (6) ◽  
pp. 1714-1723 ◽  
Author(s):  
Alison Cameron-Vendrig ◽  
Adili Reheman ◽  
M. Ahsan Siraj ◽  
Xiaohong Ruby Xu ◽  
Yiming Wang ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Receptor Activation ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Evolutionarily Conserved Residues at Glucagon-like Peptide-1 (GLP-1) Receptor Core Confer Ligand-induced Receptor Activation

2011 ◽  
Vol 287 (6) ◽  
pp. 3873-3884 ◽  
Author(s):  
Mi Jin Moon ◽  
Hee Young Kim ◽  
Sumi Park ◽  
Dong-Kyu Kim ◽  
Eun Bee Cho ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Conserved Residues ◽  
Evolutionarily Conserved ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1
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