Abstract
Glucagon-like peptide-1 (GLP-1) exerts its anorexigenic effect at least partly via the proopiomelanocortin (POMC) neurons of the arcuate (ARC) nucleus. These neurons are known to express GLP-1 receptor (GLP-1R). The aim of the study was 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 guanosine 5′-[β-thio]diphosphate trilithium salt (GDP-β-S). Ex4 also influenced the miniature postsynaptic currents (mPSCs) and evoked PSCs of POMC neurons. Ex4 increased the frequency of miniature excitatory PSCs (EPSCs) and the amplitude of the evoked EPSCs in half of the POMC neurons. Ex4 increased the frequency of miniature inhibitory PSCs (IPSCs) and the amplitudes of the evoked IPSCs 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.
Journal Section:
Editor's choice
References
1.
Baggio
LL
, Drucker
DJ
. Biology of incretins: GLP-1 and GIP
. Gastroenterology
. 2007 May
;132
(6
):2131
–57
.http://dx.doi.org/10.1053/j.gastro.2007.03.054.2.
Holst
JJ
. The physiology of glucagon-like peptide 1
. Physiol Rev
. 2007 Oct
;87
(4
):1409
–39
.3.
Llewellyn-Smith
IJ
, Reimann
F
, Gribble
FM
, Trapp
S
. Preproglucagon neurons project widely to autonomic control areas in the mouse brain
. Neuroscience
. 2011 Apr 28
;180
:111
–21
.4.
Nadkarni
P
, Chepurny
OG
, Holz
GG
. Regulation of glucose homeostasis by GLP-1
. Prog Mol Biol Transl Sci
. 2014
;121
:23
–65
.5.
NamKoong
C
, Kim
MS
, Jang
BT
, Lee
YH
, Cho
YM
, Choi
HJ
. Central administration of GLP-1 and GIP decreases feeding in mice
. Biochem Biophys Res Commun
. 2017 Aug 19
;490
(2
):247
–52
.6.
Drucker
DJ
. Biologic actions and therapeutic potential of the proglucagon-derived peptides
. Nat Clin Pract Endocrinol Metab
. 2005 Nov
;1
(1
):22
–31
.7.
Yang
Y
, Moghadam
AA
, Cordner
ZA
, Liang
NC
, Moran
TH
. Long term exendin-4 treatment reduces food intake and body weight and alters expression of brain homeostatic and reward markers
. Endocrinology
. 2014 Sep
;155
(9
):3473
–83
.8.
Muller
TD
, Finan
B
, Bloom
SR
, D’Alessio
D
, Drucker
DJ
, Flatt
PR
, . Glucagon-like peptide 1 (GLP-1)
. Mol Metab
. 2019 Dec
;30
:72
–130
.9.
Schwartz
MW
, Woods
SC
, Porte
D
Jr, Seeley
RJ
, Baskin
DG
. Central nervous system control of food intake
. Nature
. 2000 Apr 6
;404
(6778
):661
–71
.10.
Gropp
E
, Shanabrough
M
, Borok
E
, Xu
AW
, Janoschek
R
, Buch
T
, . Agouti-related peptide-expressing neurons are mandatory for feeding
. Nat Neurosci
. 2005 Oct
;8
(10
):1289
–91
.11.
Secher
A
, Jelsing
J
, Baquero
AF
, Hecksher-Sørensen
J
, Cowley
MA
, Dalbøge
LS
, . The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss
. J Clin Invest
. 2014 Oct
;124
(10
):4473
–88
.12.
Knudsen
LB
, Secher
A
, Hecksher-Sørensen
J
, Pyke
C
. Long-acting glucagon-like peptide-1 receptor agonists have direct access to and effects on pro-opiomelanocortin/cocaine- and amphetamine-stimulated transcript neurons in the mouse hypothalamus
. J Diabetes Investig
. 2016 Apr
;7
(Suppl 1
):56
–63
.13.
He
Z
, Gao
Y
, Lieu
L
, Afrin
S
, Cao
J
, Michael
NJ
, . Direct and indirect effects of liraglutide on hypothalamic POMC and NPY/AgRP neurons: implications for energy balance and glucose control
. Mol Metab
. 2019 Oct
;28
:120
–34
.14.
Farkas
E
, Szilvásy-Szabó
A
, Ruska
Y
, Sinkó
R
, Rasch
MG
, Egebjerg
T
, . Distribution and ultrastructural localization of the glucagon-like peptide-1 receptor (GLP-1R) in the rat brain
. Brain Stuct Funct
. 2021
. https://rdcu.be/ccw7Q. In press
.15.
McHugh
TJ
, Jones
MW
, Quinn
JJ
, Balthasar
N
, Coppari
R
, Elmquist
JK
, . Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network
. Science
. 2007 Jul 6
;317
(5834
):94
–9
.16.
Madisen
L
, Zwingman
TA
, Sunkin
SM
, Oh
SW
, Zariwala
HA
, Gu
H
, . A robust and high-throughput Cre reporting and characterization system for the whole mouse brain
. Nat Neurosci
. 2010 Jan
;13
(1
):133
–40
.17.
Varga
E
, Farkas
E
, Zséli
G
, Kádár
A
, Venczel
A
, Kővári
D
, . Thyrotropin-releasing-hormone-synthesizing neurons of the hypothalamic paraventricular nucleus are inhibited by glycinergic inputs
. Thyroid
. 2019 Dec
;29
(12
):1858
–68
.18.
Jensen
CB
, Pyke
C
, Rasch
MG
, Dahl
AB
, Knudsen
LB
, Secher
A
. Characterization of the glucagonlike peptide-1 receptor in male mouse brain using a novel antibody and in situ hybridization
. Endocrinology
. 2018 Feb 1
;159
(2
):665
–75
.19.
Padilla
SL
, Carmody
JS
, Zeltser
LM
. Pomc-expressing progenitors give rise to antagonistic neuronal populations in hypothalamic feeding circuits
. Nat Med
. 2010 Apr
;16
(4
):403
–5
.20.
McDermott
CM
, Schrader
LA
. Activation of κ opioid receptors increases intrinsic excitability of dentate gyrus granule cells
. J Physiol
. 2011 Jul 15
;589
(Pt 14
):3517
–32
.21.
Sandoval
DA
, Bagnol
D
, Woods
SC
, D’Alessio
DA
, Seeley
RJ
. Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake
. Diabetes
. 2008 Aug
;57
(8
):2046
–54
.22.
Harris
KM
, Weinberg
RJ
. Ultrastructure of synapses in the mammalian brain
. Cold Spring Harb Perspect Biol
. 2012 May 1
;4
(5
):a005587
.23.
Ronnekleiv
OK
, Fang
Y
, Zhang
C
, Nestor
CC
, Mao
P
, Kelly
MJ
. Research resource: gene profiling of G protein-coupled receptors in the arcuate nucleus of the female
. Mol Endocrinol
. 2014 Aug
;28
(8
):1362
–80
.24.
Ruff
RL
. Effects of temperature on slow and fast inactivation of rat skeletal muscle Na(+) channels
. Am J Physiol
. 1999 Nov
;277
(5 Pt 1
):C937
–47
.25.
Evans
MH
. Tetrodotoxin, saxitoxin, and related substances: their applications in neurobiology
. Int Rev Neurobiol
. 1972
;15
:83
–166
.26.
Peterfi
Z
, Farkas
I
, Denis
RGP
, Farkas
E
, Uchigashima
M
, Fuzesi
T
, . Endocannabinoid and nitric oxide systems of the hypothalamic paraventricular nucleus mediate effects of NPY on energy expenditure
. Mol metab
. 2018 Dec
;18
:120
–33
.27.
Doyle
ME
, Egan
JM
. Mechanisms of action of glucagon-like peptide 1 in the pancreas
. Pharmacol Ther
. 2007 Mar
;113
(3
):546
–93
.28.
Shigeto
M
, Cha
CY
, Rorsman
P
, Kaku
K
. A role of PLC/PKC-dependent pathway in GLP-1-stimulated insulin secretion
. J Mol Med
. 2017 Apr
;95
(4
):361
–8
.29.
Andrade-Talavera
Y
, Duque-Feria
P
, Sihra
TS
, Rodriguez-Moreno
A
. Pre-synaptic kainate receptor-mediated facilitation of glutamate release involves PKA and Ca(2+) -calmodulin at thalamocortical synapses
. J Neurochem
. 2013 Sep
;126
(5
):565
–78
.30.
Hori
T
, Takai
Y
, Takahashi
T
. Presynaptic mechanism for phorbol ester-induced synaptic potentiation
. J Neurosci
. 1999 Sep 1
;19
(17
):7262
–7
.31.
Melnick
I
, Pronchuk
N
, Cowley
MA
, Grove
KL
, Colmers
WF
. Developmental switch in neuropeptide Y and melanocortin effects in the paraventricular nucleus of the hypothalamus
. Neuron
. 2007 Dec 20
;56
(6
):1103
–15
.32.
Wittmann
G
, Hrabovszky
E
, Lechan
RM
, . Distinct glutamatergic and GABAergic subset of hypothalamic pro-opiomelanocortin neurons revealed by in situ hybridization in male rats and mice
. J Comp Neurol
. 2013 Oct
;521
(14
):3287
–3302
.33.
Lam
BYH
, Cimino
I
, Polex-Wolf
J
, Nicole Kohnke
S
, Rimmington
D
, Iyemere
V
, . Heterogeneity of hypothalamic pro-opiomelanocortin-expressing neurons revealed by single-cell RNA sequencing
. Mol Metab
. 2017 May
;6
(5
):383
–92
.© 2020 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2020
You do not currently have access to this content.
