A neuronal circuit driven by GLP-1 in the olfactory bulb regulates insulin secretion

Mireia  Montaner; Jessica  Denom; Vincent  Simon; Wanqing Jiang; Marie K.  Holt; Daniel I.  Brierley; Claude  Rouch; Ewout  Foppen; Nadim  Kassis; David Jarriault; Dawood Khan; Louise  Eygret; Francois  Mifsud; David J.  Hodson; Johannes  Broichhagen; Lukas Van  Oudenhove; Xavier  Fioramonti; Victor A Gault; Daniela  Cota; Frank  Reimann; Fiona M.  Gribble; Stephanie  Migrenne-Li; Stefan  Trapp; Hirac  Gurden; Christophe  Magnan

doi:10.1038/s41467-024-51076-4

A neuronal circuit driven by GLP-1 in the olfactory bulb regulates insulin secretion

Mireia Montaner
, Jessica Denom
, Vincent Simon
, Wanqing Jiang
, Marie K. Holt
, Daniel I. Brierley
, Claude Rouch
, Ewout Foppen
, Nadim Kassis
, David Jarriault
, Dawood Khan
, Louise Eygret
, Francois Mifsud
, David J. Hodson
, Johannes Broichhagen
, Lukas Van Oudenhove
, Xavier Fioramonti
, Victor A Gault
, Daniela Cota
, Frank Reimann

Fiona M. Gribble, Stephanie Migrenne-Li, Stefan Trapp, Hirac Gurden, Christophe Magnan

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

57 Downloads (Pure)

Abstract

Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α2-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABAA receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS.

Original language	English
Article number	6941
Pages (from-to)	1-14
Number of pages	14
Journal	Nature Communications
Volume	15
Issue number	1
Early online date	13 Aug 2024
DOIs	https://doi.org/10.1038/s41467-024-51076-4
Publication status	Published online - 13 Aug 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

We thank Dr Serge Luquet, Giuseppe Gangarossa, Nicolas Thiebaud and Claire Martin for their advice and helpful discussions. The help of Zahra Boudra is also acknowledged. We thank the technical platform Functional and Physiological Exploration platform (FPE) of the Universit\u00E9 Paris CIt\u00E9 (BFA-UMR 8251), the animal core facility Buffon of the Universit\u00E9 Paris Cit\u00E9 for animal experiments. We would also like to thank Eric Marty for the design of the cannulas used for intrabulbar injections. We thank the core imaging facility of Institut Jacques Monod (ImagoSeine facility) for help in image acquisition and processing. The microscopy for LH cFos analysis was done in the Bordeaux Imaging Center, a service unit of the CNRS-INSERM and Bordeaux University, member of the national infrastructure France BioImaging supported by the French National Research Agency (ANR-10-INBS-04). The help of S\u00E9bastien Marais is acknowledged. This work was supported by Research grant of the French Society for Study of Diabetes (SFD-017-2019 to C.M. and H.G., the Medical Research Council UK (MR/N02589X/1 to S.T.), a British Heart Foundation Postdoctoral Fellowship (FS/IPBSRF/20/27001 to M.K.H.), a Wellcome Trust Sir Henry Dale Fellowship (223279/Z/21/Z to D.B.), and a grant from the European Foundation for the Study of Diabetes Germany (Merck Sharpe Dohme grant to S.T. and D.B.). F.R. and F.M.G.\u2019s work was funded by Wellcome (220271/Z/20/Z) and the MRC (MRC_MC_UU_12012/3). Additional support was obtained from the Cities Partnership program UCL to S.T., C.M. and H.G.; M.M. was supported by a \u201CUniversit\u00E9 Paris Cit\u00E9 IdEx\u201D PhD Fellowship and a \u201CEUR GENE, G.E.N.E. Graduate School\u201D Fellowship. WJ was supported by a UCL ORS Scholarship and a CSC Scholarship from the Chinese Government. L.V.O. is a research professor of the KU Leuven Special Research Fund (Bijzonder Onderzoeksfonds, BOF). We also acknowledge INSERM (to DC) and Agence Nationale de la Recherche (ANR-21-CE14-0018 to D.C.). D.J.H. was supported by MRC (MR/S025618/1) and Diabetes UK (17/0005681) Project Grants, as well as a UKRI ERC Frontier Research Guarantee Grant (EP/X026833/1).

Funders	Funder number
KU Leuven
European Foundation for the Study of Diabetes
University College London
Université Paris Cité
Wellcome Trust	220271/Z/20/Z
EP/X026833/1
Medical Research Council	MRC_MC_UU_12012/3, MR/N02589X/1
Université Paris Cité	BFA-UMR 8251
ANR-21-CE14-0018, ANR-10-INBS-04
Diabetes UK	17/0005681
223279/Z/21/Z
SFD-017-2019
British Heart Foundation	FS/IPBSRF/20/27001
China Scholarship Council	MR/S025618/1

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Neural circuits
Obesity

Access to Document

10.1038/s41467-024-51076-4Licence: CC BY-ND

s41467-024-51076-4Final published version, 7.07 MBLicence: CC BY-ND

Cite this

Montaner, M., Denom, J., Simon, V., Jiang, W., Holt, M. K., Brierley, D. I., Rouch, C., Foppen, E., Kassis, N., Jarriault, D., Khan, D., Eygret, L., Mifsud, F., Hodson, D. J., Broichhagen, J., Oudenhove, L. V., Fioramonti, X., Gault, V. A., Cota, D., ... Magnan, C. (2024). A neuronal circuit driven by GLP-1 in the olfactory bulb regulates insulin secretion. Nature Communications, 15(1), 1-14. Article 6941. Advance online publication. https://doi.org/10.1038/s41467-024-51076-4

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title = "A neuronal circuit driven by GLP-1 in the olfactory bulb regulates insulin secretion",

abstract = "Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α2-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABAA receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS.",

keywords = "Neural circuits, Obesity",

author = "Mireia Montaner and Jessica Denom and Vincent Simon and Wanqing Jiang and Holt, \{Marie K.\} and Brierley, \{Daniel I.\} and Claude Rouch and Ewout Foppen and Nadim Kassis and David Jarriault and Dawood Khan and Louise Eygret and Francois Mifsud and Hodson, \{David J.\} and Johannes Broichhagen and Oudenhove, \{Lukas Van\} and Xavier Fioramonti and Gault, \{Victor A\} and Daniela Cota and Frank Reimann and Gribble, \{Fiona M.\} and Stephanie Migrenne-Li and Stefan Trapp and Hirac Gurden and Christophe Magnan",

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month = aug,

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doi = "10.1038/s41467-024-51076-4",

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Montaner, M, Denom, J, Simon, V, Jiang, W, Holt, MK, Brierley, DI, Rouch, C, Foppen, E, Kassis, N, Jarriault, D, Khan, D, Eygret, L, Mifsud, F, Hodson, DJ, Broichhagen, J, Oudenhove, LV, Fioramonti, X, Gault, VA, Cota, D, Reimann, F, Gribble, FM, Migrenne-Li, S, Trapp, S, Gurden, H & Magnan, C 2024, 'A neuronal circuit driven by GLP-1 in the olfactory bulb regulates insulin secretion', Nature Communications, vol. 15, no. 1, 6941, pp. 1-14. https://doi.org/10.1038/s41467-024-51076-4

TY - JOUR

T1 - A neuronal circuit driven by GLP-1 in the olfactory bulb regulates insulin secretion

AU - Montaner, Mireia

AU - Denom, Jessica

AU - Simon, Vincent

AU - Jiang, Wanqing

AU - Holt, Marie K.

AU - Brierley, Daniel I.

AU - Rouch, Claude

AU - Foppen, Ewout

AU - Kassis, Nadim

AU - Jarriault, David

AU - Khan, Dawood

AU - Eygret, Louise

AU - Mifsud, Francois

AU - Hodson, David J.

AU - Broichhagen, Johannes

AU - Oudenhove, Lukas Van

AU - Fioramonti, Xavier

AU - Gault, Victor A

AU - Cota, Daniela

AU - Reimann, Frank

AU - Gribble, Fiona M.

AU - Migrenne-Li, Stephanie

AU - Trapp, Stefan

AU - Gurden, Hirac

AU - Magnan, Christophe

PY - 2024/8/13

Y1 - 2024/8/13

N2 - Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α2-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABAA receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS.

AB - Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α2-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABAA receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS.

KW - Neural circuits

KW - Obesity

UR - https://www.scopus.com/pages/publications/85201243278

U2 - 10.1038/s41467-024-51076-4

DO - 10.1038/s41467-024-51076-4

M3 - Article

C2 - 39138162

SN - 2041-1723

VL - 15

SP - 1

EP - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6941

ER -

A neuronal circuit driven by GLP-1 in the olfactory bulb regulates insulin secretion

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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