Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation

Alessia Costa; Minrong Ai; Nicolas Nunn; Isabella Culotta; Jenna Hunter; Mehdi Boutagouga Boudjadja; Lourdes Valencia-Torres; Gabriella Aviello; David J. Hodson; Brandy M. Snider; Tamer Coskun; Paul J. Emmerson; Simon M. Luckman; Giuseppe D'Agostino

doi:10.1016/j.molmet.2021.101407

Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation

Alessia Costa, Minrong Ai^* (Corresponding Author), Nicolas Nunn, Isabella Culotta, Jenna Hunter, Mehdi Boutagouga Boudjadja, Lourdes Valencia-Torres, Gabriella Aviello, David J. Hodson, Brandy M. Snider, Tamer Coskun, Paul J. Emmerson, Simon M. Luckman, Giuseppe D'Agostino

^*Corresponding author for this work

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Abstract

Objective Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective medications to reduce appetite and body weight. These actions are centrally mediated; however, the neuronal substrates involved are poorly understood. Methods We employed a combination of neuroanatomical, genetic, and behavioral approaches in the mouse to investigate the involvement of caudal brainstem cholecystokinin-expressing neurons in the effect of the GLP-1RA exendin-4. We further confirmed key neuroanatomical findings in the non-human primate brain. Results We found that cholecystokinin-expressing neurons in the caudal brainstem are required for the anorectic and body weight-lowering effects of GLP-1RAs and for the induction of GLP-1RA-induced conditioned taste avoidance. We further show that, while cholecystokinin-expressing neurons are not a direct target for glucose-dependent insulinotropic peptide (GIP), GIP receptor activation results in a reduced recruitment of these GLP-1RA-responsive neurons and a selective reduction of conditioned taste avoidance. Conclusions In addition to disclosing a neuronal population required for the full appetite- and body weight-lowering effect of GLP-1RAs, our data also provide a novel framework for understanding and ameliorating GLP-1RA-induced nausea — a major factor for withdrawal from treatment.

Original language	English
Pages (from-to)	101407
Number of pages	10
Journal	Molecular Metabolism
Volume	55
Early online date	16 Dec 2021
DOIs	https://doi.org/10.1016/j.molmet.2021.101407
Publication status	Published - 1 Jan 2022

Bibliographical note

This work was funded by an MRC Career Development Award (MR/ P009824/1 and MR/P009824/2) to GD’A, as well as an MRC grant to SML/GD’A (MR/T032669/1), a BBSRC grant to SML (BB/M001067/1), and an additional direct contribution from Eli Lilly. D.J.H. was sup- ported by MRC (MR/N00275X/1 and MR/S025618/1), Diabetes UK (17/ 0005681), and the European Research Council (ERC) under the Eu- ropean Union’s Horizon 2020 research and innovation programme (Starting Grant 715884 to D.J.H.). AC was supported for part of this project by a travel grant from the Italian Society of Pharmacology and a fellowship from the Veronesi Foundation (Italy).

Data Availability Statement

Supplementary data to this article can be found online at https://doi.org/10.1016/j. molmet.2021.101407.

Keywords

Brain
Appetite
Nausea
Glucagon-like peptide-1
Glucose-dependent insulinotropic polypeptide
Cholecystokinin
Area postrema
Nucleus of the solitary tract

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Costa, A., Ai, M., Nunn, N., Culotta, I., Hunter, J., Boudjadja, M. B., Valencia-Torres, L., Aviello, G., Hodson, D. J., Snider, B. M., Coskun, T., Emmerson, P. J., Luckman, S. M., & D'Agostino, G. (2022). Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation. Molecular Metabolism, 55, 101407. https://doi.org/10.1016/j.molmet.2021.101407

Costa, A, Ai, M, Nunn, N, Culotta, I, Hunter, J, Boudjadja, MB, Valencia-Torres, L, Aviello, G, Hodson, DJ, Snider, BM, Coskun, T, Emmerson, PJ, Luckman, SM & D'Agostino, G 2022, 'Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation', Molecular Metabolism, vol. 55, pp. 101407. https://doi.org/10.1016/j.molmet.2021.101407

@article{31c7d7bf233c48beb4f4ca6a8c184ca7,

title = "Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation",

abstract = "Objective Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective medications to reduce appetite and body weight. These actions are centrally mediated; however, the neuronal substrates involved are poorly understood. Methods We employed a combination of neuroanatomical, genetic, and behavioral approaches in the mouse to investigate the involvement of caudal brainstem cholecystokinin-expressing neurons in the effect of the GLP-1RA exendin-4. We further confirmed key neuroanatomical findings in the non-human primate brain. Results We found that cholecystokinin-expressing neurons in the caudal brainstem are required for the anorectic and body weight-lowering effects of GLP-1RAs and for the induction of GLP-1RA-induced conditioned taste avoidance. We further show that, while cholecystokinin-expressing neurons are not a direct target for glucose-dependent insulinotropic peptide (GIP), GIP receptor activation results in a reduced recruitment of these GLP-1RA-responsive neurons and a selective reduction of conditioned taste avoidance. Conclusions In addition to disclosing a neuronal population required for the full appetite- and body weight-lowering effect of GLP-1RAs, our data also provide a novel framework for understanding and ameliorating GLP-1RA-induced nausea — a major factor for withdrawal from treatment.",

keywords = "Brain, Appetite, Nausea, Glucagon-like peptide-1, Glucose-dependent insulinotropic polypeptide, Cholecystokinin, Area postrema, Nucleus of the solitary tract",

author = "Alessia Costa and Minrong Ai and Nicolas Nunn and Isabella Culotta and Jenna Hunter and Boudjadja, {Mehdi Boutagouga} and Lourdes Valencia-Torres and Gabriella Aviello and Hodson, {David J.} and Snider, {Brandy M.} and Tamer Coskun and Emmerson, {Paul J.} and Luckman, {Simon M.} and Giuseppe D'Agostino",

note = "This work was funded by an MRC Career Development Award (MR/ P009824/1 and MR/P009824/2) to GD{\textquoteright}A, as well as an MRC grant to SML/GD{\textquoteright}A (MR/T032669/1), a BBSRC grant to SML (BB/M001067/1), and an additional direct contribution from Eli Lilly. D.J.H. was sup- ported by MRC (MR/N00275X/1 and MR/S025618/1), Diabetes UK (17/ 0005681), and the European Research Council (ERC) under the Eu- ropean Union{\textquoteright}s Horizon 2020 research and innovation programme (Starting Grant 715884 to D.J.H.). AC was supported for part of this project by a travel grant from the Italian Society of Pharmacology and a fellowship from the Veronesi Foundation (Italy).",

year = "2022",

month = jan,

day = "1",

doi = "10.1016/j.molmet.2021.101407",

language = "English",

volume = "55",

pages = "101407",

journal = "Molecular Metabolism",

issn = "2212-8778",

publisher = "Elsevier GmbH",

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TY - JOUR

T1 - Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation

AU - Costa, Alessia

AU - Ai, Minrong

AU - Nunn, Nicolas

AU - Culotta, Isabella

AU - Hunter, Jenna

AU - Boudjadja, Mehdi Boutagouga

AU - Valencia-Torres, Lourdes

AU - Aviello, Gabriella

AU - Hodson, David J.

AU - Snider, Brandy M.

AU - Coskun, Tamer

AU - Emmerson, Paul J.

AU - Luckman, Simon M.

AU - D'Agostino, Giuseppe

N1 - This work was funded by an MRC Career Development Award (MR/ P009824/1 and MR/P009824/2) to GD’A, as well as an MRC grant to SML/GD’A (MR/T032669/1), a BBSRC grant to SML (BB/M001067/1), and an additional direct contribution from Eli Lilly. D.J.H. was sup- ported by MRC (MR/N00275X/1 and MR/S025618/1), Diabetes UK (17/ 0005681), and the European Research Council (ERC) under the Eu- ropean Union’s Horizon 2020 research and innovation programme (Starting Grant 715884 to D.J.H.). AC was supported for part of this project by a travel grant from the Italian Society of Pharmacology and a fellowship from the Veronesi Foundation (Italy).

PY - 2022/1/1

Y1 - 2022/1/1

N2 - Objective Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective medications to reduce appetite and body weight. These actions are centrally mediated; however, the neuronal substrates involved are poorly understood. Methods We employed a combination of neuroanatomical, genetic, and behavioral approaches in the mouse to investigate the involvement of caudal brainstem cholecystokinin-expressing neurons in the effect of the GLP-1RA exendin-4. We further confirmed key neuroanatomical findings in the non-human primate brain. Results We found that cholecystokinin-expressing neurons in the caudal brainstem are required for the anorectic and body weight-lowering effects of GLP-1RAs and for the induction of GLP-1RA-induced conditioned taste avoidance. We further show that, while cholecystokinin-expressing neurons are not a direct target for glucose-dependent insulinotropic peptide (GIP), GIP receptor activation results in a reduced recruitment of these GLP-1RA-responsive neurons and a selective reduction of conditioned taste avoidance. Conclusions In addition to disclosing a neuronal population required for the full appetite- and body weight-lowering effect of GLP-1RAs, our data also provide a novel framework for understanding and ameliorating GLP-1RA-induced nausea — a major factor for withdrawal from treatment.

AB - Objective Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective medications to reduce appetite and body weight. These actions are centrally mediated; however, the neuronal substrates involved are poorly understood. Methods We employed a combination of neuroanatomical, genetic, and behavioral approaches in the mouse to investigate the involvement of caudal brainstem cholecystokinin-expressing neurons in the effect of the GLP-1RA exendin-4. We further confirmed key neuroanatomical findings in the non-human primate brain. Results We found that cholecystokinin-expressing neurons in the caudal brainstem are required for the anorectic and body weight-lowering effects of GLP-1RAs and for the induction of GLP-1RA-induced conditioned taste avoidance. We further show that, while cholecystokinin-expressing neurons are not a direct target for glucose-dependent insulinotropic peptide (GIP), GIP receptor activation results in a reduced recruitment of these GLP-1RA-responsive neurons and a selective reduction of conditioned taste avoidance. Conclusions In addition to disclosing a neuronal population required for the full appetite- and body weight-lowering effect of GLP-1RAs, our data also provide a novel framework for understanding and ameliorating GLP-1RA-induced nausea — a major factor for withdrawal from treatment.

KW - Brain

KW - Appetite

KW - Nausea

KW - Glucagon-like peptide-1

KW - Glucose-dependent insulinotropic polypeptide

KW - Cholecystokinin

KW - Area postrema

KW - Nucleus of the solitary tract

U2 - 10.1016/j.molmet.2021.101407

DO - 10.1016/j.molmet.2021.101407

M3 - Article

SN - 2212-8778

VL - 55

SP - 101407

JO - Molecular Metabolism

JF - Molecular Metabolism

ER -

Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation

Abstract

Bibliographical note

Data Availability Statement

Keywords

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