Time and metabolic state-dependent effects of GLP-1R agonists on NPY/AgRP and POMC neuronal activity in vivo

Objective: Long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs), like liraglutide and semaglutide, are viable treatments for diabetes and obesity. Liraglutide directly activates hypothalamic proopiomelanocortin (POMC) neurons while indirectly inhibiting Neuropeptide Y/Agouti-related pept...

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Autores principales:	Yanbin Dong, Jamie Carty, Nitsan Goldstein, Zhenyan He, Eunsang Hwang, Dominic Chau, Briana Wallace, Anita Kabahizi, Linh Lieu, Yunqian Peng, Yong Gao, Ling Hu, J. Nicholas Betley, Kevin W. Williams
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Liraglutide and semaglutide Long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs) TRPC5 subunit Metabolic state-dependent effects GLP-1R Agonists on NPY/AgRP neuron POMC Neuronal activity Internal medicine RC31-1245
Acceso en línea:	https://doaj.org/article/4ec2aa488f164583b0cbb499e20a9df9
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spelling	oai:doaj.org-article:4ec2aa488f164583b0cbb499e20a9df92021-11-10T04:25:25ZTime and metabolic state-dependent effects of GLP-1R agonists on NPY/AgRP and POMC neuronal activity in vivo2212-877810.1016/j.molmet.2021.101352https://doaj.org/article/4ec2aa488f164583b0cbb499e20a9df92021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S221287782100199Xhttps://doaj.org/toc/2212-8778Objective: Long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs), like liraglutide and semaglutide, are viable treatments for diabetes and obesity. Liraglutide directly activates hypothalamic proopiomelanocortin (POMC) neurons while indirectly inhibiting Neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons ex vivo. While temporal control of GLP-1R agonist concentration as well as accessibility to tissues/cells can be achieved with relative ease ex vivo, in vivo this is dependent upon the pharmacokinetics of these agonists and relative penetration into structures of interest. Thus, whether liraglutide or semaglutide modifies the activity of POMC and NPY/AgRP neurons in vivo as well as mechanisms required for any changes in cellular activity remains undefined. Methods: In order to resolve this issue, we utilized neuron-specific transgenic mouse models to examine changes in the activity of POMC and NPY/AgRP neurons after injection of either liraglutide or semaglutide (intraperitoneal - I.P. and subcutaneous - S·C.). POMC and NPY/AgRP neurons were targeted for patch-clamp electrophysiology as well as in vivo fiber photometry. Results: We found that liraglutide and semaglutide directly activate and increase excitatory tone to POMC neurons in a time-dependent manner. This increased activity of POMC neurons required GLP-1Rs in POMC neurons as well as a downstream mixed cation channel comprised of TRPC5 subunits. We also observed an indirect upregulation of excitatory input to POMC neurons originating from glutamatergic cells that also required TRPC5 subunits. Conversely, GLP-1Ra's decreased excitatory input to and indirectly inhibited NPY/AgRP neurons through activation of K-ATP and TRPC5 channels in GABAergic neurons. Notably, the temporal activation of POMC and inhibition of NPY/AgRP neuronal activity after liraglutide or semaglutide was injected [either intraperitoneal (I.P.) or subcutaneous (S·C.)] was dependent upon the nutritional state of the animals (fed vs food-deprived). Conclusions: Our results support a mechanism of liraglutide and semaglutide in vivo to activate POMC while inhibiting NPY/AgRP neurons, which depends upon metabolic state and mirrors the pharmacokinetic profile of these compounds in vivo.Yanbin DongJamie CartyNitsan GoldsteinZhenyan HeEunsang HwangDominic ChauBriana WallaceAnita KabahiziLinh LieuYunqian PengYong GaoLing HuJ. Nicholas BetleyKevin W. WilliamsElsevierarticleLiraglutide and semaglutideLong-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs)TRPC5 subunitMetabolic state-dependent effectsGLP-1R Agonists on NPY/AgRP neuronPOMC Neuronal activityInternal medicineRC31-1245ENMolecular Metabolism, Vol 54, Iss , Pp 101352- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Liraglutide and semaglutide Long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs) TRPC5 subunit Metabolic state-dependent effects GLP-1R Agonists on NPY/AgRP neuron POMC Neuronal activity Internal medicine RC31-1245
spellingShingle	Liraglutide and semaglutide Long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs) TRPC5 subunit Metabolic state-dependent effects GLP-1R Agonists on NPY/AgRP neuron POMC Neuronal activity Internal medicine RC31-1245 Yanbin Dong Jamie Carty Nitsan Goldstein Zhenyan He Eunsang Hwang Dominic Chau Briana Wallace Anita Kabahizi Linh Lieu Yunqian Peng Yong Gao Ling Hu J. Nicholas Betley Kevin W. Williams Time and metabolic state-dependent effects of GLP-1R agonists on NPY/AgRP and POMC neuronal activity in vivo
description	Objective: Long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs), like liraglutide and semaglutide, are viable treatments for diabetes and obesity. Liraglutide directly activates hypothalamic proopiomelanocortin (POMC) neurons while indirectly inhibiting Neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons ex vivo. While temporal control of GLP-1R agonist concentration as well as accessibility to tissues/cells can be achieved with relative ease ex vivo, in vivo this is dependent upon the pharmacokinetics of these agonists and relative penetration into structures of interest. Thus, whether liraglutide or semaglutide modifies the activity of POMC and NPY/AgRP neurons in vivo as well as mechanisms required for any changes in cellular activity remains undefined. Methods: In order to resolve this issue, we utilized neuron-specific transgenic mouse models to examine changes in the activity of POMC and NPY/AgRP neurons after injection of either liraglutide or semaglutide (intraperitoneal - I.P. and subcutaneous - S·C.). POMC and NPY/AgRP neurons were targeted for patch-clamp electrophysiology as well as in vivo fiber photometry. Results: We found that liraglutide and semaglutide directly activate and increase excitatory tone to POMC neurons in a time-dependent manner. This increased activity of POMC neurons required GLP-1Rs in POMC neurons as well as a downstream mixed cation channel comprised of TRPC5 subunits. We also observed an indirect upregulation of excitatory input to POMC neurons originating from glutamatergic cells that also required TRPC5 subunits. Conversely, GLP-1Ra's decreased excitatory input to and indirectly inhibited NPY/AgRP neurons through activation of K-ATP and TRPC5 channels in GABAergic neurons. Notably, the temporal activation of POMC and inhibition of NPY/AgRP neuronal activity after liraglutide or semaglutide was injected [either intraperitoneal (I.P.) or subcutaneous (S·C.)] was dependent upon the nutritional state of the animals (fed vs food-deprived). Conclusions: Our results support a mechanism of liraglutide and semaglutide in vivo to activate POMC while inhibiting NPY/AgRP neurons, which depends upon metabolic state and mirrors the pharmacokinetic profile of these compounds in vivo.
format	article
author	Yanbin Dong Jamie Carty Nitsan Goldstein Zhenyan He Eunsang Hwang Dominic Chau Briana Wallace Anita Kabahizi Linh Lieu Yunqian Peng Yong Gao Ling Hu J. Nicholas Betley Kevin W. Williams
author_facet	Yanbin Dong Jamie Carty Nitsan Goldstein Zhenyan He Eunsang Hwang Dominic Chau Briana Wallace Anita Kabahizi Linh Lieu Yunqian Peng Yong Gao Ling Hu J. Nicholas Betley Kevin W. Williams
author_sort	Yanbin Dong
title	Time and metabolic state-dependent effects of GLP-1R agonists on NPY/AgRP and POMC neuronal activity in vivo
title_short	Time and metabolic state-dependent effects of GLP-1R agonists on NPY/AgRP and POMC neuronal activity in vivo
title_full	Time and metabolic state-dependent effects of GLP-1R agonists on NPY/AgRP and POMC neuronal activity in vivo
title_fullStr	Time and metabolic state-dependent effects of GLP-1R agonists on NPY/AgRP and POMC neuronal activity in vivo
title_full_unstemmed	Time and metabolic state-dependent effects of GLP-1R agonists on NPY/AgRP and POMC neuronal activity in vivo
title_sort	time and metabolic state-dependent effects of glp-1r agonists on npy/agrp and pomc neuronal activity in vivo
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/4ec2aa488f164583b0cbb499e20a9df9
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Time and metabolic state-dependent effects of GLP-1R agonists on NPY/AgRP and POMC neuronal activity in vivo

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