دورية أكاديمية

Obesity medication lorcaserin activates brainstem GLP-1 neurons to reduce food intake and augments GLP-1 receptor agonist induced appetite suppression.

التفاصيل البيبلوغرافية
العنوان: Obesity medication lorcaserin activates brainstem GLP-1 neurons to reduce food intake and augments GLP-1 receptor agonist induced appetite suppression.
المؤلفون: Wagner S; The Rowett Institute, University of Aberdeen, Aberdeen, UK., Brierley DI; Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, University College London, London, UK., Leeson-Payne A; The Rowett Institute, University of Aberdeen, Aberdeen, UK., Jiang W; Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, University College London, London, UK., Chianese R; The Rowett Institute, University of Aberdeen, Aberdeen, UK., Lam BYH; Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK., Dowsett GKC; Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK., Cristiano C; The Rowett Institute, University of Aberdeen, Aberdeen, UK., Lyons D; The Rowett Institute, University of Aberdeen, Aberdeen, UK., Reimann F; Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK., Gribble FM; Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK., Martinez de Morentin PB; The Rowett Institute, University of Aberdeen, Aberdeen, UK., Yeo GSH; Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK., Trapp S; Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, University College London, London, UK. Electronic address: s.trapp@ucl.ac.uk., Heisler LK; The Rowett Institute, University of Aberdeen, Aberdeen, UK. Electronic address: lora.heisler@abdn.ac.uk.
المصدر: Molecular metabolism [Mol Metab] 2023 Feb; Vol. 68, pp. 101665. Date of Electronic Publication: 2022 Dec 30.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Elsevier GmbH Country of Publication: Germany NLM ID: 101605730 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2212-8778 (Electronic) Linking ISSN: 22128778 NLM ISO Abbreviation: Mol Metab Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [München] : Elsevier GmbH, 2012-
مواضيع طبية MeSH: Glucagon-Like Peptide 1*/pharmacology , Glucagon-Like Peptide 1*/metabolism , Liraglutide*/pharmacology , Liraglutide*/therapeutic use, Humans ; Glucagon-Like Peptide-1 Receptor/metabolism ; Serotonin/metabolism ; Appetite ; Obesity/drug therapy ; Obesity/metabolism ; Solitary Nucleus/metabolism ; Eating ; Neurons/metabolism
مستخلص: Objective: Overweight and obesity are endemic in developed countries, with a substantial negative impact on human health. Medications developed to treat obesity include agonists for the G-protein coupled receptors glucagon-like peptide-1 (GLP-1R; e.g. liraglutide), serotonin 2C (5-HT 2C R; e.g, lorcaserin), and melanocortin4 (MC4R) which reduce body weight primarily by suppressing food intake. However, the mechanisms underlying the therapeutic food intake suppressive effects are still being defined and were investigated here.
Methods: We profiled PPG neurons in the nucleus of the solitary tract (PPG NTS ) using single nucleus RNA sequencing (Nuc-Seq) and histochemistry. We next examined the requirement of PPG NTS neurons for obesity medication effects on food intake by virally ablating PPG NTS neurons. Finally, we assessed the effects on food intake of the combination of liraglutide and lorcaserin.
Results: We found that 5-HT 2C Rs, but not GLP-1Rs or MC4Rs, were widespread in PPG NTS clusters and that lorcaserin significantly activated PPG NTS neurons. Accordingly, ablation of PPG NTS neurons prevented the reduction of food intake by lorcaserin but not MC4R agonist melanotan-II, demonstrating the functional significance of PPG NTS 5-HT 2C R expression. Finally, the combination of lorcaserin with GLP-1R agonists liraglutide or exendin-4 produced greater food intake reduction as compared to either monotherapy.
Conclusions: These findings identify a necessary mechanism through which obesity medication lorcaserin produces its therapeutic benefit, namely brainstem PPG NTS neurons. Moreover, these data reveal a strategy to augment the therapeutic profile of the current frontline treatment for obesity, GLP-1R agonists, via coadministration with 5-HT 2C R agonists.
(Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)
معلومات مُعتمدة: BB/S017593/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; MC_UU_12012/3 United Kingdom MRC_ Medical Research Council; BB/V016849/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; MC_UU_00014/3 United Kingdom MRC_ Medical Research Council; 223279/Z/21/Z United Kingdom WT_ Wellcome Trust; 106263/Z/14/Z United Kingdom WT_ Wellcome Trust; 106262/Z/14/Z United Kingdom WT_ Wellcome Trust; MC_UU_12012/1 United Kingdom MRC_ Medical Research Council; 208363/Z/17/Z United Kingdom WT_ Wellcome Trust; R01 DK095757 United States DK NIDDK NIH HHS; MC_UU_00014/1 United Kingdom MRC_ Medical Research Council; MC_UU_12012/5 United Kingdom MRC_ Medical Research Council; United Kingdom CRUK_ Cancer Research UK; MR/S026193/1 United Kingdom MRC_ Medical Research Council; BB/R01857X/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; MC/PC/15077 United Kingdom MRC_ Medical Research Council; 204815/Z/16/Z United Kingdom WT_ Wellcome Trust; WT081713 United Kingdom WT_ Wellcome Trust; MR/N02589X/1 United Kingdom MRC_ Medical Research Council; MC_UU_00014/5 United Kingdom MRC_ Medical Research Council; MC_PC_15077 United Kingdom MRC_ Medical Research Council; United Kingdom WT_ Wellcome Trust
فهرسة مساهمة: Keywords: Brainstem; Liraglutide; Lorcaserin; Nucleus tractus solitarii; Preproglucagon; Serotonin 2C receptor
المشرفين على المادة: 89750-14-1 (Glucagon-Like Peptide 1)
839I73S42A (Liraglutide)
637E494O0Z (lorcaserin)
0 (Glucagon-Like Peptide-1 Receptor)
333DO1RDJY (Serotonin)
تواريخ الأحداث: Date Created: 20230102 Date Completed: 20230207 Latest Revision: 20240306
رمز التحديث: 20240306
مُعرف محوري في PubMed: PMC9841057
DOI: 10.1016/j.molmet.2022.101665
PMID: 36592795
قاعدة البيانات: MEDLINE
الوصف
تدمد:2212-8778
DOI:10.1016/j.molmet.2022.101665