UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

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

Wagner, Stefan; Brierley, Daniel I; Leeson-Payne, Alasdair; Jiang, Wanqing; Chianese, Raffaella; Lam, Brian YH; Dowsett, Georgina KC; ... Heisler, Lora K; + view all (2023) Obesity medication lorcaserin activates brainstem GLP-1 neurons to reduce food intake and augments GLP-1 receptor agonist induced appetite suppression. Molecular Metabolism , 68 , Article 101665. 10.1016/j.molmet.2022.101665. Green open access

[thumbnail of 1-s2.0-S2212877822002344-main.pdf]
Preview
PDF
1-s2.0-S2212877822002344-main.pdf - Published Version

Download (3MB) | Preview

Abstract

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-HT2CR; e.g, lorcaserin), and melanocortin4 receptor (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 (PPGNTS) using single nucleus RNA sequencing (Nuc-Seq) and histochemistry. We next examined the requirement of PPGNTS neurons for obesity medication effects on food intake by virally ablating PPGNTS neurons. Finally, we assessed the effects on food intake of the combination of liraglutide and lorcaserin. RESULTS: We found that 5-HT2CRs, but not GLP-1Rs or MC4Rs, were widespread in PPGNTS clusters and that lorcaserin significantly activated PPGNTS neurons. Accordingly, ablation of PPGNTS neurons prevented the reduction of food intake by lorcaserin but not MC4R agonist melanotan-II, demonstrating the functional significance of PPGNTS 5-HT2CR 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 PPGNTS 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-HT2CR agonists.

Type: Article
Title: Obesity medication lorcaserin activates brainstem GLP-1 neurons to reduce food intake and augments GLP-1 receptor agonist induced appetite suppression
Location: Germany
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.molmet.2022.101665
Publisher version: https://doi.org/10.1016/j.molmet.2022.101665
Language: English
Additional information: © 2023 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Brainstem, Liraglutide, Lorcaserin, Nucleus tractus solitarii, Preproglucagon, Serotonin 2C receptor
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10163046
Downloads since deposit
39Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item