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

Stefan Wagner, Daniel I Brierley, Alasdair Leeson-Payne, Wanqing Jiang, Raffaella Chianese, Brian Y H Lam, Georgina K C Dowsett, Claudia Cristiano, David Lyons, Frank Reimann, Fiona M Gribble, Pablo B Martinez de Morentin, Giles S H Yeo, Stefan Trapp, Lora K Heisler* (Corresponding Author)

*Corresponding author for this work

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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-HT 2CR; 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 (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 2CRs, 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 2CR 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 2CR agonists.

Original languageEnglish
Article number101665
Number of pages11
JournalMolecular Metabolism
Volume68
Early online date10 Jan 2023
DOIs
Publication statusPublished - Feb 2023

Bibliographical note

Acknowledgements
The authors thank Dr Alasdair S. Garfield, and staff within the University of Aberdeen Medical Research Facility and the Microscopy Facility for their technical assistance. pAAV-mCherry-flex-dtA was a gift from Naoshige Uchida. Work was supported by the Biotechnology and Biological Sciences Research Council (BB/R01857X/1, BB/V016849/1 to LKH and BB/S017593/1 to BYHL), the European Foundation for the Study of Diabetes (Merck Sharpe Dohme grant to ST), the Medical Research Council (MC/PC/15077 to LKH, MR/N02589X/1 to ST and MRC_MC_UU_12012/3 to FR and FMG, and MC_UU_00014/1 to GSHY), the NIH (R01 DK095757 to ST), the Wellcome Trust (WT081713 to LKH, 106262/Z/14/Z, 106263/Z/14/Z to FR and FMG, and 223279/Z/21/Z to DIB) and the Wellcome Trust Institutional Strategic Support Fund to the University of Aberdeen (204815/Z/16/Z to LKH). Next-generation sequencing was performed by IMS Genomics and transcriptomics core facility, which is supported by the MRC (MC_UU_00014/5) and the Wellcome Trust (208363/Z/17/Z), and the Cancer Research UK Cambridge Institute Genomics Core. GKCD is funded by a BBSRC CASE 4-year PhD studentship, co-funded by Novo Nordisk. WJ is supported by a UCL ORS scholarship and a CSC scholarship from the Chinese Government.

Data Availability Statement

Data will be made available on request.

Keywords

  • Lorcaserin
  • Liraglutide
  • Preproglucagon
  • Nucleus tractus solitarii
  • Brainstem
  • Serotonin 2C receptor

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