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

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, lorcas...

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Main Authors: Stefan Wagner (Author), Daniel I. Brierley (Author), Alasdair Leeson-Payne (Author), Wanqing Jiang (Author), Raffaella Chianese (Author), Brian Y.H. Lam (Author), Georgina K.C. Dowsett (Author), Claudia Cristiano (Author), David Lyons (Author), Frank Reimann (Author), Fiona M. Gribble (Author), Pablo B. Martinez de Morentin (Author), Giles S.H. Yeo (Author), Stefan Trapp (Author), Lora K. Heisler (Author)
Format: Book
Published: Elsevier, 2023-02-01T00:00:00Z.
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042 |a dc 
100 1 0 |a Stefan Wagner  |e author 
700 1 0 |a Daniel I. Brierley  |e author 
700 1 0 |a Alasdair Leeson-Payne  |e author 
700 1 0 |a Wanqing Jiang  |e author 
700 1 0 |a Raffaella Chianese  |e author 
700 1 0 |a Brian Y.H. Lam  |e author 
700 1 0 |a Georgina K.C. Dowsett  |e author 
700 1 0 |a Claudia Cristiano  |e author 
700 1 0 |a David Lyons  |e author 
700 1 0 |a Frank Reimann  |e author 
700 1 0 |a Fiona M. Gribble  |e author 
700 1 0 |a Pablo B. Martinez de Morentin  |e author 
700 1 0 |a Giles S.H. Yeo  |e author 
700 1 0 |a Stefan Trapp  |e author 
700 1 0 |a Lora K. Heisler  |e author 
245 0 0 |a Obesity medication lorcaserin activates brainstem GLP-1 neurons to reduce food intake and augments GLP-1 receptor agonist induced appetite suppression 
260 |b Elsevier,   |c 2023-02-01T00:00:00Z. 
500 |a 2212-8778 
500 |a 10.1016/j.molmet.2022.101665 
520 |a 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 (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. 
546 |a EN 
690 |a Lorcaserin 
690 |a Liraglutide 
690 |a Preproglucagon 
690 |a Nucleus tractus solitarii 
690 |a Brainstem 
690 |a Serotonin 2C receptor 
690 |a Internal medicine 
690 |a RC31-1245 
655 7 |a article  |2 local 
786 0 |n Molecular Metabolism, Vol 68, Iss , Pp 101665- (2023) 
787 0 |n http://www.sciencedirect.com/science/article/pii/S2212877822002344 
787 0 |n https://doaj.org/toc/2212-8778 
856 4 1 |u https://doaj.org/article/a7f4d6b4357e4a4d9af68e183e845a6f  |z Connect to this object online.