{"doi":"10.1101/2022.05.06.490598","title":"Obesity medication lorcaserin requires brainstem GLP-1 neurons to reduce food intake in mice","abstract":"Abstract Overweight and obesity are rapidly becoming the “new normal” in developed countries, which promotes a widespread negative impact on human health. Amongst recently developed obesity medications are the serotonin 2C receptor (5-HT 2C R) agonist lorcaserin and glucagon-like peptide-1 receptor (GLP-1R) agonists, but the brain circuits employed by these medications to produce their therapeutic effects remain to be fully defined. 5-HT 2C Rs and GLP-1Rs are widely distributed in the brain, including in the key homeostatic region the nucleus of the solitary tract (NTS) where GLP-1 is produced by preproglucagon (PPG NTS ) neurons. PPG NTS cells were profiled using histochemistry and single nucleus RNA sequencing (Nuc-Seq) of mouse brainstem. Transcriptomic analyses revealed 5-HT 2C R expression was widespread in PPG NTS clusters. Demonstrating the functional significance of this co-expression, lorcaserin required PPG NTS to reduce food intake. Analysis of second order neurons revealed that local GLP1-R neurons within the NTS are necessary for 5-HT 2C R NTS food intake suppression. In contrast, GLP-1R NTS were not required for GLP-1R agonist liraglutide and exendin-4’s short term feeding reduction, suggesting scope for lorcaserin and GLP1-R agonist combination therapy. In support of this, lorcaserin+liraglutide and lorcaserin+exendin-4 produced greater reductions in food intake when administered in combination as compared to monotherapies. These data provide insight into the therapeutic mechanisms of lorcaserin and identify a combination strategy to improve the therapeutic profile of lorcaserin and GLP1-R agonists.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":308473,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":260264,"name":"Daniel I. Brierley","orcid":"0000-0002-4360-2648","position":1,"is_corresponding":false},{"id":885716,"name":"Alasdair Leeson-Payne","orcid":"0000-0002-1823-2913","position":2,"is_corresponding":false},{"id":886357,"name":"Wanqing Jiang","orcid":null,"position":3,"is_corresponding":false},{"id":886358,"name":"Raffaella Chianese","orcid":null,"position":4,"is_corresponding":false},{"id":355554,"name":"Brian Lam","orcid":"0000-0002-3638-9025","position":5,"is_corresponding":false},{"id":704743,"name":"Georgina K.C. Dowsett","orcid":"0000-0002-2134-8554","position":6,"is_corresponding":false},{"id":543916,"name":"Claudia Cristiano","orcid":"0000-0002-4806-1764","position":7,"is_corresponding":false},{"id":885717,"name":"D. Lyons","orcid":"0000-0002-3391-5878","position":8,"is_corresponding":false},{"id":260268,"name":"Frank Reimann","orcid":"0000-0001-9399-6377","position":9,"is_corresponding":false},{"id":325589,"name":"Fiona M. Gribble","orcid":"0000-0002-4232-2898","position":10,"is_corresponding":false},{"id":614545,"name":"Giles S.H. Yeo","orcid":"0000-0001-8823-3615","position":11,"is_corresponding":false},{"id":237000,"name":"Stefan Trapp","orcid":"0000-0003-0665-4948","position":12,"is_corresponding":false},{"id":543918,"name":"Lora K. Heisler","orcid":"0000-0002-7731-1419","position":13,"is_corresponding":false},{"id":322555,"name":"Stefan Wagner","orcid":"0000-0002-9471-1166","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T00:33:03.486542Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}