Obesity medication lorcaserin requires brainstem GLP-1 neurons to reduce food intake in mice
Obesity medication lorcaserin requires brainstem GLP-1 neurons to reduce food intake in mice
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-HT2CR) 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-HT2CRs 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 (PPGNTS) neurons. PPGNTS cells were profiled using histochemistry and single nucleus RNA sequencing (Nuc-Seq) of mouse brainstem. Transcriptomic analyses revealed 5-HT2CR expression was widespread in PPGNTS clusters. Demonstrating the functional significance of this co-expression, lorcaserin required PPGNTS to reduce food intake. Analysis of second order neurons revealed that local GLP1-R neurons within the NTS are necessary for 5-HT2CRNTS food intake suppression. In contrast, GLP-1RNTS 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.
Brierley Daniel I.、Chianese Raffaella、Lam Brian Y. H.、Cristiano Claudia、Yeo Giles S.H.、Heisler Lora K.、Leeson-Payne Alasdair、Gribble Fiona M.、Lyons David、Wagner Stefan、Dowsett Georgina K. C.、Trapp Stefan、Jiang Wanqing、Reimann Frank
Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, University College LondonThe Rowett Institute, University of AberdeenWellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, Medical Research Council Metabolic Diseases Unit, University of CambridgeThe Rowett Institute, University of AberdeenWellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, Medical Research Council Metabolic Diseases Unit, University of CambridgeThe Rowett Institute, University of AberdeenThe Rowett Institute, University of AberdeenWellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, Medical Research Council Metabolic Diseases Unit, University of CambridgeThe Rowett Institute, University of AberdeenThe Rowett Institute, University of AberdeenWellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, Medical Research Council Metabolic Diseases Unit, University of CambridgeCentre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, University College LondonCentre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, University College LondonWellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, Medical Research Council Metabolic Diseases Unit, University of Cambridge
医药卫生理论医学研究方法基础医学
Brierley Daniel I.,Chianese Raffaella,Lam Brian Y. H.,Cristiano Claudia,Yeo Giles S.H.,Heisler Lora K.,Leeson-Payne Alasdair,Gribble Fiona M.,Lyons David,Wagner Stefan,Dowsett Georgina K. C.,Trapp Stefan,Jiang Wanqing,Reimann Frank.Obesity medication lorcaserin requires brainstem GLP-1 neurons to reduce food intake in mice[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/2022.05.06.490598.点此复制
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