GLP-1 and nicotine combination therapy engages hypothalamic and mesolimbic pathways to reverse obesity

Sarah Falk, Jonas Odgaard Petersen, Charlotte Sashi Aier Svendsen, Cesar Ramon Romero Leguizamon, Søren Heide Jørgensen, Nathalie Krauth, Mette Q Ludwig, Kathrine Lundø, Urmas Roostalu, Grethe Skovbjerg Hjort-Gregersen, Duy Anh Gurskov Nielsen, Aske Lykke Ejdrup, Tune H Pers, Oksana Dmytriyeva, Jacob Hecksher-Soerensen, Ulrik Gether, Kristi Anne Kohlmeier, Christoffer Clemmensen

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Abstract

Glucagon-like peptide-1 receptor (GLP-1R) agonists promote nicotine avoidance. Here, we show that the crosstalk between GLP-1 and nicotine extends beyond effects on nicotine self-administration and can be exploited pharmacologically to amplify the anti-obesity effects of both signals. Accordingly, combined treatment with nicotine and the GLP-1R agonist, liraglutide, inhibits food intake and increases energy expenditure to lower body weight in obese mice. Co-treatment with nicotine and liraglutide gives rise to neuronal activity in multiple brain regions, and we demonstrate that GLP-1R agonism increases excitability of hypothalamic proopiomelanocortin (POMC) neurons and dopaminergic neurons in the ventral tegmental area (VTA). Further, using a genetically encoded dopamine sensor, we reveal that liraglutide suppresses nicotine-induced dopamine release in the nucleus accumbens in freely behaving mice. These data support the pursuit of GLP-1R-based therapies for nicotine dependence and encourage further evaluation of combined treatment with GLP-1R agonists and nicotinic receptor agonists for weight loss.
Original languageEnglish
Article number112466
JournalCell Reports
Volume42
Issue number5
Number of pages18
ISSN2211-1247
DOIs
Publication statusPublished - 2023

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