TY - JOUR
T1 - GLP-1 and nicotine combination therapy engages hypothalamic and mesolimbic pathways to reverse obesity
AU - Falk, Sarah
AU - Petersen, Jonas Odgaard
AU - Svendsen, Charlotte Sashi Aier
AU - Leguizamon, Cesar Ramon Romero
AU - Jørgensen, Søren Heide
AU - Krauth, Nathalie
AU - Ludwig, Mette Q
AU - Lundø, Kathrine
AU - Roostalu, Urmas
AU - Hjort-Gregersen, Grethe Skovbjerg
AU - Nielsen, Duy Anh Gurskov
AU - Ejdrup, Aske Lykke
AU - Pers, Tune H
AU - Dmytriyeva, Oksana
AU - Hecksher-Soerensen, Jacob
AU - Gether, Ulrik
AU - Kohlmeier, Kristi Anne
AU - Clemmensen, Christoffer
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
U2 - 10.1016/j.celrep.2023.112466
DO - 10.1016/j.celrep.2023.112466
M3 - Journal article
C2 - 37148870
VL - 42
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 5
M1 - 112466
ER -