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

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 lira-glutide 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 loss.

Automated summary

GLP-1R agonists can promote nicotine avoidance and combined treatment with nicotine and GLP-1R agonist can enhance the anti-obesity effects. GLP-1R agonism increases the excitability of hypothalamic POMC neurons and VTA dopaminergic neurons to suppress nicotine-induced dopamine release, resulting in weight loss. These findings support the use of GLP-1R-based therapies for nicotine dependence and further evaluation of combined treatment.