GLP-1 and Nicotine Combination Therapy Engages Hypothalamic and Mesolimbic Pathways to Reverse Obesity

Glucagon-like peptide-1 receptor (GLP-1R) agonists are nicotine sensitizers and 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, lowers food intake and increases energy expenditure to synergistically reverse obesity in 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 POMC neurons and dopaminergic neurons in the ventral tegmental area. 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 a translational evaluation of combined treatment with GLP-1R agonists and nicotinic receptor agonists for weight loss.