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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. [Display omitted] • Nicotine and liraglutide synergistically lower body weight in obese mice • Nicotine and liraglutide reduce food intake and increase energy expenditure • There is cross-sensitization between GLP-1R and nAChR in the ARC and VTA • Liraglutide diminishes nicotine-induced dopamine signaling in the accumbens Falk et al. demonstrate that nicotine potentiates GLP-1 receptor agonist-driven weight loss in obese mice. Co-administration of nicotine and liraglutide triggers neuronal activity in the hypothalamus, brainstem, and mesolimbic reward system, leading to increased energy expenditure and decreased food intake. Liraglutide attenuates nicotine-induced dopamine release in the nucleus accumbens. [ABSTRACT FROM AUTHOR]