GLP1R Signaling as a Neural Switch Governing Food vs. Smoking Preference

Glucagon-like peptide-1 receptor (GLP1R) signaling, the pharmacological target of GLP1 receptor agonists used for diabetes and obesity, has been implicated in both metabolic regulation and central reward pathways. While observational studies suggest that GLP1R agonists may reduce addictive behaviors such as smoking and alcohol use, the causal relationship between GLP1R activity and smoking remains unclear. Using Mendelian randomization (MR) with rs10305420, a cis-eQTL influencing GLP1R expression, we investigated the association between genetically proxied GLP1R activity and smoking initiation. Contrary to our initial hypothesis, higher GLP1R expression was significantly associated with increased smoking initiation (P = 1.26×10⁻¹¹) and cannabis use disorder, but not problematic alcohol use. Two-step MR demonstrated that GLP1R-driven reductions in body mass index (BMI) were linked to elevated smoking risk, suggesting a reward-transfer mechanism between food and nicotine. Multivariable MR incorporating binge eating disorder (BED) further supported this model, though with reduced precision. Together, these findings highlight a paradoxical role of GLP1R in addictive behaviors: while dampening hedonic eating, increased GLP1R signaling may heighten susceptibility to smoking. This work underscores the importance of considering cross-addiction dynamics in interpreting GLP1R’s neurobiological functions and informs both clinical use of GLP1R agonists and future research on shared reward circuitry.