Nucleus accumbens GLP-1 signaling and its role in reward and metabolic regulation: a systematic review

Introduction Glucagon-like peptide-1 (GLP-1) is an incretin hormone involved in glucose homeostasis, appetite regulation, and energy balance. Beyond its peripheral metabolic actions, growing evidence indicates that GLP-1 signalling within the central nervous system modulates reward-related processes. The nucleus accumbens (NAc), a key component of the mesolimbic reward pathway, represents a critical site where metabolic and motivational signals converge. However, the role of GLP-1 signalling within the human NAc remains incompletely understood. This systematic review aimed to synthesize current human evidence on GLP-1 expression and receptor signalling in the NAc and their role in reward and metabolic regulation. Methods A systematic search of PubMed, Scopus, and Web of Science was conducted in December 2025. Human studies assessing GLP-1 or GLP-1 receptor (GLP-1R) in relation to NAc structure, function, or connectivity were included. Study selection and data extraction were performed independently by two reviewers. Results From 276 screened records, five studies were included, totalling 284 participants. No consistent evidence emerged for direct GLP-1-related alterations in isolated NAc activation or GLP-1R expression. Instead, GLP-1 modulation of mesolimbic connectivity, particularly between the NAc and orbitofrontal cortex (OFC), was observed. Discussion Current human evidence suggests that GLP-1 modulates reward processing primarily through cortico-striatal connectivity rather than localized changes within the NAc, with potential translational implications for obesity and addiction. Further harmonized neuroimaging studies incorporating direct pharmacological manipulation are needed to clarify NAc-specific GLP-1 mechanisms. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251250453 .