Abstract
Glutamatergic neurons represent 40% of neurons in the human central nervous system. Glutamate accounts for approximately 90% of all excitatory neurotransmitters. Previous research reports the presence of glucagon-like peptide-1 (GLP-1) receptors on neurons that produce glutamate. Herein, we aim to evaluate whether GLP-1 receptor agonists' (GLP-1 RAs) modulate glutamatergic signaling and whether GLP-1 RAs' anti-obesity effects are mediated through the glutamatergic system. We conducted a systematic review of extant literature published on PubMed, Ovid and Scopus databases from inception to March, 2025. Identified studies were screened independently by two reviewers (S.W. and G.H.L.) using the Covidence platform. We sought to include in vitro, in vivo, and human clinical studies. A total of 31 studies were identified as meeting eligibility for an inclusion in this review. No human studies were identified. Across the included preclinical and pharmacologic studies, GLP-1 RAs were associated with increased glutamate release, NMDA/AMPA receptor activation and increased release of neurotrophic factors associated with neurogenesis, neurodifferentiation, and synaptic plasticity. In addition, GLP-1 RA-induced suppression of food intake was reported to be dependent on AMPA, but not NMDA, receptor signaling. The effect of GLP-1 RAs on feeding behavior is mediated via central glutamatergic signaling. A comprehensive mechanistic framework mediating GLP-1 RA activity implicates crosstalk between GLP-1 and ionotropic glutamate receptors. The aforementioned trends instantiate a need to evaluate the therapeutic efficacy of GLP-1 RAs for disparate neuropsychiatric disorders. Conducting target engagement studies of GLP-1 RAs with the glutamatergic system in humans is a future research vista.