GPR83 is an orphan G protein-coupled receptor primarily expressed in brain regions involved in reward, stress/anxiety, learning, memory, and metabolism, as well as in immune tissues including spleen and thymus 1. Recent studies have identified conflicting ligands for GPR83, with some reports suggesting PEN (a proSAAS-derived neuropeptide) as its endogenous ligand 2, while other research demonstrates that FAM237A, rather than PEN, binds to and activates GPR83 with nanomolar affinity 3. The receptor signals through Gi- and Gq-alpha-mediated pathways and induces receptor internalization upon activation 3. GPR83 plays important roles in food intake and body weight regulation, with recent genetic studies identifying it as amplifying MC3R signaling, a key nutritional sensor involved in pubertal timing 4. The receptor is also implicated in anxiety-related behaviors, pain mechanisms, and drug addiction/reward disorders 25. In immune function, GPR83 expression is regulated by Foxp3 in T-regulatory cells involved in autoimmune responses 1. The receptor represents a promising therapeutic target for treating neurological, immune, and metabolic disorders, though clarification of its true endogenous ligand remains necessary for further functional studies 6.