Glucagon-Like Peptide-2 Receptor: A Master Integrator of Gut-Brain-Liver Communication in Metabolic and Cognitive...

Glucagon-like peptide-2 (GLP-2) has historically been defined by its primary role as an intestinal hormone essential for mucosal growth and epithelial barrier integrity. However, a surge of recent research has sparked a paradigm shift, recasting the GLP-2 receptor (GLP-2R) as a master orchestrator of communication between the gut, brain, and liver. This review synthesizes these advances, highlighting the receptor's strategic expression across this tripartite axis and its functional significance in bidirectional signaling pathways. We also detail its distinct quantitative distribution compared to the GLP-1 receptor (GLP-1R). We examine how GLP-2R serves as a molecular hub in these bidirectional signaling networks critical for both metabolic and cognitive health. Through convergent neural and endocrine pathways, GLP-2R modulates appetite, gastrointestinal motility, metabolic homeostasis, and neuroinflammatory processes that underpin cognitive function. These pathways include vagal afferent circuits, sympathetic innervation, and restricted central access via circumventricular organs. Notably, we also address species-specific differences in GLP-2R function and their critical translational significance for human therapeutics. This is particularly relevant regarding appetite regulation and pancreatic expression. We review the latest pharmacological innovations, including long-acting analogs, synergistic dual agonists, and novel delivery systems. These dual agonists specifically leverage the structural and signaling non-overlap between GLP-1R and GLP-2R to unlock the receptor's full therapeutic potential. Finally, we discuss ongoing challenges and highlight specific unanswered mechanistic questions. This positions GLP-2R as both a promising therapeutic target and a fundamental research tool for dissecting the integrated crosstalk between the gut, brain, and liver that governs whole-body physiology and behavior.