G-Protein-Coupled Receptor (GPCR) Signaling and Pharmacology in Metabolism: Physiology, Mechanisms, and Therapeutic Potential.

G-protein coupled receptors (GPCRs), the largest family of integral membrane proteins, enable cells to sense and appropriately respond to the environment through mediating extracellular signaling to intercellular messenger molecules. GPCRs' pairing with a diverse array of G protein subunits and related downstream secondary messengers, combined with their ligand versatility-from conventional peptide hormone to numerous bioactive metabolites, allow GPCRs to comprehensively regulate metabolism and physiology. Consequently, GPCRs have garnered significant attention for their therapeutic potential in metabolic diseases. This review focuses on six GPCRs, GPR40, GPR120, GLP-1R, and ß-adrenergic receptors (ADRB1, ADRB2, and ADRB3), with GLP-1R recognized as a prominent regulator of system-level metabolism, while the roles of GPR40, GPR120 and ß-adrenergic receptors in central carbon metabolism and energy homeostasis are increasingly appreciated. Here, we discuss their physiological functions in metabolism, the current pharmacological landscape, and the intricacies of their signaling pathways via G protein and ß-arrestin activation. Additionally, we discuss the limitations of existing GPCR-targeted strategies for treating metabolic diseases and offer insights into future perspectives for advancing GPCR pharmacology.