GPCR Biased Signaling in Metabolism.

G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors and the most prominent drug targets. GPCR-biased signaling exerts different functions through distinct downstream signaling pathways of receptor to maintain body homeostasis. Metabolism is the series of biochemical processes that occur within a living organism to maintain life. GPCR-biased signaling and metabolism exhibit bidirectional interplay. On the one hand, metabolites including short-chain fatty acids (SCFAs) and long-chain fatty acids (LCFAs) act as ligands inducing biased GPCRs signaling. On the other hand, activated GPCRs regulate diverse metabolic functions by biased signal sorting (G protein or β-arrestin-mediated). G protein signaling mainly mediates rapid metabolic reaction, and β-arrestin signaling mainly mediates sustained metabolic effects. In clinical drug applications, GPCR-biased drugs can revolutionize metabolic disease therapeutics by enabling pathway-selective drug design to enhance efficacy while reducing side effects. Thus, delving deeper into the relationship between GPCR-biased signaling and metabolism is of great importance in physiology, pathology, and pharmacology. A systematic exploration of biased signaling will enhance insights into GPCRs-metabolism interactions, aiding disease mechanism studies, drug discovery, and clinical treatment strategies.