Emerging roles of olfactory receptors in glucose metabolism

HighlightsOlfactory receptors (ORs) are distributed in glucose metabolism-regulating tissues with unique patterns, which might be correlated with their regulatory roles in glucose metabolism.Different ORs in metabolically relevant tissues modulate insulin secretion, gluconeogenesis, glucose reabsorption, lipid metabolism, and appetitive behaviors.ORs not only detect odorants and metabolites, but also sense endogenous polypeptides and proteins with high affinity and regulate important metabolic effects.ORs activate multiple G protein or arrestin pathways in response to ligand stimulation, and 'biased' ligands might be able to preferentially stimulate selective pathways.Emerging methodologies for ligand development might provide new paths to target metabolically relevant ORs and, thus, have therapeutic potential.AbstractOlfactory receptors (ORs) are widely expressed in extra-nasal tissues, where they participate in the regulation of divergent physiological processes. An increasing body of evidence over the past decade has revealed important regulatory roles for extra-nasal ORs in glucose metabolism. Recently, nonodorant endogenous ligands of ORs with metabolic significance have been identified, implying the therapeutic potential of ORs in the treatment of metabolic diseases, such as diabetes and obesity. In this review, we summarize current understanding of the expression patterns and functions of ORs in key tissues involved in glucose metabolism modulation, describe odorant and endogenous OR ligands, explain the biased signaling downstream of ORs, and outline OR therapeutic potential.