Identification of Or5v1/Olfr110 as an oxylipin receptor and anti-obesity target

Oxylipins are important metabolic messengers for normal life activities, and olfactory receptors (ORs) are known for their low affinity for odor and are not considered oxylipin receptors. By developing the “anonymous receptor identification by reverse-G-protein pull-down” (ARIG) method, we identify orphan OR Or5v1/Olfr110 as an oxylipin 12(S)-hydroxyeicosapentaenoic acid (12(S)-HEPE) receptor. The serum from obese patients with increased BMI showed lower Or5v1/Olfr110-Gs activation compared with normal people. Systemic Or5v1/Olfr110 deficiency or liver-specific Or5v1/Olfr110 deficiency impaired glucose homeostasis, even after stimulation with 12(S)-HEPE. Engagement of 12(S)-HEPE with Olfr110 activated Gs-PKA-pATF2-Cpt1α signaling to reduce obesity through promotion of fatty acid oxidation in liver. Structural aided development of synthetic agonist HOR1-C59 improved glucose homeostasis, which is dependent on Or5v1/Olfr110 expression. Overall, we revealed that a high-affinity oxylipin-sensing OR plays key roles in metabolism. The beneficial effects of HOR1-C59 underscore the therapeutic value of small synthetic compounds that target ORs for disease treatment.