1. Academic Validation
  2. Identification of Or5v1/Olfr110 as an oxylipin receptor and anti-obesity target

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

  • Cell. 2026 Jan 21:S0092-8674(25)01429-1. doi: 10.1016/j.cell.2025.12.016.
Xiao-Yan Ge 1 Jie Cheng 1 Li-Jun Zhang 2 Lu-Lu Guo 1 Rui Xiang 3 Yan Lu 2 Shang-Lei Ning 4 Kai-Yu Wang 2 Kong-Kai Zhu 1 Ming-Xin Gao 2 Yue Li 1 Yu-Song Zhang 2 Nai-Kang Rong 2 Xiang Han 2 Ming-Hui Zhang 4 Le Fang 5 Yun-Fei Xu 4 Su-Wen Zhao 6 Qian Li 7 Fan Yang 8 Yong Hao 9 Ren-Jie Chai 10 Xiao Yu 11 Ji-Chun Yang 12 Jin-Peng Sun 13
Affiliations

Affiliations

  • 1 Advanced Medical Research Institute, NHC Key Laboratory of Otorhinolaryngology, Qi lu Hospital, New Cornerstone Science Laboratory, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
  • 2 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shandong Key Laboratory of Mental Disorders and Intelligent Control, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
  • 3 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing 100191, China.
  • 4 Department of Hepatobiliary Surgery, General Surgery, Qilu Hospital, Gheeloo College of Medicine, Shandong University, Jinan 250012, China.
  • 5 Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China.
  • 6 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 7 Department of Otolaryngology, Songjiang Hospital and Songjiang Research Institute, Ministry of Education Key Laboratory of Children's Environmental Health, Shanghai Key Laboratory of Emotions and Affective Disorders, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 201318, China.
  • 8 Advanced Medical Research Institute, NHC Key Laboratory of Otorhinolaryngology, Qi lu Hospital, New Cornerstone Science Laboratory, Cheeloo College of Medicine, Shandong University, Jinan 250012, China; State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong University, Jinan 250012, China.
  • 9 Department of Neurology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. Electronic address: yhao23@126.com.
  • 10 State Key Laboratory of Bioelectronics, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing 210096, China. Electronic address: renjiec@seu.edu.cn.
  • 11 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shandong Key Laboratory of Mental Disorders and Intelligent Control, Cheeloo College of Medicine, Shandong University, Jinan 250012, China. Electronic address: yuxiao@sdu.edu.cn.
  • 12 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing 100191, China. Electronic address: yangj@bjmu.edu.cn.
  • 13 Advanced Medical Research Institute, NHC Key Laboratory of Otorhinolaryngology, Qi lu Hospital, New Cornerstone Science Laboratory, Cheeloo College of Medicine, Shandong University, Jinan 250012, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing 100191, China. Electronic address: sunjinpeng@sdu.edu.cn.
Abstract

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.

Keywords

GPCR signal transduction; drug development; obesity; olfactory receptor.

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