Functional screening and rational design of compounds targeting GPR132 to treat diabetes

  • Nat Metab. 2023 Oct;5(10):1726-1746. doi: 10.1038/s42255-023-00899-4.
Jia-Le Wang  #  1 ,  Xiao-Dong Dou  #  2 ,  Jie Cheng  #  3  4 ,  Ming-Xin Gao  #  4 ,  Guo-Feng Xu  #  2 ,  Wei Ding  #  5 ,  Jin-Hui Ding  #  1 ,  Yu Li  1 ,  Si-Han Wang  4 ,  Zhao-Wei Ji  4 ,  Xin-Yi Zhao  2 ,  Tong-Yu Huo  2 ,  Cai-Fang Zhang  2 ,  Ya-Meng Liu  2  6 ,  Xue-Ying Sha  1 ,  Jia-Rui Gao  4 ,  Wen-Hui Zhang  4 ,  Yong Hao  7 ,  Cheng Zhang  8 ,  Jin-Peng Sun  9  10  11 ,  Ning Jiao  12  13 ,  Xiao Yu  14
Affiliations
  • 1. State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
  • 2. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
  • 3. Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 4. Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, China.
  • 5. Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China.
  • 6. Changping Laboratory, Yard 28, Science Park Road, Chanaping District,, Beijing, China.
  • 7. Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 8. The Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, China.
  • 9. State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China. [email protected].
  • 10. Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China. [email protected].
  • 11. NHC Key Laboratory of Otorhinolaryngology, Qilu hospital and advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, China. [email protected].
  • 12. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China. [email protected].
  • 13. Changping Laboratory, Yard 28, Science Park Road, Chanaping District,, Beijing, China. [email protected].
  • 14. Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, China. [email protected].
  • # Contributed equally.
PMID: 37770763 DOI: 10.1038/s42255-023-00899-4
Abstract

Chronic inflammation due to islet-residing macrophages plays key roles in the development of type 2 diabetes mellitus. By systematically profiling intra-islet lipid-transmembrane receptor signalling in islet-resident macrophages, we identified endogenous 9(S)-hydroxy-10,12-octadecadienoic acid-G-protein-coupled receptor 132 (GPR132)-Gi signalling as a significant contributor to islet macrophage reprogramming and found that GPR132 deficiency in macrophages reversed metabolic disorders in mice fed a high-fat diet. The cryo-electron microscopy structures of GPR132 bound with two endogenous agonists, N-palmitoylglycine and 9(S)-hydroxy-10,12-octadecadienoic acid, enabled us to rationally design both GPR132 agonists and antagonists with high potency and selectivity through stepwise translational approaches. We ultimately identified a selective GPR132 antagonist, NOX-6-18, that modulates macrophage reprogramming within pancreatic islets, decreases weight gain and enhances glucose metabolism in mice fed a high-fat diet. Our study not only illustrates that intra-islet lipid signalling contributes to islet macrophage reprogramming but also provides a broadly applicable strategy for the identification of important G-protein-coupled receptor targets in pathophysiological processes, followed by the rational design of therapeutic leads for refractory diseases such as diabetes.

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