Volume 34, No 3, Mar 2024

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 34 Issue 3, March 2024: 232-244   |  Open Access

ORIGINAL ARTICLES

Identification of oleic acid as an endogenous ligand of GPR3

Yangjie Xiong^1,† , Zhenmei Xu^1,† , Xinzhi Li^1,† , Yuqin Wang^1,† , Jing Zhao^2,† , Na Wang¹ , Yaning Duan¹ , Ruixue Xia¹ , Zhengbin Han¹ , Yu Qian¹ , Jiale Liang¹ , Anqi Zhang¹ , Changyou Guo¹ , Asuka Inoue³ , Yu Xia^2,* , Zheng Chen^1,4,* , Yuanzheng He^1,4,*

¹HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang, China
²MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, China
³Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, Japan
⁴Frontiers Science Center for Matter Behave in Space Environment, Harbin Institute of Technology, Harbin, Heilongjiang, China
^†These authors contributed equally: Yangjie Xiong, Zhenmei Xu, Xinzhi Li, Yuqin Wang, Jing Zhao
Correspondence: Yu Xia(xiayu@mail.tsinghua.edu.cn)Zheng Chen(chenzheng@hit.edu.cn)Yuanzheng He(ajian.he@hit.edu.cn)

Although GPR3 plays pivotal roles in both the nervous system and metabolic processes, such as cold-induced thermogenesis, its endogenous ligand remains elusive. Here, by combining structural approach (including cryo-electron microscopy), mass spectrometry analysis, and functional studies, we identify oleic acid (OA) as an endogenous ligand of GPR3. Our study reveals a hydrophobic tunnel within GPR3 that connects the extracellular side of the receptor to the middle of plasma membrane, enabling fatty acids to readily engage the receptor. Functional studies demonstrate that OA triggers downstream Gs signaling, whereas lysophospholipids fail to activate the receptor. Moreover, our research reveals that cold stimulation induces the secretion of OA in mice, subsequently activating Gs/cAMP/PKA signaling in brown adipose tissue. Notably, brown adipose tissues from Gpr3 knockout mice do not respond to OA during cold stimulation, reinforcing the significance of GPR3 in this process. Finally, we propose a “born to be activated and cold to enhance” model for GPR3 activation. Our study provides a starting framework for the understanding of GPR3 signaling in cold-stimulated thermogenesis.

https://doi.org/10.1038/s41422-024-00932-5

FULL TEXT | PDF

Browse 120