Type 2 diabetes mellitus is characterized by the dysregulation of glucose homeostasis and insulin sensitivity, resulting in hyperglycemia. The exploration of a complex regulatory network in host metabolism homeostasis may raise a novel strategy for the prevention of T2D. A variety of metabolites serve as the endogenous ligand of G protein-coupled receptors (GPCR) and play an important role in the pathophysiological process of T2D and insulin resistance, however, the roles of remaining endogenous metabolites in insulin resistance and GPCRs still need to be explored.The effect of LPC (17:0) on hyperglycemia were proved in high fat diet (HFD) mice, and qPCR with Western blot technology was used to verify the downstream targets.Herein, we found that LPC (17:0) reduced blood glucose and alleviated insulin resistance and related metabolic disorders in high-fat diet induced (HFD) mice through activating GLP-1 and promoting insulin secretion. Further, the LPC (17:0) was found to stimulate intestinal GPR120, GPR35 and CALCR, with potential effect on GLP-1 stimulation.The above observation revealed LPC (17:0) as an endogenous protective factor with potential role on GPCRs, and it provided theoretical support for the development of LPC (17:0) as a potent drug candidate or health food additive for insulin resistance and hyperglycemia.© 2022 Bao et al.