Background: Animal studies have found that GPHB5 has a similar effect on system metabolism as TSH. However, the relationship between GPHB5 and metabolic diseases remains unknown. This study investigates the relationship between GPHB5 and MetS in young women. Methods: Bioinformatics analysis was undertaken to explore the relationship between GPHB5 and metabolic-related genes and signaling pathways. EHC and OGTT were performed on all individuals. Lipid-infusion, physical activity, and cold-exposure tests were performed on healthy individuals. Serum GPHB5 concentrations were measured by an ELISA kit. Results: PPI network showed that 11 genes interacted with GPHB5, in which POMC and KISS1R were involved in glucose and lipid metabolism. GO analysis showed 56 pathways for BP and 16 pathways for MF, in which OPRM1 and MCR families were related to energy metabolism. KEGG analysis found that GPHB5 is associated with lipolysis and neuroactive ligand-receptor interaction pathways. The levels of circulating GPHB5 were significantly increased, while serum adiponectin levels were lower in MetS women compared with healthy women. Obese/overweight individuals had lower adiponectin levels and higher GPHB5 levels. Circulating GPHB5 levels were positively correlated with BMI, WHR, blood pressure, FBG, 2 h-BG, HbA1c, FIns, 2h-Ins, LDL-C, FFA, HOMA-IR, and AUCg, etc. but negatively correlated with HDL-C, adiponectin, and M-values. Serum GPHB5 levels did not change significantly during the OGTT, EHC, and lipid infusion. Physical activity and cold-exposure tests did not lead to changes in GPHB5 levels. GLP-1RA treatment resulted in a significant decrease in serum GPHB5 levels. Conclusions: GPHB5 may be a biomarker for MetS.