Chronic treatment with anti-GIPR mAb alone and combined with DPP-4 inhibitor correct obesity, dyslipidemia and nephropathy in rodent animals

Objective: Glucose-dependent insulinotropic polypeptide receptor (GIPR) has been identified as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). Therefore, we developed the anti-GIPR antagonistic monoclonal antibody (mAb) alone and in combination with DPP-4 inhibitor as potential therapeutic strategy for treating obesity and dyslipidemia based on this genetic evidence. Methods: Fully neutralized GIPR activity of GIPR-monoclonal antibody (mAb) was assessed by regulating the in vitro production of cAMP in the mouse GIPR stably expressing cells. Chronic efficacies of GIPR-mAb alone and in combination with DPP-4 inhibitor Sitagliptin in diabetic or DIO mice were both investigated. Multiple metabolic parameters including body weight, glucose level, fat mass, lipid metabolism-related indicators as well as H&E staining and immunohistochemical analysis were performed. Role of GIPR in pancreatic cells on regulating fat metabolism was explored in GIPR beta-cell knockout mouse model. Results: Chronic treatment of GIPR-mAb improved body weight control, glucose metabolism, and was associated with reduced fat mass, enhanced pancreatic function and exchange ratio of the resting respiratory in diabetic mice. In addition, further study of anti-GIPR mAb combined with Sitagliptin in DIO mice demonstrated significantly improved weight loss compare to the both monomer treatment. Furthermore, we demonstrated important role of GIPR in beta-cell in regulating the fat mass and response to antagonistic GIPR-mAb in a conditional GIPRknockout mouse. Conclusion: Chronic treatment with anti-GIPR mAb alone and combined with DPP-4 inhibitor provide preclinical therapeutic approaches to treat obesity.

Automated summary

The study shows that chronic treatment with anti-GIPR mAb alone or in combination with DPP-4 inhibitor can improve body weight control, glucose metabolism, and pancreatic function in diabetic or DIO mice. The combined treatment exhibits a significantly improved weight loss compared to individual treatment, indicating a potential therapeutic approach for obesity. The study also highlights the important role of GIPR in regulating fat metabolism in pancreatic cells.