Related Experiment Video
Updated: Jul 8, 2026

Techniques of Sleeve Gastrectomy and Modified Roux-en-Y Gastric Bypass in Mice
Published on: March 20, 2017
A Sequential Dual GLP-1R/GIPR Agonist-To-Antagonist Molecule Achieves Superior Weight Loss in Obese Mice
Yunxiao Zhang1, Bo Zhu1, Binhui Peng1
1School of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang, Hunan, China.
Background:
The GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) are key targets for diabetes and obesity therapies. Pharmacological agents including GLP-1R agonists (e.g., Semaglutide), dual GLP-1R/GIPR agonists (e.g., Tirzepatide) and a GLP-1R agonist/GIPR antagonist (AMG133) have demonstrated considerable promise in anti-diabetic and weight management applications. However, a systematic comparison of the specific contributions of GIPR activation versus GIPR inhibition to weight loss within the context of GLP-1/GIP dual-targeting therapies remains unexplored.
Research Design And Methods:
To address this, we designed three IgG4 Fc-fusion proteins: a GLP-1R agonist/GIPR agonist, (i) GLP-1(A8G)/GIP(A2G)-Fc; a GLP-1R agonist/GIPR inhibitor, (ii) GLP-1(A8G)/GIP(3-30)-Fc; and a sequential molecule that hypothesised to transition from dual GLP-1R/GIPR agonism to GLP-1R agonism/GIPR inhibition, (iii) GLP-1(A8G)/GIP(1-30)-Fc. Mono-agonist GLP-1(A8G)-Fc and dual-agonist GLP-1(A8G)/GIP(A2G)-Fc were used as controls to investigate the weight loss effects of GIPR activation and inhibition in DIO mice.
Results:
Our findings revealed that the sequential molecule GLP-1(A8G)/GIP(1-30)-Fc produced the greatest body weight reduction (21.59%), significantly outperforming GLP-1(A8G)/GIP(3-30)-Fc (14.5%; p < 0.001). Furthermore, both GIPR activation and inhibition, when combined with GLP-1R agonism, markedly improved serum and hepatic lipid metabolism, as evidenced by reduced triglycerides and total cholesterol.
Conclusion:
Together, these findings validate a peptide-based inhibitory strategy for synergistic weight loss and provide insights into the differential metabolic roles of GIPR activation versus inhibition, guiding the development of novel anti-obesity therapeutics.
Related Concept Videos
Glucagon-like Receptor Agonists
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by the...
Dipeptidyl Peptidase 4 Inhibitors
Oral Hypoglycemic Agents: Glinides
Oral Hypoglycemic Agents: α-Glucosidase Inhibitors
Acarbose and miglitol are typically...
Pharmacokinetics in Obese Patients: Drug Absorption and Distribution
Oral Hypoglycemic Agents: Biguanides and Glitazones
