Science translational medicineDec 21, 2018

Anti-obesity effects of GIP receptor blockers alone and combined with GLP-1 receptor activators in animal models

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 4, 2026

Abstract

Administration of anti-GIPR antibodies resulted in reduced body weight gain and improved metabolic parameters in mice and nonhuman primates.

GIP receptor (GIPR) has been linked to obesity through multiple genetic studies.
Knockout of GIPR in mice protects against diet-induced obesity.
A mouse anti-murine GIPR antibody reduced food intake and improved metabolic parameters in diet-induced obesity mice.
In obese nonhuman primates, an anti-human GIPR antibody led to more pronounced weight loss compared to mice.
Codosing anti-GIPR antibodies with GLP-1 receptor agonists enhanced weight loss effects in both mice and nonhuman primates.
GIPR's role in pancreatic β-cells was excluded from influencing body weight regulation.

Simplified

Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) has been identified in multiple genome-wide association studies (GWAS) as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). On the basis of this genetic evidence, we developed anti-GIPR antagonistic antibodies as a potential therapeutic strategy for the treatment of obesity and observed that a mouse anti-murine GIPR antibody (muGIPR-Ab) protected against body weight gain, improved multiple metabolic parameters, and was associated with reduced food intake and resting respiratory exchange ratio (RER) in DIO mice. We replicated these results in obese nonhuman primates (NHPs) using an anti-human GIPR antibody (hGIPR-Ab) and found that weight loss was more pronounced than in mice. In addition, we observed enhanced weight loss in DIO mice and NHPs when anti-GIPR antibodies were codosed with glucagon-like peptide-1 receptor (GLP-1R) agonists. Mechanistic and crystallographic studies demonstrated that hGIPR-Ab displaced GIP and bound to GIPR using the same conserved hydrophobic residues as GIP. Further, using a conditional knockout mouse model, we excluded the role of GIPR in pancreatic β-cells in the regulation of body weight and response to GIPR antagonism. In conclusion, these data provide preclinical validation of a therapeutic approach to treat obesity with anti-GIPR antibodies.

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Anti-obesity effects of GIP receptor blockers alone and combined with GLP-1 receptor activators in animal models

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