Research ArticleMetabolism

Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models

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Science Translational Medicine  19 Dec 2018:
Vol. 10, Issue 472, eaat3392
DOI: 10.1126/scitranslmed.aat3392

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Win one for the GIPR

Glucose-dependent insulinotropic polypeptide (GIP), secreted by the gut to help stimulate insulin release, is a promising therapeutic target in obesity. Here, Killion et al. developed an antibody-based strategy to target the GIP receptor (GIPR) to block the action of GIP. GIPR-Ab treatment of obese mice and nonhuman primates elicited improvements in body weight and fat mass, and also improved fasting serum insulin and triglycerides but not glucose tolerance. Combination with glucagon-like peptide-1 receptor (GLP-1R) agonists further enhanced weight loss. These studies suggest that antagonistic GIPR antibodies are promising candidates for obesity treatment meriting further study.

Abstract

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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