Aims
Targeting the glucose dependent insulinotropic polypeptide receptor (GIPR) is of growing interest for treating type 2 diabetes and obesity, though the optimal approach remains unclear. Both GIPR agonism and antagonism, respectively, incorporated into drugs like tirzepatide and maridebart cafraglutide, have paradoxically both shown significant weight loss effects in humans.

Materials and methods
In this study, the metabolic impacts of a GIPR agonist (GIP108) and antagonist (NN-GIPR-Ant) were evaluated in lean and high-fat diet (HFD)–induced obese male mice. We assessed the impacts on food intake, body weight, glucose and insulin tolerance, liver triglyceride levels, bone markers and adipose tissue lipolytic gene expression.

Results
In lean mice, neither peptide affected food intake or body weight, but GIP108 improved glucose tolerance. In obese mice, both agents reduced food intake and body weight, with NN-GIPR-Ant producing more sustained appetite suppression. Energy expenditure remained unchanged, as weight loss matched that of pair-fed controls. GIP108 improved glucose tolerance independently of weight loss, whereas NN-GIPR-Ant reduced insulin sensitivity compared to pair-fed controls. Both treatments slightly increased liver triglyceride content compared to their pair-fed controls, and no treatment significantly affected plasma bone marker levels. Finally, NN-GIPR-Ant reduced the expression of adipose tissue lipolytic genes.

Conclusions
Our data highlights the distinct metabolic effects of GIPR agonism and antagonism, offering insights for their future application in personalised metabolic disease treatments. Further human studies are needed to understand the long-term metabolic impacts of these therapies.