BACKGROUND AND PURPOSE: The incretin hormone, gastric inhibitory peptide/glucose-dependent insulinotropic polypeptide (GIP), secreted by the enteroendocrine K-cells in the proximal intestine, may regulate lipid metabolism and adiposity, but its exact role in these processes is unclear.

EXPERIMENTAL APPROACH: We characterized in vitro and in vivo antagonistic properties of a novel GIP analogue, mGIPAnt-1. We further assessed the in vivo pharmacokinetic profile of this antagonist, as well as its ability to affect high-fat diet (HFD)-induced body weight gain in ovariectomised mice during an 8-week treatment period.

KEY RESULTS: mGIPAnt-1 showed competitive antagonistic properties to the GIP receptor in vitro as it inhibited GIP-induced cAMP accumulation in COS-7 cells. Furthermore, mGIPAnt-1 was capable of inhibiting GIP-induced glucoregulatory and insulinotropic effects in vivo and has a favourable pharmacokinetic profile with a half-life of 7.2 h in C57Bl6 female mice. Finally, sub-chronic treatment with mGIPAnt-1 in ovariectomised HFD mice resulted in a reduction of body weight and fat mass.

CONCLUSION AND IMPLICATIONS: mGIPAnt-1 successfully inhibited acute GIP-induced effects in vitro and in vivo and sub-chronically induces resistance to HFD-induced weight gain in ovariectomised mice. Our results support the development of GIP antagonists for the therapy of obesity.