Glucose‐dependent insulinotropic polypeptide receptor antagonist treatment causes a reduction in weight gain in ovariectomised high fat diet‐fed mice

Abstract

Background and purpose: The incretin hormone, gastric inhibitory peptide/glucosedependent 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.

Enteroendocrine cells and gut hormones as potential targets in the crossroad of the gut-kidney axis communication

“…GLP-2 also can reduce intestinal permeability and systemic inflammatory phenotype ( Cani et al, 2009 ). As we mentioned before, the existence of communication between the intestine and the kidneys may be supported by the expression of hormone receptors in the renal tissue, for the EEC hormones, suggesting that they can exert some effects in the kidney ( Seino and Yabe, 2013 ; Boer et al, 2022 ). In this review, we discuss the findings considering each EEC hormone and its receptors in different kidney diseases.…”

“…However, due to its ability to postprandially stimulate insulin secretion in a glucose-dependent manner, it was later renamed glucose-dependent insulinotropic polypeptide ( Khan et al, 2020 ). Apart from its insulin-stimulating effects, GIP, during hypoglycemia, stimulates glucagon secretion ( Gasbjerg et al, 2018 ), enhances the absorption of fatty acids in adipocytes, increases the deposition of triglycerides in subcutaneous adipose tissue ( Boer et al, 2022 ) and decreases bone reabsorption ( Gasbjerg et al, 2018 ). Similar to GLP-1, GIP is rapidly degraded by dipeptidyl peptidase 4 (DPP-4), resulting in a short half-life of a few minutes ( Idorn et al, 2014 ).…”

Discovery of a potent GIPR peptide antagonist that is effective in rodent and human systems

“…Therefore, we conclude that the C18-OH protractor proves deleterious for potent GIPR antagonism compared to the C16 iterations, and such reductions in potency should be balanced with the improved pharmacokinetics predicted for C18-OH protraction. This should be taken into consideration when examining the effects seen in other reports [ 15 ]. Additionally, during our residue protraction position screening studies, specifically moving the C16 protractor from position 11 as seen in 7 to position 10 ( 12 ), did not significantly alter the potency at hGIPR (IC 50 = 0.61 nM) but reduced the potency at mGIPR (IC 50 = 12.4 nM; Table 1 ).…”

“…Previously, N-terminal or C-terminal truncated GIP fragments were systematically studied for GIPR binding and cAMP signal transduction [ 12 ]. (Pro3)GIP and N- or C-terminally truncated fragments including GIP (3-30) , GIP (5-30) , GIP (6-30) , GIP (3-42) , and GIP (5-42) have been studied for their antagonistic effects on GIPR-mediated insulin release, insulin resistance, glucose control, lipid metabolism, and body weight regulation [ [13] , [14] , [15] ]. However, these GIP fragments demonstrated variable profiles of antagonism and agonism in vitro.…”