Glucose-Dependent Insulinotropic Polypeptide Receptor Therapies For The Treatment Of Obesity, Do Agonists = Antagonists?

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) is associated with obesity in human genome-wide association studies (GWAS). Similarly, mouse genetic studies indicate that loss of function alleles and GIP overexpression both protect from high-fat diet (HFD)-induced weight gain. Together, these data provide compelling evidence to develop therapies targeting GIPR for the treatment of obesity. Further, both antagonists and agonists alone prevent weight gain, but result in remarkable weight loss when co-dosed or molecularly combined with glucagon-like peptide-1 (GLP-1) analogs preclinically. Here, we review the current literature on GIPR, including biology, human and mouse genetics, and pharmacology of both agonists and antagonists, discussing the similarities and differences between the two approaches. Despite opposite approaches being investigated preclinically and clinically, there may be viability of both agonists and antagonists for the treatment of obesity and we expect this area to continue to evolve with new clinical data and molecular and pharmacological analyses of GIPR function.

GIPR Signaling in Immune Cells Maintains Metabolically Beneficial Type 2 Immune Responses in the White Fat From Obese Mice

“…Nevertheless, it remains elusive whether these cells can indeed directly recognize and respond to GIP. While loss-of-function studies indicate that GIP drives weight gain, when it comes to GIPR agonism and antagonism, compelling evidence paradoxically indicate that both approaches can reduce body weight, especially if combined with GLP-1 agonists (12,59). This paradox may reflect the partial agonistic activity of certain antagonists (60), compensatory relationship and overlapping signaling axes between GIPR and GLP-1R incretin receptors (59,61), as well as desensitization of GIPR achieved by chronic agonism (62).…”

“…Specifically, the directional importance of GIP in obesity-associated inflammatory responses is surrounded by controversy, with studies reporting both pro- (8,9) and anti-inflammatory (10,11) effects in the white adipose tissue (WAT). These opposing results likely reflect the integrated pleiotropic functions of GIP in different tissues and cells, and the utilization in many studies of GIP analogues that can serve as both agonists and antagonists (12). Therefore, studying GIP biology in a cell-specifi c manner can benefi t our comprehension of its immunometabolic pathways.…”

Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease

“…An additional layer of complexity underlying the rational development of GLP-1:GIP co-agonists stems from multiple studies demonstrating that GIPR antagonism may also be metabolically beneficial [ 91 ]. Notably, GIPR agonists and antagonists exhibit similar efficacy in preventing weight gain or promoting weight loss when combined with a GLP-1R agonist, providing support for developing GIPR antagonist:GLP-1R agonist combinations [ 91 ].…”

“…An additional layer of complexity underlying the rational development of GLP-1:GIP co-agonists stems from multiple studies demonstrating that GIPR antagonism may also be metabolically beneficial [ 91 ]. Notably, GIPR agonists and antagonists exhibit similar efficacy in preventing weight gain or promoting weight loss when combined with a GLP-1R agonist, providing support for developing GIPR antagonist:GLP-1R agonist combinations [ 91 ]. Agonist-induced GIPR desensitization has been proposed as a potential unifying mechanism to explain this paradoxical observation [ 91 , 92 ], raising the fascinating possibility that we may witness the development of competing therapeutic strategies based on either GIPR agonism or antagonism, together with GLP-1R agonism, to treat T2D or obesity.…”

Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms

“…The effect of Gipg013 on body weight was modest (∼20% decreases) compared with GLP-1R agonism with dulaglutide in a parallel group of mice (50–90% decreases). These results were largely in line with the effects of an another GIPR-antagonizing antibody that was developed to target the mGIPR (muGIPR-Ab) [ 59 , 82 , 83 ]. Peripheral treatment of high-fat fed obese mice with muGIPR-Ab produced modest (∼5%) decreases in body weight, while dulaglutide given over the same time period induced ∼15% weight loss.…”