Optimized GIP analogs promote body weight lowering in mice through GIPR agonism not antagonism

Abstract

Objective Structurally-improved GIP analogs were developed to determine precisely whether GIP receptor (GIPR) agonism or antagonism lowers body weight in obese mice. Methods A series of peptide-based GIP analogs, including structurally diverse agonists and a long-acting antagonist, were generated and characterized in vitro using functional assays in cell systems overexpressing human and mouse derived receptors. These analogs were characterized in vivo in DIO mice following acute dosing for effects on glycemic control, and following chronic dosing for effects on body weight and food intake. Pair-feeding studies and indirect calorimetry were used to survey the mechanism for body weight lowering. Congenital Gipr−/− and Glp1r−/− DIO mice were used to investigate the selectivity of the agonists and to ascribe the pharmacology to effects mediated by the GIPR. Results Non-acylated, Aib2 substituted analogs derived from human GIP sequence showed full in vitro potency at human GIPR and subtly reduced in vitro potency at mouse GIPR without cross-reactivity at GLP-1R. These GIPR agonists lowered acute blood glucose in wild-type and Glp1r−/− mice, and this effect was absent in Gipr−/− mice, which confirmed selectivity towards GIPR. Chronic treatment of DIO mice resulted in modest yet consistent, dose-dependent decreased body weight across many studies with diverse analogs. The mechanism for body weight lowering is due to reductions in food intake, not energy expenditure, as suggested by pair-feeding studies and indirect calorimetry assessment. The weight lowering effect was preserved in DIO Glp-1r−/− mice and absent in DIO Gipr −/− mice. The body weight lowering efficacy of GIPR agonists was enhanced with analogs that exhibit higher mouse GIPR potency, with increased frequency of administration, and with fatty-acylated peptides of extended duration of action. Additionally, a fatty-acylated, N-terminally truncated GIP analog was shown to have high in vitro antagonism potency for human and mouse GIPR without cross-reactive activity at mouse GLP-1R or mouse glucagon receptor (GcgR). This acylated antagonist sufficiently inhibited the acute effects of GIP to improve glucose tolerance in DIO mice. Chronic treatment of DIO mice with high doses of this acylated GIPR antagonist did not result in body weight change. Further, co-treatment of this acylated GIPR antagonist with liraglutide, an acylated GLP-1R agonist, to DIO mice did not result in increased body weight lowering relative to liraglutide-treated mice. Enhanced body weight lowering in DIO mice was evident however following co-treatment of long-acting selective individual agonists for GLP-1R and GIPR, consis...

Enhanced GIP Secretion in Obesity Is Associated with Biochemical Alteration and miRNA Contribution to the Development of Liver Steatosis

“…Killion et al [41] provided a preclinical validation of a therapeutic approach to treat obesity with anti-GIPR antibodies. However, there is no agreement on whether GIP receptor agonism or antagonism lowers body weight [42]. Recently published in The Lancet, data from a phase II trial on dual human agonist with an imbalance in favour of GIP agonism showed significantly better efficacy with regard to weight loss than did selective stimulation of GLP-1 receptor [43,44].…”

Spatiotemporal regulation of GIPR signaling impacts glucose homeostasis as revealed in studies of a common GIPR variant

“…Studies have targeted either GIP (Barbosa-Yañez et al, 2019;Boylan et al, 2015) or GIPR (Killion et al, 2018) with antagonist antibodies and have revealed a protective effect against dietinduced body weight gain. Others have used GIPR peptide agonists to show that by chronically infusing either GIP analog (Mroz et al, 2019) or by a dual treatment with a GLP-1 analog (Finan et al, 2013), a decreased weight and metabolic benefits can be achieved. These discrepancies argue that a modulation rather than a complete abolition or chronic activation of GIPR activity is key to a better metabolism.…”

Twincretin as a potential therapeutic for the management of type 2 diabetes with obesity

“…In contrast, it was reported that GIP overexpression in mice results in improved glucose tolerance with enhanced β‐cell function and resistance to high‐fat diet‐induced obesity, and that chronic activation of GIPR using acylated GIP analog, (d‐Ala(2))GIP[Lys(37)PAL], improves glycemia without excess bodyweight gain in high‐fat diet‐induced obesity in mice. Importantly, the bodyweight reduction by the GIP analog was abolished by pair‐feeding, suggesting that GIP agonist treatment reduces bodyweight mainly due to suppression of food intake. Thus, conflicting results in GIPR‐deficient mice and mice receiving GIP analog might be due to pharmacological levels of the GIP signal in the central nervous system that decrease food intake and overcome the obesogenic effects of GIP at physiological levels in the adipose tissues.…”