GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist–Induced Nausea and Emesis in Preclinical Models

Abstract

Experimental models and experimental designsAll procedures were approved by the Institutional Care and Use Committee of the University of Pennsylvania and Eli Lilly and Company. Adult male C57BL/6 mice (Taconic) weighing ~20g at arrival (n=84) were housed under a 12-hour:12-hour light/dark cycle in a temperature-and humidity-controlled vivarium. Mice were individually housed in standard cages with ad libitum access to chow diet (2014, Research Diets) and tap water for all experiments except when noted.Adult male Sprague-Dawley rats (Charles River) weighing ~250-270 g (n=93) at arrival were housed under a 12-hour:12-hour light/dark cycle in a temperature-and humidity-controlled vivarium. Rats were individually housed in hanging wire-bottomed cage with ad libitum access to chow diet (Purina Lab Diet 5001), tap water and also had ad libitum access to kaolin pellets (Research Diets, K50001). Rats were exposed to kaolin for at least 5 days prior to measuring kaolin consumption in pica testing.Adult male shrews (Suncus murinus) weighing ~50-80 g (n=118 total), where bred and

Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation

“…These findings suggest that the negative valence associated with GLP-1RAs is scalable and, to some extent, dissociable from the anorectic effect. These findings are also in line and expand on recent findings showing that GIPR activation reduces emesis induced by GLP-1RA in musk shrews [ 41 ]. Considering that the tolerability of GLP-1RAs is reduced because of drug-related nausea, the findings that GIP receptor activation opposes the aversive effect of GLP-1RAs could have significant therapeutic implications.…”

Recent Advances in Incretin-Based Pharmacotherapies for the Treatment of Obesity and Diabetes

“…The mechanism of how GIPR and GLP-1R agonism synergizes to enhance body weight loss are not known, but a series of experimental results indicates that GIP acts on the GIP receptor in the brain to decrease body weight via inhibition of food intake (156,179,187). Consistent with this, GIPR is expressed in the hypothalamus (156) and the hindbrain (157,188) and DREADD-mediated activation of GIPR neurons/cells in the hypothalamus decreases food intake in rodents (156). Central and peripheral administration of a long-acting (fattyacylated) GIP increases cFOS neuronal activation in key feeding areas of the hypothalamus (179) and several long-acting GIPR agonists have been shown to decreases body weight and food intake in DIO mice without affecting energy expenditure (179,184).…”

“…These data indicate that fatty-acyl GIP acts in the brain to decrease body weight via inhibition of food intake but also decreases body weight independent of GIPR in the CNS ( 179 ). Although GIPR agonists do not require GLP-1R to decrease body weight ( 179 , 184 ), GIPR agonism was recently shown to attenuate the emetic effects of GLP-1R agonism in mice, rats and musk shrews ( 188 ). Given the role of the caudal hindbrain in emetic/aversive behavior ( 191 ) and in mediating GLP-1 effects on food intake ( 56 , 192 , 193 ), these data collectively suggest that GIP potentially acts on the hindbrain-hypothalamus axis to decrease food intake and to improve tolerability of GLP-1R agonism.…”

Reagents and models for detecting endogenous GLP1R and GIPR

“…These approaches are less amenable to the brain, since neurons are difficult to dissociate and purify. snRNA-seq has proved more fruitful in this tissue, with a number of labs showing Glp1r and Gipr expression in various neuronal (sub)populations [ 46 , 47 ]. However, results should ideally be confirmed using in situ hybridization [32] , since neurons may be falsely assigned as Glp1r -/ Gipr - given the high transcript drop-out rate.…”

“…Moreover, GIPR peptide antagonists demonstrate poor IC 50 s for cAMP inhibition and are largely unsuitable for installation of fluorophores. However, Aib2-stablized GIP analogs represent strong candidates for fluorophore installation [ 16 , 69 ], as well as recently reported short (GIP-532) and long (GIP-085) acting GIPR agonists [46] , although any compound should be carefully validated using Gipr-Cre reporter and Gipr −/− mice.…”