639-P: GIP Receptor Agonism Enhances Weight Loss from Either a Biased or an Unbiased GLP-1 Receptor Agonist in DIO Mice

GIP receptor (GIPR) agonism enhances the reduction of food intake and weight loss induced by GLP-1 receptor (GLP-1R) agonism. Recently, GLP-1R agonists have been described that exhibit biased agonism as determined using cells engineered to facilitate measuring the two canonical signaling pathways engaged upon binding the GLP-1R. Such “biased agonists” retain the ability to activate the G alpha S/cyclic AMP (cAMP) pathway to a similar magnitude as native GLP-1 but exhibit markedly weaker ability to induce receptor recruitment of beta-arrestin. The prototype biased GLP-1R agonist Exendin-Phe1 (Ex-Phe1) is reported to exhibit greater weight and glucose control in diet-induced obese (DIO) mice than its unbiased parent Exendin-4 (Ex4). Herein, we investigated whether the enhanced weight loss of Ex-Phe1 erodes the ability of GIPR agonism to further enhance the efficacy of GLP-1R agonism. The peptides were first characterized in vitro to validate the biased nature of Ex-Ph1. In cells expressing either the human or murine GLP-1R, Ex-Phe1 activated cAMP signaling to a similar magnitude as GLP-1 and Ex4 but with approximately 5-fold lower potency than Ex4. The maximum effect of Ex-Phe1 upon human or mouse GLP-1R recruitment of beta-arrestin was 20% compared with full efficacy for Ex4 relative to GLP-1. In this assay Ex-Phe1 was marginally less potent than Ex4. In a 14-day osmotic minipump DIO mice study, Ex4 and Ex-Phe1 each dose dependently reduced food intake and lowered body weight. Ex-Phe1 was 10-fold more potent than Ex4, and at the maximum dose, delivered superior weight loss. Combination treatment with d-Ala-GIP resulted in similar additional body weight loss to that achieved by either Ex-Phe1 or Ex4 alone by enhancing food intake reduction and increasing energy expenditure. D-Ala-GIP alone had no effect on body weight. These findings indicate that GIPR agonism enhances GLP-1R agonism mediated weight loss irrespective of the pathway bias nature of the latter.