Pharmacological effects of GLP-1R, GIPR, and GcgR agonism alone or in combination in DIO mice. Body weight (A–C) and IPGTT blood glucose (D–F) for DIO mice. Animals were given subcutaneous injections once per day with semaglutide (1; 1 nmol/kg), acyl-GLP-1R/GIPR co-agonist (2; 1 nmol/kg), acyl-GcgR agonist (3; 3 nmol/kg), or combinations thereof. Body weight was measured daily over 8 days. The IPGTT was performed on day 8 (24 h after compound administration). In vitro potency at mouse-derived receptors is provided in panel G. Average starting body weight for mice in these studies was 62.6 g and did not differ significantly between any group. ∗ indicate a p-value < 0.05 compared to vehicle control; ˆ indicate a p-value < 0.05 relative to a treatment group as indicated.