Fig. 1: Validation of small-molecule GLP1R agonist-responsive mouse model.

a, Characteristics of GLP1, liraglutide, danuglipron and orforglipron. MW, molecular weight. b, Two-hour SD intake after treatment with liraglutide (Lira), vehicle (Veh) or danuglipron (Dan) (n = 11 per group). c, Serine (TCA or S) to tryptophan (TGG or W) CRISPR-mediated substitution in Glp1r^S33W mice. d,e, Sequencing chromatograms of WT mouse Glp1r (d) and Glp1r^S33W (e). f–h, Glucose (dextrose; Dex) tolerance test. Blood glucose levels on liraglutide (f; WT n = 8, Glp1r^S33W n = 6), danuglipron (g; WT n = 9, Glp1r^S33W n = 6) or orforglipron (Orfo) (h; WT n = 5, Glp1r^S33W n = 5) in WT and Glp1r^S33W mice. i–n, SD intake after treatment with liraglutide (i,j; WT n = 10, Glp1r^S33W n = 9), danuglipron (k,l; WT n = 16, Glp1r^S33W n = 15), orforglipron (m,n; WT n = 8, Glp1r^S33W n = 9) or their vehicle controls in WT and Glp1r^S33W mice. o–t, HFD intake after treatment with liraglutide (o,p; WT n = 10, Glp1r^S33W n = 8), danuglipron (q,r; WT n = 16, Glp1r^S33W n = 14), orforglipron (s,t; WT n = 8, Glp1r^S33W n = 9) or their vehicle controls in WT and Glp1r^S33W mice. u, GTT after oral administration of danuglipron (Oral dan) in Glp1r^S33W and WT mice (n = 6 per group). v,x, HFD intake after oral administration of danuglipron (n = 9) or vehicle (n = 8) (v) or oral administration of orforglipron (n = 8) or vehicle (n = 8) (x) in Glp1r^S33W mice. w,y, Four-hour food intake (HFD) after intraperitoneal (IP) or oral administration of danuglipron (w; IP n = 14 per injection, oral vehicle n = 8, oral dan n = 9) or orforglipron (y; IP n = 9 per injection, oral n = 8 per injection). z, Change in body weight in male mice on HFD (at least 8 weeks) treated with daily (ZT6) orforglipron or vehicle (n = 10 per group). All data are mean ± s.e.m. Statistical tests: one-way ANOVA (b; two-way ANOVA) with Bonferroni correction (f–z). *P < 0.05; **P < 0.01; ***P < 0.001. See Supplementary Table 1 for statistical details.

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