Fig. 5: Weight loss generated by the mGIPR-Ab/GLP-1 peptide–antibody conjugate is dependent on GLP-1R activity in the CNS.
a, Breeding schematic for generation of CNS Glp1r KO mice (created with BioRender.com). Male (blue) and female (red) Glp1rfl/fl and Glp1rWnt1−/− littermates were fed HFD for 13 weeks and then treated with vehicle (2 ml kg−1 every 6 days) or mGIPR-Ab/P1 (1.5 mg kg−1 every 6 days) for 18 days. b,j, Day 18 body weight per cent change, c,k, per cent body weight change from day 0 and d, change in body weight over time in male and female Glp1rfl/fl and Glp1rWnt1−/− littermates. e, Average daily food intake in male Glp1rfl/fl and Glp1rWnt1−/− littermates. l, Day 18 body weight change in grams in female Glp1rfl/fl and Glp1rWnt1−/− littermates. Average body weight of female mice at study start (day 0) for Glp1rfl/fl vehicle-treated mice was 29.07 g, Glp1rWnt1−/− vehicle-treated mice was 32.44 g, Glp1rfl/fl mGIPR-Ab/P1-treated mice was 34.07 g and Glp1rWnt1−/− mGIPR-Ab/P1-treated mice was 33.57 g. f,m, Fat mass measured by MRI on day 17. Day 18 necropsy tissue weights for g,n inguinal WAT, h,o, gonadal WAT and i,p, liver. For b–i (males), Glp1rfl/fl / vehicle (n = 10), Glp1rfl/fl / mGIPR-Ab/P1 (n = 11), Glp1rWnt1−/− / vehicle (n = 10) and Glp1rWnt1−/− / mGIPR-Ab/P1 (n = 10). For j–p (females), Glp1rfl/fl / vehicle (n = 7), Glp1rfl/fl / mGIPR-Ab/P1 (n = 4), Glp1rWnt1−/− / vehicle (n = 6) and Glp1rWnt1−/− / mGIPR-Ab/P1 (n = 7). In b, f–i, j and l–o, two-way ANOVA with Tukey’s multiple comparisons test; in c–e and k, two-way repeated measures ANOVA with genotype and treatment as main factors or mixed-effects analysis followed by a Tukey’s multiple comparisons test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 where comparison indicated by bracket; # indicates P < 0.05 versus vehicle within genotype (Glp1rfl/fl), ^ indicates P < 0.05 versus vehicle within genotype (Glp1rWnt1−/−), + (blue or red) indicates P < 0.05 versus Glp1rfl/fl within mGIPR-Ab/P1 treatment, + (black) indicates P < 0.05 versus Glp1rfl/fl within vehicle treatment. Data represent means; error bars, s.e.m. ns, not significant.
