Fig. 1: Anti-GIPR antibody administration to the brain reduces body weight and food intake in obese mice.
a, Timeline of ICV and ICV versus IP dosing studies in obese mice (created with BioRender.com). To examine the dose response from central administration of mGIPR-Ab, male DIO mice received ICV cannula targeting the third ventricle in the brain. Mice were randomized into one of six groups: (1) vehicle/aCSF (1 µl per mouse, n = 11), (2) IgG1 (15 µg per µl per mouse, n = 11), (3) IgG1 (30 µg per µl per mouse, n = 11), (4) mGIPR-Ab (7.5 µg per µl per mouse, n = 12), (5) mGIPR-Ab (15 µg per µl per mouse, n = 11) or (6) mGIPR-Ab (30 µg per µl per mouse, n = 12). All mice were dosed every 2 days for ten treatments. b–d, Change in body weight (b), body weight (c) and cumulative food intake (d) were measured daily. To directly compare central versus systemic administration of mGIPR-Ab, all male DIO mice received ICV cannula and were randomized into one of four groups: (1) central IgG1 (15 µg per µl per mouse), (2) central mGIPR-Ab (15 µg per µl per mouse), (3) systemic IgG1 (5 mg kg−1) or (4) systemic mGIPR-Ab (5 mg kg−1). All mice were dosed every 2 days for seven treatments. e–g, Change in body weight (e), body weight (f) and food intake (g) were measured daily. h–m, Pharmacokinetic exposure to mGIPR-Ab treatment from central (ICV) and systemic (IP) dosing in forebrain (h), hindbrain (i), total brain (j), plasma (k), inguinal WAT (l) and epididymal WAT (m) was measured 48 h after the last dose. The forebrain and hindbrain were separated at around −3.87 mm from bregma. For b,c, aCSF (1 µl per mouse, n = 11), IgG1 (15 µg per µl per mouse, n = 11), IgG1 (30 µg per µl per mouse, n = 11), mGIPR-Ab (7.5 µg per µl per mouse, n = 12), mGIPR-Ab (15 µg per µl per mouse, n = 11) and mGIPR-Ab (30 µg per µl per mouse, n = 12); for d, aCSF (1 µl per mouse, n = 9), IgG1 (15 µg per µl per mouse, n = 10), 3) IgG1 (30 µg per µl per mouse, n = 11), mGIPR-Ab (7.5 µg per µl per mouse, n = 11), mGIPR-Ab (15 µg per µl per mouse, n = 8) and mGIPR-Ab (30 µg per µl per mouse, n = 12); for e–m, n = 15 per group. In b–g, one-way or two-way repeated measures ANOVA with Tukey’s test for multiple comparisons; in h–m, two-tailed unpaired t-test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus aCSF (b–d) or versus IgG1 from respective dosing route or as noted by brackets (e–g); +P < 0.05, central IgG1 versus systemic IgG1; #P < 0.05, central mGIPR-Ab versus systemic mGIPR-Ab. Data represent means; error bars, s.e.m. aCSF, artificial cerebrospinal fluid.
