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. 2022 Nov 25;66:101645. doi: 10.1016/j.molmet.2022.101645

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© 2022 The Author(s)

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PMC Copyright notice

Stim1 mutagenesis in POMC neurons attenuates body mass, fat, and food intake in mice on a high fat diet. Male Pomc^Cre mice were placed on high fat diet (45%) 10 days after being injected with AAV1- FLEX-SaCas9-U6-sgStim1 (n = 8) or AAV1-FLEX-SaCas9-U6-sgControl (n = 8). A, percent change in body weight measured once a week for seven weeks. The high fat diet caused significant weight gain in both groups relative to their baseline, with the controls gaining significantly more by 5 weeks (two-way ANOVA: main effect of treatment (F_{(1, 13)} = 7.076, p = 0.0196), main effect of time (F_{(7, 91)} = 78.14, p < 0.0001) and interaction (F_{(7, 91)} = 5.341, p < 0.0001); control, n = 8, Stim1^Mut, n = 8; post hoc Bonferroni test, ∗p < 0.05, ∗∗p < 0.01). Total body fat (B) and Lean mass (C) measured by an EchoMRI Whole Body Composition Analyzer (Echo Medical Systems, Houston, TX, USA). Lean mass does not include bone and fluids within organs. The difference in body fat percentage (B) and lean mass percentage (C) between the groups became significantly different by 4 weeks on high fat diet (two-way ANOVA for B: main effect of treatment (F_{(1, 14)} = 3.092, p = 0.1005), main effect of time (F_{(1, 14)} = 260.3, p < 0.0001) and interaction (F_{(1, 14)} = 7.379, p = 0.0167); control, n = 8, Stim1^Mut, n = 8; post hoc Bonferroni test, ∗p < 0.05. Two-way ANOVA for C: main effect of treatment F_{(1, 14)} = 5.801, p = 0.0304, main effect of time F_(1,14) = 205.1, p < 0.0001 and interaction (F_{(1, 14)} = 4.833, p = 0.0452); control, n = 8, Stim1^Mut, n = 8; post hoc Bonferroni test, ∗∗p < 0.01). D, five weeks after viral injection, average 24-hour food intake was measured for four consecutive days (representative data shown). Stim1^Mut significantly reduced food intake (unpaired two-tailed t-test of each animal's average, t₍₁₄₎ = 2.380, ∗p = 0.0321). E, six weeks after viral injection and 5 weeks on high fat diet, the GTTs showed no significant difference between the two groups (two-way ANOVA: main effect of treatment (F_{(1, 14)} = 0.9184, p = 0.35), main effect of time (F_{(4, 56)} = 175.5, p < 0.0001) and interaction (F_{(4, 56)} = 0.7049, p = 0.5919); control, n = 8, Stim1^Mut, n = 8; post hoc Bonferroni test, p > 0.05). F, Fat pad of Stim1^Mut mice on high fat diet for 7–8 weeks were 30% lighter than control DIO mice at the time that they were euthanized for electrophysiology studies (unpaired two-tailed t-test, t₍₁₄₎ = 2.724, ∗p = 0.0165).