Vagal-FFAR3KO increases WD-induced food intake and weight gain and eliminates the anorectic effect of propionate supplementation in DIO mice. (A–D) Indirect calorimetry of lean FFAR3 flox and vagal-FFAR3KO mice during the first 48 hours of WD challenge. Hourly (A) and cumulative food intake (B), energy expenditure vs. body mass (C), and average energy balance (D) (multiple t-tests, ∗p < 0.05; two-way ANOVA with repeated measures, Fischer's LSD Multiple Comparison's #p < 0.05; n = 8–13 males/group). (E) Change in body mass after two weeks of WD feeding (Student's t-test, n = 8–17 male mice/group). (F–G) Hourly (F) and cumulative food intake (G) of WT DIO mice (fed WD at 9 weeks) after supplementation of saline or 25 mg/mL sodium propionate in drinking water (multiple t-tests, ∗p < 0.05; two-way ANOVA with repeated measures, Fischer's LSD Multiple Comparison's, #p < 0.05, n = 5–6 males/group). (H) Subsequent change in body mass of WT DIO mice after 1 week of propionate supplementation in drinking water (Student's t-test, ∗∗p < 0.01, n = 8–9 males/group). (I–K) Hourly (I) and cumulative food intake (J) of DIO Vagal-FFAR3KO mice (fed WD at 9 weeks) after supplementation of saline or 25 mg/mL sodium propionate in drinking water and the subsequent change in body mass (K) (n = 4–5 males/group). Error bars indicate mean ± SEM.