Genetic-by-diet interactions in the methylation status of the Avpr1a locus and liver metabolome alterations. (a) B6 mice fed the American diet are hypermethylated relative to those fed the control mouse diet at the Avpr1a locus (n = 8), P < 0.0001 by Student’s t-test. (b) American diet feeding did not alter methylation status in the A strain (n = 7–8), P = 0.49 by Student’s t-test. (c) Transcript expression of Avpr1a was reduced by 84% in B6 mice fed the American diet relative to other strain-diet groups in mice fed diets for 6 months (n = 4–5), P < 0.0001 by ANOVA. (d) Transcript expression of Avpr1a is reduced by 54% in B6 mice fed the American diet for 2 weeks (n = 4), P = 0.0077 by Student’s t-test. (e) Number of liver metabolites, including both known and unknown, significantly altered by the American diet relative to the control mouse diet. (f) Proportion of metabolites significantly changed in all four strains (2%), three strains (4%), two strains (10%), or unique to one strain (84%). (g) Heatmap of effect sizes (Cohen’s d) for known metabolites significantly altered by the American diet relative to the control mouse diet across strains. * P < 0.05, ** P < 0.01, and *** P < 0.001 by ANOVA between means with Benjamin–Hochberg correction factor. A, A/J strain mice; B6, C57BL/6J strain mice; FVB, FVB/NJ strain mice; NOD, NOD/ShiLtJ strain mice.