iSIRT3 mice on HFD showed an induction of the ketogenic gene Hmgcs2 in the small intestine but not in the liver. (A–C) Relative mRNA expression of Hmgcs2, Cpt1a, ATPsyn, Lcad, and Pgc1a in the duodenum, jejunum, and liver of S3fl and iSIRT3 mice on CD or HFD. (A) Duodenum [n = 6–8; 2-way ANOVA (diet × genotype) with Tukey's multiple comparison post hoc test. Hmgcs2, diet, #P < 0.0001; genotype, P < 0.05; diet × genotype, $P < 0.05; S3fl HFD vs iSIRT3 HFD, ∗∗P < 0.01. Cpt1a, diet, #P < 0.0001. Lcad, diet, ∗∗P < 0.001. Pgc1a, diet, ∗∗∗P < 0.001]. (B) Jejunum [n = 5–8; 2-way ANOVA (diet × genotype) with Tukey's multiple comparison post hoc test. Hmgcs2, genotype, P < 0.05; diet, #P < 0.0001; diet × genotype, P = 0.06, ns; S3fl HFD vs iSIRT3 HFD, ∗P < 0.05. Cpt1a, genotype, P < 0.05; diet, #P < 0.0001, diet × genotype, ns. ATPsyn, genotype, P < 0.05; diet, ns; diet × genotype, ns. Lcad, genotype, ns; diet, #P < 0.0001, diet × genotype, ns. Pgc1a, genotype, ns; diet, #P < 0.0001, diet × genotype, ns]. (C) Liver [n = 6–9; 2-way ANOVA (diet × genotype) with Tukey's multiple comparison post hoc test. Hmgcs2, diet, #P < 0.0001. Cpt1a, diet, #P < 0.0001. ATPsyn, diet, ∗∗∗P < 0.001. Lcad, diet, #P < 0.0001. Pgc1a, diet, ∗P < 0.05]. Data are presented as mean values ± SEM.