Fig. 3

Ketogenic diets induce metabolic changes in plasma of melanoma xenograft-bearing mice beyond glucose reduction and ketosis. A–D Principal component analysis (PCA) of polar metabolite profiling data obtained from plasma samples of A A375, B WM47, C WM3311, and D WM3000 xenograft-bearing mice treated with CTRL, LCT, or LCT-MCT diet. n = 7–13. E Heatmap of metabolites quantified in plasma of xenograft-bearing mice. The two clusters highlighted in the heatmap represent up- or downregulated metabolites by KDs vs. CTRL. n = 7–13. F–G Identification of significant differential metabolites in plasma between both KDs and CTRL for each xenograft model by one-way ANOVA and Fisher´s LSD post hoc test. Plasma metabolites were filtered based on an FDR-adjusted p value < 0.05 for both KDs vs. CTRL. The Venn diagrams represent the intersections among the 4 xenograft models (A375, WM47, WM3311, WM3000) for significantly F upregulated and G downregulated plasma metabolites (see also Table S4). H–K Overview of metabolic pathway analysis (MetPA) using plasma metabolites of H A375, I WM47, J WM3311, and K WM3000 melanoma-bearing mice. Pathways consistently altered by KDs across the melanoma models are highlighted in the MetPA results overview, indicating matched pathways arranged by p values from pathway enrichment analysis (Y-axis) and pathway impact values from pathway topology analysis (X-axis). Node color and radius are based on the p value and pathway impact value, respectively. n = 10–13 in CTRL groups and n = 14-24 in KD groups. Alpha-AAA: alpha-aminoadipic acid, BABA: beta-aminobutyric acid, BHB: beta-hydroxybutyrate, HArg, homoarginine, Ile: isoleucine, Leu: leucine, Lys: lysine, TCA: taurocholic acid, TCDCA: taurochenodeoxycholic acid, TMCA: Tauromuricholic acid, Trp: tryptophan, Val: valine, ↑: increased, ↓: decreased