Fig. 4

FGF21 deficiency induces a hypometabolic and mitochondrial hypoenergy state leading to cardiac dysfunction during fasting. a, b Changes in mitochondrial metabolite/energy flux and key metabolic pathway enzymes involved in the TCA cycle, ETC and OXPHOS in Fgf21^-/- (n = 5-15) vs WT (n = 6-14) mice after 12 hours of fasting (fs) or 2 hours of rhFGF21 treatment, as analyzed by targeted cardiac energy metabolomics and qRT-PCR. See Fig. S12a for a summary heatmap. c Transcriptomic and pathway enrichment in mitochondrial energy metabolism and cardiac function changes in Fgf21^-/- (n = 3) vs WT (n = 3) mice, with Reactome terms. For the GO-term and KEGG-term results, see Fig. S13a, b. For pathway enrichments in the Reactome term, GO term and KEGG term in Fgf21^-/- mice before and after rhFGF21 treatment, see Fig. S14. For mitochondrial biogenesis, TCA cycle, ETC complexes I-IV, and OXPHOS, see Figs. S15, S16d, and S17a. For 24-h fasting effects, see Fig. S16a–c. d, e Significant pathway defects associated with striated muscle contraction and heart rate regulation in the hearts of Fgf21^-/- (n = 3) vs WT (n = 3) mice and pathway normalization after 2 hours of FGF21 treatment (n = 3). For cardiac conduction, blood vessel diameter maintenance, and blood pressure regulation, see Fig. S13c–e and S17c. f Inhibiting the TCA cycle with Cpi-613 (1 mg/mouse, i.p.) reduced rhFGF21-promoted heart rate (HR) improvements in fasted Fgf21^-/- mice (same n = 6-16 mice per group). See Echo parameters in Fig. S17b. Data are means ± s.e.m.s; c two-tailed unpaired Student’s t-test; a, b, d–f ordinary one-way ANOVA followed by Tukey’s test. a, f images are generated in PowerPoint