Fig. 5

FGF21 promotes cardiac catabolic pathways for diverse metabolites to ensure cardiac energetic efficiency under stress. a, b Analysis of the expression of representative mitochondrial FAO pathway genes by qRT-PCR in the hearts of fasted Fgf21^-/- (n = 7-14) vs WT (n = 7-15) mice and with rhFGF21 treatment (n = 8-15). For transcriptomic enrichment of the FAO pathway, see Fig. S18a. For FAO under a 24-h fast, see Fig. S18b, c. For the metabolism of TG, phospholipids, and lipoproteins, see Fig. S18d, e. c Effects of palmitate supplementation (2 mmol per mouse, i.p.) on the heart rate (HR) of fasted Fgf21^-/- (n = 11) vs WT (n = 10) mice. See Fig. S19a for other related comparisons. d, e Changes in mitochondrial beta-hydroxybutyrate (BHB) ketolysis pathway determined by qRT-PCR in the hearts of fasted Fgf21^-/- (n = 7-15) vs WT (n = 7-14) mice and those with rhFGF21 treatment (n = 8-15). See Fig. S19b for transcriptomic enrichment of ketolysis and Fig. S19c for ketolysis after a 24-h fast. For utilization of other ketones, see Fig. S19d, e. f Effects of 1,3-butanediol monoester (BHB precursor, 10 mmol/mouse via tail vein) on HR in fasted Fgf21^-/- (n = 11) vs WT (n = 12) mice. See Fig. S20a for other related comparisons. g Effects of 1,3-butanediol monoester on EF in fasted Fgf21^-/- (n = 29) vs WT (n = 30) mice. See Fig. S20b for effects on CO. h Effects of 1,3-butanediol monoester on serum BHB levels in fasted Fgf21^-/- (n = 6) vs WT (n = 6) mice. See Fig. S20c for effects on serum FFA, TG, glucose, and total cholesterol. i Effects of cardiac Oxct1 knockdown (KD) by AAV-mediated shRNA (2.5 ×10¹¹ GC/mouse via tail vein) on rhFGF21-promoted HR improvement in fasted Fgf21^-/- mice (n = 10) vs those with control AAV (n = 11-12). See Fig. S20d for the knockdown efficiency and Fig. S20e, f for more detailed comparisons and Echo parameters. j, k Transcriptomic changes in branched-chain amino acid (BCAA) oxidation pathway in the hearts of fasted Fgf21^-/- (n = 3) vs WT (n = 3) mice and those with rhFGF21 treatment (n = 3). See Fig. S21b, c for detailed pathway changes under both 12-h and 24-h fasts, and Figs. S21a, S22d, e and S23a for amino acid metabolism and protein turnover. See Fig. S22a–c for leucine supplementation effects. IV-CoA, isovaleryl-CoA; MB-CoA, 2-methylbutyryl-CoA; IB-CoA, isobutyryl-CoA. Data are means ± s.e.m.s; (c, f, i) two-tailed unpaired Student’s t-test; (b, e, g, h, k) ordinary one-way ANOVA followed by Tukey’s test. (a, d, g) Images are generated in PowerPoint