| First Author | Kawakami R | Year | 2022 |
| Journal | Sci Rep | Volume | 12 |
| Issue | 1 | Pages | 7338 |
| PubMed ID | 35513524 | Mgi Jnum | J:342793 |
| Mgi Id | MGI:7275882 | Doi | 10.1038/s41598-022-10993-4 |
| Citation | Kawakami R, et al. (2022) Ketone body and FGF21 coordinately regulate fasting-induced oxidative stress response in the heart. Sci Rep 12(1):7338 |
| abstractText | Ketone body beta-hydroxybutyrate (betaOHB) and fibroblast growth factor-21 (FGF21) have been proposed to mediate systemic metabolic response to fasting. However, it remains elusive about the signaling elicited by ketone and FGF21 in the heart. Stimulation of neonatal rat cardiomyocytes with betaOHB and FGF21 induced peroxisome proliferator-activated receptor alpha (PPARalpha) and PGC1alpha expression along with the phosphorylation of LKB1 and AMPK. betaOHB and FGF21 induced transcription of peroxisome proliferator-activated receptor response element (PPRE)-containing genes through an activation of PPARalpha. Additionally, betaOHB and FGF21 induced the expression of Nrf2, a master regulator for oxidative stress response, and catalase and Ucp2 genes. We evaluated the oxidative stress response gene expression after 24 h fast in global Fgf21-null (Fgf21(-/-)) mice, cardiomyocyte-specific FGF21-null (cmFgf21(-/-)) mice, wild-type (WT), and Fgf21(fl/fl) littermates. Fgf21(-/-) mice but not cmFgf21(-/-) mice had unexpectedly higher serum betaOHB levels, and higher expression levels of PPARalpha and oxidative stress response genes than WT mice or Fgf21(fl/fl) littermates. Notably, expression levels of oxidative stress response genes were significantly correlated with serum betaOHB and PGC1alpha levels in both WT and Fgf21(-/-) mice. These findings suggest that fasting-induced betaOHB and circulating FGF21 coordinately regulate oxidative stress response gene expression in the heart. |
