Journal
SCIENTIFIC REPORTS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41598-022-10993-4
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Funding
- Japan Society for the Promotion of Science [20H03671, 19gm0910003h0105]
- Gunma University Initiative for Advanced Research
- Japan Heart Foundation and Research Foundation for Community Medicine
- Grants-in-Aid for Scientific Research [20H03671] Funding Source: KAKEN
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The study found that fasting-induced β-OHB and FGF21 coordinately regulate oxidative stress response gene expression in the heart by modulating the expression of PPARα and oxidative stress response genes. Additionally, the absence of FGF21 exacerbates the expression levels of β-OHB and PPG1α in the heart.
Ketone body beta-hydroxybutyrate (beta OHB) 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 beta OHB and FGF21 induced peroxisome proliferator-activated receptor alpha (PPAR alpha) and PGC1 alpha expression along with the phosphorylation of LKB1 and AMPK. beta OHB and FGF21 induced transcription of peroxisome proliferator-activated receptor response element (PPRE)-containing genes through an activation of PPAR alpha. Additionally, beta OHB 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 beta OHB levels, and higher expression levels of PPAR alpha 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 beta OHB and PGC1 alpha levels in both WT and Fgf21(-/-) mice. These findings suggest that fasting-induced beta OHB and circulating FGF21 coordinately regulate oxidative stress response gene expression in the heart.
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