Fibroblast growth factor 21 (FGF21), a metabolic hormone with pleiotropic effects, is beneficial for various cardiac disorders. However, FGF21's role in heart failure with preserved ejection fraction (HFpEF) remains unclear. Here, we show that elevated circulating FGF21 levels are negatively associated with cardiac diastolic function in patients with HFpEF. Global or adipose FGF21 deficiency exacerbates cardiac diastolic dysfunction and damage in high-fat diet (HFD) plus N[w]-nitro-L-arginine methyl ester (L-NAME)-induced HFpEF mice, whereas these effects are notably reversed by FGF21 replenishment. Mechanistically, FGF21 enhances the production of adiponectin (APN), which in turn indirectly acts on cardiomyocytes, or FGF21 directly targets cardiomyocytes, to negatively regulate pyruvate dehydrogenase kinase 4 (PDK4) production by activating PI3K/AKT signals, then promoting mitochondrial bioenergetics. Additionally, APN deletion strikingly abrogates FGF21's protective effects against HFpEF, while genetic PDK4 inactivation markedly mitigates HFpEF in mice. Thus, FGF21 protects against HFpEF via fine-tuning the multiorgan crosstalk among the adipose, liver, and heart.
- MeSH
- adiponektin * metabolismus genetika MeSH
- dieta s vysokým obsahem tuků * škodlivé účinky MeSH
- energetický metabolismus * účinky léků MeSH
- fibroblastové růstové faktory * metabolismus genetika MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- kardiomyocyty * metabolismus účinky léků MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- PDH-kinasa * metabolismus genetika MeSH
- protoonkogenní proteiny c-akt metabolismus MeSH
- signální transdukce MeSH
- srdeční mitochondrie * metabolismus účinky léků MeSH
- srdeční selhání * metabolismus prevence a kontrola genetika MeSH
- tepový objem účinky léků MeSH
- tuková tkáň metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
