FGF21 protects against HFpEF by improving cardiac mitochondrial bioenergetics in mice

Ke Zhang, Jing Gan, Baile Wang, Wei Lei, Dong Zhen, Jie Yang, Ningrui Wang, Congcong Wen, Xiaotang Gao, Xiaokun Li, Aimin Xu, Xinguang Liu (), Yulin Li (), Fan Wu () and Zhuofeng Lin ()
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Ke Zhang: Wenzhou Medical University
Jing Gan: Guangdong Medical University
Baile Wang: The University of Hong Kong
Wei Lei: Wenzhou Medical University
Dong Zhen: The Affiliated Hospital of Wenzhou Medical University
Jie Yang: Anzhen Hospital of Capital Medical University
Ningrui Wang: Wenzhou Medical University
Congcong Wen: Wenzhou Medical University
Xiaotang Gao: Wenzhou Medical University
Xiaokun Li: Wenzhou Medical University
Aimin Xu: The University of Hong Kong
Xinguang Liu: Guangdong Medical University
Yulin Li: Anzhen Hospital of Capital Medical University
Fan Wu: Guangdong Medical University
Zhuofeng Lin: Wenzhou Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-56885-9

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