FGF21 protects against HFpEF by improving cardiac mitochondrial bioenergetics in mice
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 negativel...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56885-9 |
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| author | 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 Zhuofeng Lin |
| author_facet | 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 Zhuofeng Lin |
| author_sort | Ke Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b64cbfe4c8f849128d0a62d0f2fee0ab |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b64cbfe4c8f849128d0a62d0f2fee0ab2025-08-20T02:12:59ZengNature PortfolioNature Communications2041-17232025-02-0116112110.1038/s41467-025-56885-9FGF21 protects against HFpEF by improving cardiac mitochondrial bioenergetics in miceKe Zhang0Jing Gan1Baile Wang2Wei Lei3Dong Zhen4Jie Yang5Ningrui Wang6Congcong Wen7Xiaotang Gao8Xiaokun Li9Aimin Xu10Xinguang Liu11Yulin Li12Fan Wu13Zhuofeng Lin14School of Pharmaceutical Sciences, Wenzhou Medical UniversityThe Affiliated Dongguan Songshan Lake Center Hospital, The Innovative Center of Cardiometabolic Disease, Guangdong Medical UniversityState Key Laboratory of Pharmaceutical Biotechnology, The University of Hong KongSchool of Pharmaceutical Sciences, Wenzhou Medical UniversityThe Affiliated Hospital of Wenzhou Medical UniversityBeijing Institute of Heart, Lung, and Blood Vessel Diseases, Anzhen Hospital of Capital Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversityState Key Laboratory of Pharmaceutical Biotechnology, The University of Hong KongGuangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical UniversityBeijing Institute of Heart, Lung, and Blood Vessel Diseases, Anzhen Hospital of Capital Medical UniversityThe Affiliated Dongguan Songshan Lake Center Hospital, The Innovative Center of Cardiometabolic Disease, Guangdong Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversityAbstract 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.https://doi.org/10.1038/s41467-025-56885-9 |
| spellingShingle | 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 Zhuofeng Lin FGF21 protects against HFpEF by improving cardiac mitochondrial bioenergetics in mice Nature Communications |
| title | FGF21 protects against HFpEF by improving cardiac mitochondrial bioenergetics in mice |
| title_full | FGF21 protects against HFpEF by improving cardiac mitochondrial bioenergetics in mice |
| title_fullStr | FGF21 protects against HFpEF by improving cardiac mitochondrial bioenergetics in mice |
| title_full_unstemmed | FGF21 protects against HFpEF by improving cardiac mitochondrial bioenergetics in mice |
| title_short | FGF21 protects against HFpEF by improving cardiac mitochondrial bioenergetics in mice |
| title_sort | fgf21 protects against hfpef by improving cardiac mitochondrial bioenergetics in mice |
| url | https://doi.org/10.1038/s41467-025-56885-9 |
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