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.

Affiliated Hospital of Guangdong Medical University Zhanjiang China

Beijing Institute of Heart Lung and Blood Vessel Diseases Anzhen Hospital of Capital Medical University Beijing China

Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics Guangdong Medical University Dongguan China

School of Pharmaceutical Sciences Wenzhou Medical University Wenzhou China

State Key Laboratory of Pharmaceutical Biotechnology The University of Hong Kong Hong Kong China

The Affiliated Dongguan Songshan Lake Center Hospital The Innovative Center of Cardiometabolic Disease Guangdong Medical University Dongguan China

The Affiliated Hospital of Wenzhou Medical University Wenzhou China

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Kharitonenkov, A. et al. FGF-21 as a novel metabolic regulator. J. Clin. Investig.115, 1627–1635 (2005). PubMed PMC

Fisher, F. M. & Maratos-Flier, E. Understanding the physiology of FGF21. Annu. Rev. Physiol.78, 223–241 (2016). PubMed

Salminen, A., Kaarniranta, K. & Kauppinen, A. Regulation of longevity by FGF21: Interaction between energy metabolism and stress responses. Ageing Res. Rev.37, 79–93 (2017). PubMed

Coskun, T. et al. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology149, 6018–6027 (2008). PubMed

Kharitonenkov, A. et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology148, 774–781 (2007). PubMed

Xu, J. et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes58, 250–259 (2009). PubMed PMC

Flippo, K. H. & Potthoff, M. J. Metabolic Messengers: FGF21. Nat. Metab.3, 309–317 (2021). PubMed PMC

Li, H. et al. Sodium butyrate stimulates expression of fibroblast growth factor 21 in liver by inhibition of histone deacetylase 3. Diabetes61, 797–806 (2012). PubMed PMC

Kim, K. H. & Lee, M. S. FGF21 as a mediator of adaptive responses to stress and metabolic benefits of anti-diabetic drugs. J. Endocrinol.226, R1–R16 (2015). PubMed

Ito, S. et al. Molecular cloning and expression analyses of mouse betaklotho, which encodes a novel Klotho family protein. Mechanisms Dev.98, 115–119 (2000). PubMed

Adams, A. C., Cheng, C. C., Coskun, T. & Kharitonenkov, A. FGF21 requires betaklotho to act in vivo. PloS ONE7, e49977 (2012). PubMed PMC

Chen, W. et al. Growth hormone induces hepatic production of fibroblast growth factor 21 through a mechanism dependent on lipolysis in adipocytes. J. Biol. Chem.286, 34559–34566 (2011). PubMed PMC

Chau, M. D., Gao, J., Yang, Q., Wu, Z. & Gromada, J. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway. Proc. Natl Acad. Sci. USA107, 12553–12558 (2010). PubMed PMC

Murata, Y., Konishi, M. & Itoh, N. FGF21 as an endocrine regulator in lipid metabolism: from molecular evolution to physiology and pathophysiology. J. Nutr. Metab.2011, 981315 (2011). PubMed PMC

Fisher, F. M. et al. FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev.26, 271–281 (2012). PubMed PMC

Lin, Z. et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab.17, 779–789 (2013). PubMed

Joki, Y. et al. FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism. Biochem. Biophys. Res. Commun.459, 124–130 (2015). PubMed

Lin, Z. et al. Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice. Circulation131, 1861–1871 (2015). PubMed PMC

Wu, F. et al. FGF21 ameliorates diabetic cardiomyopathy by activating the AMPK-paraoxonase 1 signaling axis in mice. Clin. Sci.131, 1877–1893 (2017). PubMed

Pan, X. et al. FGF21 prevents Angiotensin II-Induced hypertension and vascular dysfunction by activation of ACE2/Angiotensin-(1-7) Axis in Mice. Cell Metab.27, 1323–1337.e1325 (2018). PubMed

Redfield, M. M. & Borlaug, B. A. Heart failure with preserved ejection fraction: a review. Jama329, 827–838 (2023). PubMed

Sharma, K. & Kass, D. A. Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circ. Res.115, 79–96 (2014). PubMed PMC

Ianoș, R. D. et al. Diagnostic performance of serum biomarkers fibroblast growth factor 21, Galectin-3 and Copeptin for heart failure with preserved ejection fraction in a sample of patients with type 2 Diabetes Mellitus. Diagnostics11, 1577 (2021). PubMed PMC

Chou, R. H. et al. Circulating fibroblast growth factor 21 is associated with diastolic dysfunction in heart failure patients with preserved ejection fraction. Sci. Rep.6, 33953 (2016). PubMed PMC

Schiattarella, G. G. et al. Nitrosative stress drives heart failure with preserved ejection fraction. Nature568, 351–356 (2019). PubMed PMC

Pan, Y. et al. Pancreatic fibroblast growth factor 21 protects against type 2 diabetes in mice by promoting insulin expression and secretion in a PI3K/Akt signaling-dependent manner. J. Cell Mol. Med.23, 1059–1071 (2019). PubMed PMC

Rosales-Soto G., Diaz-Vegas A., Casas M., Contreras-Ferrat A. & Jaimovich E. Fibroblast growth factor-21 potentiates glucose transport in skeletal muscle fibers. J. Mol. Endocrinol.65, 85–95 (2020). PubMed

Hui, X., Lam, K. S., Vanhoutte, P. M. & Xu, A. Adiponectin and cardiovascular health: an update. Br. J. Pharm.165, 574–590 (2012). PubMed PMC

Tanaka, K. et al. Effects of adiponectin on calcium-handling proteins in heart failure with preserved ejection fraction. Circ. Heart Fail7, 976–985 (2014). PubMed PMC

Francisco, C., Neves, J. S., Falcão-Pires, I. & Leite-Moreira, A. Can Adiponectin help us to target diastolic dysfunction? Cardiovasc. Drugs Ther.30, 635–644 (2016). PubMed

Liu, L. et al. Adiponectin attenuates lipopolysaccharide-induced apoptosis by regulating the Cx43/PI3K/AKT pathway. Front. Pharm.12, 644225 (2021). PubMed PMC

Xu, Z. P. et al. Adiponectin Attenuates Streptozotocin-Induced Tau Hyperphosphorylation and Cognitive Deficits by Rescuing PI3K/Akt/GSK-3β Pathway. Neurochem. Res.43, 316–323 (2018). PubMed

Zhou, Y., Wei, L. L., Zhang, R. P., Han, C. W. & Cao, Y. Globular adiponectin inhibits osteoblastic differentiation of vascular smooth muscle cells through the PI3K/AKT and Wnt/β-catenin pathway. J. Mol. Histol.52, 1067–1080 (2021). PubMed PMC

Yang, X. et al. FGF21 alleviates acute liver injury by inducing the SIRT1-autophagy signalling pathway. J. Cell Mol. Med.26, 868–879 (2022). PubMed PMC

Ding, P. et al. Fibroblast growth factor 21 attenuates ventilator-induced lung injury by inhibiting the NLRP3/caspase-1/GSDMD pyroptotic pathway. Crit. Care27, 196 (2023). PubMed PMC

Xie, W. et al. Serum FGF21 levels predict the MACE in patients with myocardial infarction after coronary artery bypass graft surgery. Front. Cardiovasc. Med.9, 850517 (2022). PubMed PMC

Refsgaard Holm, M. et al. Fibroblast growth factor 21 in patients with cardiac cachexia: a possible role of chronic inflammation. ESC Heart Fail6, 983–991 (2019). PubMed PMC

Geng, L., Lam, K. S. L. & Xu, A. The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic. Nat. Rev. Endocrinol.16, 654–667 (2020). PubMed

Bottomley, P. A. et al. Metabolic rates of ATP transfer through creatine kinase (CK Flux) predict clinical heart failure events and death. Sci. Transl. Med.5, 215re213 (2013). PubMed PMC

Capone, F. et al. Cardiac metabolism in HFpEF: from fuel to signalling. Cardiovasc Res.118, 3556–3575 (2023). PubMed

Bertero, E. & Maack, C. Metabolic remodelling in heart failure. Nat. Rev. Cardiol.15, 457–470 (2018). PubMed

Karwi, Q. G., Uddin, G. M., Ho, K. L. & Lopaschuk, G. D. Loss of metabolic flexibility in the failing heart. Front. Cardiovasc. Med.5, 68 (2018). PubMed PMC

Tran, D. H. & Wang, Z. V. Glucose metabolism in cardiac hypertrophy and heart failure. J. Am. Heart Assoc.8, e012673 (2019). PubMed PMC

Mori, J. et al. Agonist-induced hypertrophy and diastolic dysfunction are associated with selective reduction in glucose oxidation: a metabolic contribution to heart failure with normal ejection fraction. Circ. Heart Fail5, 493–503 (2012). PubMed

Cluntun, A. A. et al. The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure. Cell Metab.33, 629–648.e610 (2021). PubMed PMC

Gopal, K. et al. FoxO1 inhibition alleviates type 2 diabetes-related diastolic dysfunction by increasing myocardial pyruvate dehydrogenase activity. Cell Rep.35, 108935 (2021). PubMed

Tong, D. et al. NAD(+) repletion reverses heart failure with preserved ejection fraction. Circ. Res.128, 1629–1641 (2021). PubMed PMC

Ni, J. et al. Rg3 regulates myocardial pyruvate metabolism via P300-mediated dihydrolipoamide dehydrogenase 2-hydroxyisobutyrylation in TAC-induced cardiac hypertrophy. Cell Death Dis.13, 1073 (2022). PubMed PMC

Pan, X. et al. FGF21 prevents angiotensin ii-induced hypertension and vascular dysfunction by activation of ACE2/Angiotensin-(1-7) Axis in Mice. Cell Metab.27, 1323–1337.e1325 (2018). PubMed

Pilegaard, H. & Neufer, P. D. Transcriptional regulation of pyruvate dehydrogenase kinase 4 in skeletal muscle during and after exercise. Proc. Nutr. Soc.63, 221–226 (2004). PubMed

Cardoso, A. C. et al. Mitochondrial substrate utilization regulates cardiomyocyte cell cycle progression. Nat. Metab.2, 167–178 (2020). PubMed PMC

Yin, Q., Wang, P. & Wu, X. MicroRNA -148 alleviates cardiac dysfunction, immune disorders and myocardial apoptosis in myocardial ischemia-reperfusion (MI/R) injury by targeting pyruvate dehydrogenase kinase (PDK4). Bioengineered12, 5552–5565 (2021). PubMed PMC

Zhao, G. et al. Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy. Am. J. Physiol. Heart Circ. Physiol.294, H936–H943 (2008). PubMed

Holland, W. L. et al. An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice. Cell Metab.17, 790–797 (2013). PubMed PMC

Fang, H. & Judd, R. L. Adiponectin regulation and function. Compr. Physiol.8, 1031–1063 (2018). PubMed

Hopkins, T. A., Ouchi, N., Shibata, R. & Walsh, K. Adiponectin actions in the cardiovascular system. Cardiovasc. Res.74, 11–18 (2007). PubMed PMC

Shioji, K. et al. [Hypoadiponectinemia implies the development of atherosclerosis in carotid and coronary arteries]. J. Cardiol.46, 105–112 (2005). PubMed

Ouchi, N., Shibata, R. & Walsh, K. Cardioprotection by adiponectin. Trends Cardiovasc. Med.16, 141–146 (2006). PubMed PMC

Kruszewska J., Cudnoch-Jedrzejewska A. & Czarzasta K. Remodeling and fibrosis of the cardiac muscle in the course of obesity-pathogenesis and involvement of the extracellular matrix. Int. J. Mol. Sci.23, 4195 (2022). PubMed PMC

Wang, H. T. et al. Effect of obesity reduction on preservation of heart function and attenuation of left ventricular remodeling, oxidative stress and inflammation in obese mice. J. Transl. Med.10, 145 (2012). PubMed PMC

Ke, B. et al. Aldosterone dysregulation predicts the risk of mortality and rehospitalization in heart failure with a preserved ejection fraction. Sci. China Life Sci.65, 631–642 (2022). PubMed

Xie, W. et al. Myocardial infarction accelerates the progression of MASH by triggering immunoinflammatory response and induction of periosti. Cell Metab.36, 1269–1286.e1269 (2024). PubMed

Ito, T. et al. Adenoassociated virus-mediated prostacyclin synthase expression prevents pulmonary arterial hypertension in rats. Hypertension50, 531–536 (2007). PubMed

Gao, W. et al. Inhibiting receptor of advanced glycation end products attenuates pressure overload-induced cardiac dysfunction by preventing excessive autophagy. Front. Physiol.9, 1333 (2018). PubMed PMC

Lei, I. et al. Acetyl-CoA production by specific metabolites promotes cardiac repair after myocardial infarction via histone acetylation. Elife10, e60311 (2021). PubMed PMC

Liu, Y. et al. Spexin protects cardiomyocytes from hypoxia-induced metabolic and mitochondrial dysfunction. Naunyn Schmiedebergs Arch. Pharm.393, 25–33 (2020). PubMed