Cardiokine FGF16 prevents diabetic cardiomyopathy - diabetic cardiomyopathy (DCM) is one of the major chronic complications of diabetic patients

The National Heart, Lung, and Blood Institute awarded the University of Arizona $753,662 on July 15, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate the cardioprotective effects of fibroblast growth factor 16 (FGF16) in diabetic cardiomyopathy. The research examines how a novel recombinant human FGF16 mutant (rhFGF16Δ33) prevents type 2 diabetes-induced cardiac hypertrophy, inflammation, fibrosis, and dysfunction in diabetic mouse models, with particular focus on cardiac fatty acid oxidation, mitochondrial function, and AMP-activated protein kinase signaling pathways. The award covers performance through March 31, 2030, with work conducted in Louisville, Kentucky. This is a project grant supporting basic and translational cardiovascular research aimed at developing more specific and efficient treatments for diabetic cardiomyopathy, a major chronic complication affecting diabetic patients for which current preventive and therapeutic methods remain limited.

The pathogenesis and clinical characteristics of DCM have been well documented over the past decades, but effective methods for preventing and treating the disease are still limited. Therefore, developing more specific and efficient treatments are needed. Fibroblast growth factor 16 (FGF16) is the only FGF family member that shows preferential expression in the postnatal heart; thus, IT is considered a cardiokine. Several pioneering studies have attempted to explore the cardioprotective effects of FGF16 under certain stress conditions. However, the pathophysiological roles of FGF16 in DCM remain unexplored. We examined the cardiac effects of FGF16 in diabetic mice and found that downregulated FGF16 expression in the hearts of high FAT diet/streptozotocin (HFD/STZ)-induced and DB/DB type 2 diabetic (T2D) mice was accompanied by cardiac dysfunction. Then we generated a novel recombinant human FGF16 mutant (RHFGF16DELTA33), which increased its biostability but preserved the biological activity of native HFGF16. Notably, replenishment of RHFGF16DELTA33 in DB/DB mice significantly prevented T2D-induced cardiac hypertrophy, inflammation, fibrosis and dysfunction, which was accompanied by remarkable improvements of signals involving in cardiac fatty acid oxidation (FAO) and mitochondrial oxidative phosphorylation (OXPHOS), and suppression of signals involving in leukocyte adhesion and activation, and extracellular matrix organization. However, administration of RHFGF16DELTA33 had no obvious effects on systemic metabolic status, indicating a direct cardioprotective effect of RHFGF16DELTA33 on diabetic hearts. Furthermore, kegg pathway enrichment analysis of RNA-SEQ data revealed that the cardioprotective signals of RHFGF16DELTA33 could be enriched into AMP-activated protein kinase (AMPK) pathways and RHFGF16DELTA33 could directly stimulate AMPK activation and improve FAO and OXPHOS in cardiomyocytes. More importantly, cardiomyocyte specific FGF16 deletion resulted in a compensative upregulation of both FGFR1 and FGFR2 expression but downregulation of activity, which was coincided with AMPK inactivation, implying that FGFR1 and/or FGFR2 are functional receptor(S) for FGF16 to activate AMPK in cardiomyocytes. Thus, we hypothesize that cardiokine FGF16 prevents diabetes-induced cardiac lipotoxicity and dysfunction by acting on FGFR1/2 to promote the efficiency of AMPK-mediated mitochondrial FAO and OXPHOS in cardiomyocytes. This hypothesis will be tested through three specific aims: 1) optimize the protective effects of FGF16 against the development of DCM; 2) determine whether FGF16 protects against DCM through directly protecting cardiomyocytes; 3) determine whether FGF16 prevents DCM via FGFR1/2-mediated activation of AMPK to promote cardiac FAO and mitochondrial function in cardiomyocytes. Successful completion of this project will reveal new insight into the underlying mechanisms behind FGF16 protection against DCM and provide fundamental evidence for RHFGF16DELTA33 variant as a novel approach for the prevention of DCM in future clinical studies.