biostudies-literatureYanucil CNCATS NIH HHSNEI NIH HHSNIDDK NIH HHSNational Institute of Diabetes and Digestive and Kidney DiseasesNational Heart, Lung, and Blood InstituteNHLBI NIH HHSNational Cancer InstituteNCI NIH HHS7326https://www.ebi.ac.uk/biostudies/studies/S-EPMC9072546biostudies-literatureUnknown12(1)Fibroblast growth factor (FGF) 21, a hormone that increases insulin sensitivity, has shown promise as a therapeutic agent to improve metabolic dysregulation. Here we report that FGF21 directly targets cardiac myocytes by binding β-klotho and FGF receptor (FGFR) 4. In combination with high glucose, FGF21 induces cardiac myocyte growth in width mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. While short-term FGF21 elevation can be cardio-protective, we find that in type 2 diabetes (T2D) in mice, where serum FGF21 levels are elevated, FGFR4 activation induces concentric cardiac hypertrophy. As T2D patients are at risk for heart failure with preserved ejection fraction (HFpEF), we propose that induction of concentric hypertrophy by elevated FGF21-FGFR4 signaling may constitute a novel mechanism promoting T2D-associated HFpEF such that FGFR4 blockade might serve as a cardio-protective therapy in T2D. In addition, potential adverse cardiac effects of FGF21 mimetics currently in clinical trials should be investigated.Scientific reportsFGF21-FGFR4 signaling in cardiac myocytes promotes concentric cardiac hypertrophy in mouse models of diabetes.PMC9072546UL1 TR000460U54 DK083912R01HL133011R01 HL146111UM1 DK100846U01 DK116101F31DK115074P30 EY026877F31 DK117550R01HL146111F31DK117550R01DK117599R01 DK104753R01CA227493R01HL128714R01 HL145528R01 HL126825R01 HL158052Fornoni ALi JWestbrook DKapiloff MSMartinez ECGrabner ACampos IRoche JMSchramm KYanucil CWende ARKentrup DLi XCzaya BFaul CHeitman KSloan AfalseFGF21-FGFR4 signaling in cardiac myocytes promotes concentric cardiac hypertrophy in mouse models of diabetes.Fibroblast growth factor (FGF) 21, a hormone that increases insulin sensitivity, has shown promise as a therapeutic agent to improve metabolic dysregulation. Here we report that FGF21 directly targets cardiac myocytes by binding β-klotho and FGF receptor (FGFR) 4. In combination with high glucose, FGF21 induces cardiac myocyte growth in width mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. While short-term FGF21 elevation can be cardio-protective, we find that in type 2 diabetes (T2D) in mice, where serum FGF21 levels are elevated, FGFR4 activation induces concentric cardiac hypertrophy. As T2D patients are at risk for heart failure with preserved ejection fraction (HFpEF), we propose that induction of concentric hypertrophy by elevated FGF21-FGFR4 signaling may constitute a novel mechanism promoting T2D-associated HFpEF such that FGFR4 blockade might serve as a cardio-protective therapy in T2D. In addition, potential adverse cardiac effects of FGF21 mimetics currently in clinical trials should be investigated.2022-01-01T00:00:00Z2022 May2024-11-15T09:10:23.151Z2024-11-15T09:10:23.151ZS-EPMC90725463551343110.1038/s41598-022-11033-x