title: Fibroblast growth factor 21 is induced upon cardiac stress and alters cardiac lipid homeostasis.
abstract: Fibroblast growth factor 21 (FGF21) is a PPARα-regulated gene elucidated in the liver of PPARα-deficient mice or PPARα agonist-treated mice. Mice globally lacking adipose triglyceride lipase (ATGL) exhibit a marked defect in TG catabolism associated with impaired PPARα-activated gene expression in the heart and liver, including a drastic reduction in hepatic FGF21 mRNA expression. Here we show that FGF21 mRNA expression is markedly increased in the heart of ATGL-deficient mice accompanied by elevated expression of endoplasmic reticulum (ER) stress markers, which can be reversed by reconstitution of ATGL expression in cardiac muscle. In line with this assumption, the induction of ER stress increases FGF21 mRNA expression in H9C2 cardiomyotubes. Cardiac FGF21 expression was also induced upon fasting of healthy mice, implicating a role of FGF21 in cardiac energy metabolism. To address this question, we generated and characterized mice with cardiac-specific overexpression of FGF21 (CM-Fgf21). FGF21 was efficiently secreted from cardiomyocytes of CM-Fgf21 mice, which moderately affected cardiac TG homeostasis, indicating a role for FGF21 in cardiac energy metabolism. Together, our results show that FGF21 expression is activated upon cardiac ER stress linked to defective lipolysis and that a persistent increase in circulating FGF21 levels interferes with cardiac and whole body energy homeostasis.
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Manoja K
authors.initials: MK
authors.lastname: Brahma
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Rene C
authors.initials: RC
authors.lastname: Adam
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Nina M
authors.initials: NM
authors.lastname: Pollak
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Doris
authors.initials: D
authors.lastname: Jaeger
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Kathrin A
authors.initials: KA
authors.lastname: Zierler
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Nadja
authors.initials: N
authors.lastname: Pöcher
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Renate
authors.initials: R
authors.lastname: Schreiber
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Romauch
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Tarek
authors.initials: T
authors.lastname: Moustafa
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Sandra
authors.initials: S
authors.lastname: Eder
authors.affiliation: Biomodels Austria University of Veterinary Medicine, 1210 Vienna, Austria and Institute of Laboratory Animal Science, University of Veterinary Medicine, 1210 Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruelicke
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Karina
authors.initials: K
authors.lastname: Preiss-Landl
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Achim
authors.initials: A
authors.lastname: Lass
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Guenter
authors.initials: G
authors.lastname: Haemmerle
mesh_terms: D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress; D004734:Energy Metabolism; D005215:Fasting / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D008049:Lipase / Q000172:deficiency; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism*; D009928:Organ Specificity; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015533:Transcriptional Activation; D014280:Triglycerides / Q000378:metabolism*; D000217:Acyltransferases
chemical_list: D005227:Fatty Acids; D005346:Fibroblast Growth Factors; D005947:Glucose; D008049:Lipase; D012333:RNA, Messenger; D014280:Triglycerides; C414620:fibroblast growth factor 21; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
keywords: ER stress; adipose triglyceride lipase; cardiac lipid and energy metabolism