title: FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation.
abstract: Fibroblast growth factor 21 (FGF21) plays an important role in energy homoeostasis. The unaddressed question of FGF21's effect on the development and progression of diabetic cardiomyopathy (DCM) is investigated here with FGF21 knockout (FGF21KO) diabetic mice. Type 1 diabetes was induced in both FGF21KO and C57BL/6J wild-type (WT) mice via streptozotocin. At 1, 2 and 4 months after diabetes onset, the plasma FGF21 levels were significantly decreased in WT diabetic mice compared to controls. There was no significant difference between FGF21KO and WT diabetic mice in blood glucose and triglyceride levels. FGF21KO diabetic mice showed earlier and more severe cardiac dysfunction, remodelling and oxidative stress, as well as greater increase in cardiac lipid accumulation than WT diabetic mice. Western blots showed that increased cardiac lipid accumulation was accompanied by further increases in the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its target protein CD36, along with decreases in the phosphorylation of AMP-activated protein kinase and the expression of hexokinase II and peroxisome proliferator-activated receptor gamma co-activator 1α in the heart of FGF21KO diabetic mice compared to WT diabetic mice. Our results demonstrate that FGF21 deletion-aggravated cardiac lipid accumulation is likely mediated by cardiac Nrf2-driven CD36 up-regulation, which may contribute to the increased cardiac oxidative stress and remodelling, and the eventual development of DCM. These findings suggest that FGF21 may be a therapeutic target for the treatment of DCM.
authors.affiliation: Chinese-American Research Institute for Diabetic Complications at the Wenzhou Medical University, Wenzhou, China.|Kosair Children's Hospital Research Institute, The Department of Pediatrics of the University of Louisville, School of Medicine, Louisville, USA.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Yan
authors.affiliation: Chinese-American Research Institute for Diabetic Complications at the Wenzhou Medical University, Wenzhou, China.|Kosair Children's Hospital Research Institute, The Department of Pediatrics of the University of Louisville, School of Medicine, Louisville, USA.|Scool of Nursing, Wenzhou Medical University, Wenzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Chinese-American Research Institute for Diabetic Complications at the Wenzhou Medical University, Wenzhou, China.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Kosair Children's Hospital Research Institute, The Department of Pediatrics of the University of Louisville, School of Medicine, Louisville, USA.|Department of Cardiovascular Disorders of the First Hospital of Jilin University, Changchun, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Kosair Children's Hospital Research Institute, The Department of Pediatrics of the University of Louisville, School of Medicine, Louisville, USA.|Department of Cardiovascular Disorders of the First Hospital of Jilin University, Changchun, China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Kosair Children's Hospital Research Institute, The Department of Pediatrics of the University of Louisville, School of Medicine, Louisville, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Toxicology of the University of Louisville School of Medicine, Louisville, USA.
authors.forename: Wenke
authors.initials: W
authors.lastname: Feng
authors.affiliation: Chinese-American Research Institute for Diabetic Complications at the Wenzhou Medical University, Wenzhou, China.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.affiliation: Chinese-American Research Institute for Diabetic Complications at the Wenzhou Medical University, Wenzhou, China.|Kosair Children's Hospital Research Institute, The Department of Pediatrics of the University of Louisville, School of Medicine, Louisville, USA.|Department of Pharmacology and Toxicology of the University of Louisville School of Medicine, Louisville, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D058065:Diabetic Cardiomyopathies / Q000097:blood / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D018450:Disease Progression; D015536:Down-Regulation; D005346:Fibroblast Growth Factors / Q000172:deficiency* / Q000378:metabolism; D017353:Gene Deletion; D006334:Heart Function Tests; D050356:Lipid Metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; D018955:CD36 Antigens; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D014280:Triglycerides; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors
keywords: CD36; cardiac lipotoxicity; diabetic cardiomyopathy; fibroblast growth factor 21
references.citation: Diabetes. 2010 Jul;59(7):1817-24
references.pmid: 20357365
references.citation: Circulation. 2007 Jun 26;115(25):3213-23
references.pmid: 17592090
references.citation: Pflugers Arch. 2004 Apr;448(1):1-15
references.pmid: 14872244
references.citation: Clin Endocrinol (Oxf). 2009 Sep;71(3):369-75
references.pmid: 19702724
references.citation: Diabetes. 2011 Feb;60(2):625-33
references.pmid: 21270272
references.citation: Nat Med. 2013 Jan;19(1):83-92
references.pmid: 23202295
references.citation: Endocrinology. 2007 Feb;148(2):774-81
references.pmid: 17068132
references.citation: Biochim Biophys Acta. 2005 Oct 1;1736(3):163-80
references.pmid: 16198626
references.citation: J Vasc Surg. 2009 Dec;50(6):1412-22
references.pmid: 19837544
references.citation: J Biol Chem. 2007 Sep 14;282(37):26687-95
references.pmid: 17623664
references.citation: Biochim Biophys Acta. 2000 Jun 21;1492(1):203-6
references.pmid: 10858549
references.citation: Sci Rep. 2013;3:2767
references.pmid: 24067542
references.citation: Cell Metab. 2007 Jun;5(6):426-37
references.pmid: 17550778
references.citation: Genes Dev. 2012 Feb 1;26(3):271-81
references.pmid: 22302939
references.citation: Mol Endocrinol. 2010 Oct;24(10):2050-64
references.pmid: 20667984
references.citation: J Biol Chem. 2011 Apr 15;286(15):12983-90
references.pmid: 21317437
references.citation: Diabetes. 2009 Jun;58(6):1391-402
references.pmid: 19324938
references.citation: Free Radic Biol Med. 2014 May;70:174-81
references.pmid: 24583459
references.citation: Adv Exp Med Biol. 2012;728:214-28
references.pmid: 22396172
references.citation: Circulation. 2002 Apr 9;105(14):1727-33
references.pmid: 11940554
references.citation: Mol Endocrinol. 2008 Apr;22(4):1006-14
references.pmid: 18187602
references.citation: Endocrinology. 2009 Oct;150(10):4625-33
references.pmid: 19589869
references.citation: Dis Model Mech. 2009 Sep-Oct;2(9-10):454-66
references.pmid: 19726805
references.citation: Cell Metab. 2012 Jun 6;15(6):805-12
references.pmid: 22682221
references.citation: Nat Rev Mol Cell Biol. 2012 Apr;13(4):251-62
references.pmid: 22436748
references.citation: J Hum Hypertens. 2013 Jun;27(6):397-9
references.pmid: 23190795
references.citation: Circ Res. 2004 Mar 19;94(5):609-16
references.pmid: 14752028
references.citation: Diabetes. 2011 Oct;60(10):2465-73
references.pmid: 21852674
references.citation: Eur J Endocrinol. 2012 Sep;167(3):301-9
references.pmid: 22740503
references.citation: Cardiovasc Diabetol. 2013;12:54
references.pmid: 23536959
references.citation: J Am Coll Cardiol. 2008 Aug 19;52(8):655-66
references.pmid: 18702970
references.citation: Endocrinology. 2009 Sep;150(9):4084-93
references.pmid: 19470704
references.citation: Curr Diabetes Rev. 2012 Jul 1;8(4):285-93
references.pmid: 22587513
references.citation: Cardiovasc Res. 2009 Jun 1;82(3):513-21
references.pmid: 19196827
references.citation: Nat Commun. 2013;4:2019
references.pmid: 23771152
references.citation: J Clin Invest. 1995 Sep;96(3):1382-8
references.pmid: 7544802
references.citation: PLoS One. 2013;8(9):e73011
references.pmid: 24039848
references.citation: Circulation. 2007 Nov 6;116(19):2139-47
references.pmid: 17967771
references.citation: J Clin Endocrinol Metab. 2012 Jan;97(1):E54-8
references.pmid: 22013098
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 30;106(26):10853-8
references.pmid: 19541642
references.citation: Mol Pharmacol. 2008 Aug;74(2):403-12
references.pmid: 18467542
references.citation: Am J Cardiol. 1972 Nov 8;30(6):595-602
references.pmid: 4263660
references.citation: Pediatr Surg Int. 2006 Aug;22(8):647-54
references.pmid: 16838191
references.citation: World J Diabetes. 2011 Jun 15;2(6):92-7
references.pmid: 21860692
references.citation: J Clin Invest. 2005 Jun;115(6):1627-35
references.pmid: 15902306
references.citation: Free Radic Biol Med. 2013 Aug;61:85-94
references.pmid: 23507082
references.citation: PLoS One. 2013;8(12):e82275
references.pmid: 24349242
references.citation: Cell Metab. 2013 May 7;17(5):779-89
references.pmid: 23663741
references.citation: Ann Intern Med. 2006 Apr 4;144(7):517-24
references.pmid: 16585666
references.citation: J Mol Cell Cardiol. 2013 Apr;57:82-95
references.pmid: 23353773