title: TDP-43, an ALS linked protein, regulates fat deposition and glucose homeostasis.
abstract: The identification of proteins which determine fat and lean body mass composition is critical to better understanding and treating human obesity. TDP-43 is a well-conserved RNA-binding protein known to regulate alternative splicing and recently implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). While TDP-43 knockout mice show early embryonic lethality, post-natal conditional knockout mice show weight loss, fat depletion, and rapid death, suggesting an important role for TDP-43 in regulating energy metabolism. Here we report, that over-expression of TDP-43 in transgenic mice can result in a phenotype characterized by increased fat deposition and adipocyte hypertrophy. In addition, TDP-43 over-expression in skeletal muscle results in increased steady state levels of Tbc1d1, a RAB-GTPase activating protein involved in Glucose 4 transporter (Glut4) translocation. Skeletal muscle fibers isolated from TDP-43 transgenic mice show altered Glut4 translocation in response to insulin and impaired insulin mediated glucose uptake. These results indicate that levels of TDP-43 regulate body fat composition and glucose homeostasis in vivo.
authors: Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Nancy R
authors: NR
authors: Stallings
authors: Krishna
authors: K
authors: Puttaparthi
authors: Katherine J
authors: KJ
authors: Dowling
authors: Christina M
authors: CM
authors: Luther
authors: Dennis K
authors: DK
authors: Burns
authors: Kathryn
authors: K
authors: Davis
authors: Jeffrey L
authors: JL
authors: Elliott
mesh_terms: D000273:Adipose Tissue / Q000254:growth & development / Q000378:metabolism*; D050154:Adiposity / Q000235:genetics; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020690:GTPase-Activating Proteins; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009929:Organ Size / Q000235:genetics; D021381:Protein Transport
chemical_list: D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D009687:Nuclear Proteins; C095906:Tbc1d1 protein, mouse; D005947:Glucose
references: Exp Cell Res. 2008 Oct 15;314(17):3264-74
references: 18773891
references: Hum Mol Genet. 2008 Jun 15;17(12):1798-802
references: 18325908
references: Nat Genet. 2008 May;40(5):572-4
references: 18372902
references: Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3858-63
references: 20133711
references: EMBO J. 2011 Jan 19;30(2):277-88
references: 21131904
references: J Neurol Sci. 1995 May;129 Suppl:47-9
references: 7595619
references: Am J Physiol Endocrinol Metab. 2008 Jul;295(1):E29-37
references: 18477703
references: J Biol Chem. 2010 Feb 26;285(9):6826-34
references: 20040602
references: Nat Methods. 2011 Dec 28;9(1):57-63
references: 22205519
references: Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18809-14
references: 19833869
references: Neurobiol Dis. 2010 Nov;40(2):404-14
references: 20621187
references: Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16320-4
references: 20660762
references: J Biol Chem. 2005 Nov 11;280(45):37572-84
references: 16157593
references: Biochem Biophys Res Commun. 2006 Dec 22;351(3):602-11
references: 17084815
references: Genesis. 2010 Jan;48(1):56-62
references: 20014337
references: J Clin Invest. 2011 Jun;121(6):2094-101
references: 21633177
references: Ann Neurol. 2008 Apr;63(4):535-8
references: 18288693
references: Biochem J. 2013 Jan 15;449(2):479-89
references: 23078342
references: Science. 2008 Mar 21;319(5870):1668-72
references: 18309045
references: Cell Metab. 2011 Jan 5;13(1):68-79
references: 21195350
references: Nat Neurosci. 2011 Apr;14(4):459-68
references: 21358643
references: Endocrinology. 2008 May;149(5):2138-48
references: 18258679
references: J Biol Chem. 2008 Oct 24;283(43):28852-9
references: 18703504
references: Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3347-52
references: 22323604
references: Amyotroph Lateral Scler. 2010;11(1-2):166-71
references: 20184518
references: Can J Physiol Pharmacol. 1985 Aug;63(8):958-65
references: 2416421
references: Am J Clin Nutr. 1996 Jan;63(1):130-7
references: 8604660
references: J Neurosci. 2002 Oct 15;22(20):8790-6
references: 12388585
references: J Neurol Neurosurg Psychiatry. 2011 Jun;82(6):628-34
references: 21097551
references: J Histochem Cytochem. 1997 Aug;45(8):1083-96
references: 9267469
references: Hum Mol Genet. 2006 Sep 15;15(18):2709-20
references: 16893906
references: J Neurol. 2009 Aug;256(8):1236-42
references: 19306035
references: Exp Neurol. 2005 Dec;196(2):441-51
references: 16242125
references: Nat Genet. 2008 Nov;40(11):1354-9
references: 18931681
references: Diabetes. 2006 Jul;55(7):2077-83
references: 16804078
references: Lancet Neurol. 2011 Jan;10(1):75-82
references: 21035400
references: PLoS Genet. 2008 Sep 19;4(9):e1000193
references: 18802454
references: J Neurol Sci. 1984 Mar;63(3):317-24
references: 6374040
references: Science. 2006 Oct 6;314(5796):130-3
references: 17023659
references: Nucleic Acids Res. 2009 Apr;37(6):1799-808
references: 19174564
references: Acta Neuropathol. 2010 Apr;119(4):409-19
references: 20198480
references: Am J Physiol Endocrinol Metab. 2012 Nov 15;303(10):E1273-86
references: 23011063