title: Targeting density-enhanced phosphatase-1 (DEP-1) with antisense oligonucleotides improves the metabolic phenotype in high-fat diet-fed mice.
abstract: BACKGROUND
  Insulin signaling is tightly controlled by tyrosine dephosphorylation of the insulin receptor through protein-tyrosine-phosphatases (PTPs). DEP-1 is a PTP dephosphorylating tyrosine residues in a variety of receptor tyrosine kinases. Here, we analyzed whether DEP-1 activity is differentially regulated in liver, skeletal muscle and adipose tissue under high-fat diet (HFD), examined the role of DEP-1 in insulin resistance in vivo, and its function in insulin signaling.
  
  
  RESULTS
  Mice were fed an HFD for 10 weeks to induce obesity-associated insulin resistance. Thereafter, HFD mice were subjected to systemic administration of specific antisense oligonucleotides (ASOs), highly accumulating in hepatic tissue, against DEP-1 or control ASOs. Targeting DEP-1 led to improvement of insulin sensitivity, reduced basal glucose level, and significant reduction of body weight. This was accompanied by lower insulin and leptin serum levels. Suppression of DEP-1 in vivo also induced hyperphosphorylation in the insulin signaling cascade of the liver. Moreover, DEP-1 physically associated with the insulin receptor in situ, and recombinant DEP-1 dephosphorylated the insulin receptor in vitro.
  
  
  CONCLUSIONS
  These results indicate that DEP-1 acts as an endogenous antagonist of the insulin receptor, and downregulation of DEP-1 results in an improvement of insulin sensitivity. DEP-1 may therefore represent a novel target for attenuation of metabolic diseases.
authors.forename: Janine
authors.initials: J
authors.lastname: Krüger
authors.forename: Manuela
authors.initials: M
authors.lastname: Trappiel
authors.forename: Markus
authors.initials: M
authors.lastname: Dagnell
authors.forename: Philipp
authors.initials: P
authors.lastname: Stawowy
authors.forename: Heike
authors.initials: H
authors.lastname: Meyborg
authors.forename: Christian
authors.initials: C
authors.lastname: Böhm
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.forename: Arne
authors.initials: A
authors.lastname: Ostman
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
authors.forename: Kai
authors.initials: K
authors.lastname: Kappert
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D059305:Diet, High-Fat / Q000009:adverse effects*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D009928:Organ Specificity; D010641:Phenotype; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
chemical_list: D007328:Insulin; D016376:Oligonucleotides, Antisense; D014443:Tyrosine; D011972:Receptor, Insulin; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3
references.citation: Am J Physiol. 1987 Sep;253(3 Pt 1):E264-70
references.pmid: 3115113
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 7;109(6):1985-90
references.pmid: 22308318
references.citation: DNA Cell Biol. 2006 Jun;25(6):376-82
references.pmid: 16792508
references.citation: Cell. 2009 Jan 23;136(2):352-63
references.pmid: 19167335
references.citation: Oncogene. 2006 Oct 12;25(47):6319-24
references.pmid: 16682945
references.citation: Eur J Endocrinol. 2009 Apr;160(4):585-92
references.pmid: 19155318
references.citation: J Biol Chem. 2000 May 26;275(21):16219-26
references.pmid: 10821867
references.citation: Science. 1999 Mar 5;283(5407):1544-8
references.pmid: 10066179
references.citation: J Biol Chem. 2003 Feb 21;278(8):5728-35
references.pmid: 12475979
references.citation: Obes Rev. 2005 Feb;6(1):13-21
references.pmid: 15655035
references.citation: Diabetes. 2012 Aug;61(8):1949-58
references.pmid: 22698917
references.citation: J Biol Chem. 1997 Jan 17;272(3):1639-45
references.pmid: 8999839
references.citation: PLoS Genet. 2008 Jun 27;4(6):e1000108
references.pmid: 18584035
references.citation: Drug Discov Today. 2007 May;12(9-10):373-81
references.pmid: 17467573
references.citation: Diabetes. 2008 Feb;57(2):432-9
references.pmid: 18057090
references.citation: J Cell Biol. 2006 Aug 14;174(4):593-604
references.pmid: 16893970
references.citation: Diabetes. 2003 Jan;52(1):21-8
references.pmid: 12502489
references.citation: Expert Opin Drug Metab Toxicol. 2009 Apr;5(4):381-91
references.pmid: 19379126
references.citation: FASEB J. 2007 Feb;21(2):523-34
references.pmid: 17158785
references.citation: Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9680-4
references.pmid: 7937872
references.citation: Mol Cell Biol. 2000 Aug;20(15):5479-89
references.pmid: 10891488
references.citation: Cell. 2004 Jun 11;117(6):699-711
references.pmid: 15186772
references.citation: J Biol Chem. 2009 Aug 14;284(33):22048-22058
references.pmid: 19494114
references.citation: Endocrinology. 2011 Dec;152(12):4581-8
references.pmid: 21952243
references.citation: Diabetes. 2012 Oct;61(10):2495-505
references.pmid: 22698915
references.citation: Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11357-62
references.pmid: 12169659
references.citation: Physiol Rev. 1995 Jul;75(3):473-86
references.pmid: 7624391
references.citation: J Biol Chem. 1995 Sep 1;270(35):20503-8
references.pmid: 7544790
references.citation: Curr Biol. 2009 Nov 17;19(21):1788-98
references.pmid: 19836242
references.citation: Cancer Res. 2006 Jun 15;66(12):6280-7
references.pmid: 16778204
references.citation: Brain Pathol. 2011 Jul;21(4):405-18
references.pmid: 21091576
references.citation: J Biol Chem. 2000 Mar 31;275(13):9792-6
references.pmid: 10734133
references.citation: Nat Med. 2006 May;12(5):549-56
references.pmid: 16617349
references.citation: Endocrinology. 2009 Apr;150(4):1670-9
references.pmid: 19164474
references.citation: Metabolism. 1997 Oct;46(10):1140-5
references.pmid: 9322796
references.citation: Am J Physiol Endocrinol Metab. 2003 Apr;284(4):E663-70
references.pmid: 12626322
references.citation: Biochem J. 2010 Jan 27;426(1):65-72
references.pmid: 19922411
references.citation: J Biol Chem. 2008 May 23;283(21):14230-41
references.pmid: 18281274
references.citation: Diabetes. 2012 Jun;61(6):1415-22
references.pmid: 22474028
references.citation: J Clin Invest. 1997 Jul 15;100(2):449-58
references.pmid: 9218523
references.citation: Eur J Endocrinol. 2008 Feb;158(2):179-87
references.pmid: 18230824
references.citation: Biochem J. 2008 Jul 1;413(1):193-200
references.pmid: 18348712
references.citation: J Biol Chem. 2007 May 11;282(19):14291-9
references.pmid: 17353188
references.citation: J Clin Endocrinol Metab. 2010 Feb;95(2):911-9
references.pmid: 19996310