title: Enhanced insulin signaling in density-enhanced phosphatase-1 (DEP-1) knockout mice.
abstract: OBJECTIVE
  Insulin resistance can be triggered by enhanced dephosphorylation of the insulin receptor or downstream components in the insulin signaling cascade through protein tyrosine phosphatases (PTPs). Downregulating density-enhanced phosphatase-1 (DEP-1) resulted in an improved metabolic status in previous analyses. This phenotype was primarily caused by hepatic DEP-1 reduction.
  
  
  METHODS
  Here we further elucidated the role of DEP-1 in glucose homeostasis by employing a conventional knockout model to explore the specific contribution of DEP-1 in metabolic tissues. Ptprj (-/-) (DEP-1 deficient) and wild-type C57BL/6 mice were fed a low-fat or high-fat diet. Metabolic phenotyping was combined with analyses of phosphorylation patterns of insulin signaling components. Additionally, experiments with skeletal muscle cells and muscle tissue were performed to assess the role of DEP-1 for glucose uptake.
  
  
  RESULTS
  High-fat diet fed-Ptprj (-/-) mice displayed enhanced insulin sensitivity and improved glucose tolerance. Furthermore, leptin levels and blood pressure were reduced in Ptprj (-/-) mice. DEP-1 deficiency resulted in increased phosphorylation of components of the insulin signaling cascade in liver, skeletal muscle and adipose tissue after insulin challenge. The beneficial effect on glucose homeostasis in vivo was corroborated by increased glucose uptake in skeletal muscle cells in which DEP-1 was downregulated, and in skeletal muscle of Ptprj (-/-) mice.
  
  
  CONCLUSIONS
  Together, these data establish DEP-1 as novel negative regulator of insulin signaling.
authors.affiliation: Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Hessische Str. 3-4, 10115 Berlin, Charité - Universitätsmedizin Berlin, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Krüger
authors.affiliation: Center for Cardiovascular Research/CCR, Department of Endocrinology, Diabetes and Nutrition, Hessische Str. 3-4, 10115 Berlin, Charité - Universitätsmedizin Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brachs
authors.affiliation: Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Hessische Str. 3-4, 10115 Berlin, Charité - Universitätsmedizin Berlin, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Trappiel
authors.affiliation: Center for Cardiovascular Research/CCR, Institute of Pharmacology, Hessische Str. 3-4, 10115 Berlin, Charité - Universitätsmedizin Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
authors.affiliation: Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Meyborg
authors.affiliation: Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wellnhofer
authors.affiliation: Center for Cardiovascular Research/CCR, Department of Experimental Medicine, Hessische Str. 3-4, 10115 Berlin, Charité - Universitätsmedizin Berlin, Germany.
authors.forename: Christa
authors.initials: C
authors.lastname: Thöne-Reineke
authors.affiliation: Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Stawowy
authors.affiliation: Cancer Center Karolinska, R8:03, Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Arne
authors.initials: A
authors.lastname: Östman
authors.affiliation: Center for Cardiovascular Research/CCR, Department of Endocrinology, Diabetes and Nutrition, Hessische Str. 3-4, 10115 Berlin, Charité - Universitätsmedizin Berlin, Germany.
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Birkenfeld
authors.affiliation: Center for Molecular Biomedicine, Institute of Molecular Cell Biology, Universitätsklinikum Jena, Hans-Knöll-Str. 2, 07745 Jena, Germany.
authors.forename: Frank D
authors.initials: FD
authors.lastname: Böhmer
authors.affiliation: Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Hessische Str. 3-4, 10115 Berlin, Charité - Universitätsmedizin Berlin, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Kappert
keywords: DEP-1, density-enhanced phosphatase-1; Density-enhanced phosphatase-1; GTT, glucose tolerance test; Glucose homeostasis; HFD, high-fat diet; IL-6, interleukin 6; IR, insulin receptor; ITT, insulin tolerance test; Insulin resistance; Insulin signaling; KO, knockout; LFD, low-fat diet; MCP-1, monocyte chemotactic protein-1; PTP, protein tyrosine phosphatase; Phosphorylation; RER, respiratory exchange ratio; RTK, receptor tyrosine kinase; WT, wild-type
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