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Your search keyword '"Density-enhanced phosphatase-1"' showing total 2 results
Start Over Descriptor "Density-enhanced phosphatase-1" Topic insulin receptor
2 results on '"Density-enhanced phosphatase-1"'

1. Targeting density-enhanced phosphatase-1 (DEP-1) with antisense oligonucleotides improves the metabolic phenotype in high-fat diet-fed mice.

Author

Krüger, Janine, Trappiel, Manuela, Dagnell, Markus, Stawowy, Philipp, Meyborg, Heike, Böhm, Christian, Bhanot, Sanjay, Östman, Arne, Kintscher, Ulrich, and Kappert, Kai

Subjects
*PROTEIN-tyrosine phosphatase, *OLIGONUCLEOTIDES, *INSULIN receptors, *INSULIN resistance, *TYPE 2 diabetes, *OBESITY, *LABORATORY 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. [ABSTRACT FROM AUTHOR]

Published
2013
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2. Enhanced insulin signaling in density-enhanced phosphatase-1 (DEP-1) knockout mice

Author

Ernst Wellnhofer, Manuela Trappiel, Christa Thöne-Reineke, Kai Kappert, Arne Östman, Andreas L. Birkenfeld, Sebastian Brachs, Janine Krüger, Philipp Stawowy, Heike Meyborg, Frank-D. Böhmer, and Ulrich Kintscher

Subjects
HFD, high-fat diet, lcsh:Internal medicine, medicine.medical_specialty, Protein tyrosine phosphatase, Glucose homeostasis, complex mixtures, Receptor tyrosine kinase, Dephosphorylation, Insulin resistance, Internal medicine, medicine, Density-enhanced phosphatase-1, Phosphorylation, lcsh:RC31-1245, Molecular Biology, DEP-1, density-enhanced phosphatase-1, RER, respiratory exchange ratio, ITT, insulin tolerance test, KO, knockout, biology, Insulin tolerance test, Cell Biology, respiratory system, medicine.disease, MCP-1, monocyte chemotactic protein-1, WT, wild-type, IRS2, LFD, low-fat diet, Insulin signaling, IL-6, interleukin 6, Insulin receptor, 600 Technik, Medizin, angewandte Wissenschaften::630 Landwirtschaft, Endocrinology, IR, insulin receptor, biology.protein, GTT, glucose tolerance test, Original Article, RTK, receptor tyrosine kinase, PTP, protein tyrosine phosphatase
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. Conclusion: Together, these data establish DEP-1 as novel negative regulator of insulin signaling.

Published
2015
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