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

Cell Communication and Signaling

Research

Markus Dagnell¹  Arne Östman¹  Manuela Trappiel²  Janine Krüger²  Kai Kappert²  Ulrich Kintscher³  Christian Böhm³  Philipp Stawowy⁴  Heike Meyborg⁴  Sanjay Bhanot⁵ 

[1] Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden;Center for Cardiovascular Research/CCR, and Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité–Universitätsmedizin, Berlin, Germany;Center for Cardiovascular Research/CCR, and Institute of Pharmacology, Charité–Universitätsmedizin, Berlin, Germany;Department of Medicine/Cardiology, Deutsches Herzzentrum, Berlin, Germany;ISIS Pharmaceuticals, Inc, Carlsbad, CA, USA;

关键词: Protein-tyrosine-phosphatase;    Density-enhanced phosphatase-1;    Insulin resistance;    Type 2 diabetes;    Antisense oligonucleotides;    Metabolic tissues;    Insulin signaling;    Insulin receptor;    Obesity;   

DOI  :  10.1186/1478-811X-11-49

 received in 2013-04-21, accepted in 2013-07-08,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundInsulin 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.ResultsMice 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.ConclusionsThese 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.

【 授权许可】

Unknown   
© Krüger et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.