Targeting density-enhanced phosphatase-1 (DEP-1) with antisense oligonucleotides improves the metabolic phenotype in hig
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RESEARCH
Open Access
Targeting density-enhanced phosphatase-1 (DEP-1) with antisense oligonucleotides improves the metabolic phenotype in high-fat diet-fed mice Janine Krüger1, Manuela Trappiel1, Markus Dagnell2, Philipp Stawowy3, Heike Meyborg3, Christian Böhm4, Sanjay Bhanot5, Arne Östman2, Ulrich Kintscher4 and Kai Kappert1*
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. Keywords: Protein-tyrosine-phosphatase, Density-enhanced phosphatase-1, Insulin resistance, Type 2 diabetes, Antisense oligonucleotides, Metabolic tissues, Insulin signaling, Insulin receptor, Obesity
Lay abstract Insulin resistance represents a main factor contributing to type 2 diabetes in obese patients. The tremendous increase of type 2 diabetes has developed to a world-wide epidemic burden. However, the cellular mechanisms underlying insulin resistance are only partly understood. Therefore, a better understanding of the pathophysiology and the molecular background of insulin resistance are highly warranted. Several studies have described an increased * Correspondence: [email protected] 1 Center for Cardiovascular Research/CCR, and Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité– Universitätsmedizin, Berlin, Germany Full list of author information is available at the end of the article
protein-tyrosine-phosphatase activity in metabolic tissues in obesity. Indeed, certain protein-tyrosine-phosphatases are known to target the insulin receptor and negatively regulating the insulin signaling pathway. We observed that the activity of density-enhanced phosphatase-1 (DEP-1), a receptor-like transmembr
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