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

• Published in: Cell communication and signaling Vol. 11; no. 1; p. 49
• Main Authors: Krüger, Janine, Trappiel, Manuela, Dagnell, Markus, Stawowy, Philipp, Meyborg, Heike, Böhm, Christian, Bhanot, Sanjay, Ostman, Arne, Kintscher, Ulrich, Kappert, Kai
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 26.07.2013; BioMed Central
• Subjects: Adipose tissue; Adipose Tissue - metabolism; Adipose tissues; Amino acids; Analysis; Animals; Body weight; Care and treatment; Cell Line; Diabetes; Diet, High-Fat - adverse effects; Genetic aspects; Health aspects; Insulin; Insulin - metabolism; Insulin Resistance; Kinases; Leptin; Liver; Liver - metabolism; Male; Medicin och hälsovetenskap; Metabolic disorders; Mice, Inbred C57BL; Muscle, Skeletal - metabolism; Muscles; Obesity; Obesity - etiology; Obesity - metabolism; Oligonucleotides, Antisense - pharmacology; Organ Specificity; Phenotype; Phosphorylation; Receptor, Insulin - metabolism; Receptor-Like Protein Tyrosine Phosphatases, Class 3 - metabolism; Risk factors; Rodents; Signal Transduction; Type 2 diabetes; Tyrosine; Tyrosine - metabolism; Germany
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/1478-811X-11-49

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. 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. 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.