Abstract
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.
Highlights
Insulin signaling is tightly controlled by tyrosine dephosphorylation of the insulin receptor through protein-tyrosine-phosphatases (PTPs)
This study identifies the phosphatase density-enhanced phosphatase-1 (DEP-1) as novel component in insulin signaling, and molecular target for the treatment of insulin resistance and obesity-associated diseases
density-enhanced phosphatase (DEP)-1 is recruited to the insulin receptor upon insulin stimulation in situ after showing that DEP-1 was differentially regulated in metabolic tissues in diet-induced obesity, and that DEP-1 significantly impacts on insulin signaling, we addressed whether DEP-1 physically associates with the insulin receptor by recruitment studies applying Proximity Ligation Assays (PLA)
Summary
Insulin signaling is tightly controlled by tyrosine dephosphorylation of the insulin receptor through protein-tyrosine-phosphatases (PTPs). 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. 38 so-called “classical PTPs” have been identified in the human genome, which all share a catalytic signature motif V/IHCSXG. These PTPs represent one subgroup of phosphatases with strict tyrosine-specificity [3]. PTP activity has been described to be dynamically enhanced in obesity in insulinsensitive tissue (adipose tissue, skeletal muscle and liver) [4], with significant reduction after weight loss [5,6]. Efforts have been undertaken to dissect the role of PTPs in insulin signaling and metabolic diseases
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