Abstract
Obesity-induced endoplasmic reticulum (ER) stress has been proposed as an important pathway in the development of insulin resistance. Protein-tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling and is tethered to the ER-membrane. The aim of the study was to determine the mechanisms involved in the crosstalk between ER-stress and PTP1B. PTP1B whole body knockout and C57BL/6J mice were subjected to a high-fat or normal chow-diet for 20 weeks. High-fat diet feeding induced body weight gain, increased adiposity, systemic glucose intolerance, and hepatic steatosis were attenuated by PTP1B deletion. High-fat diet- fed PTP1B knockout mice also exhibited improved glucose uptake measured using [3H]-2-deoxy-glucose incorporation assay and Akt phosphorylation in the skeletal muscle tissue, compared to their wild-type control mice which received similar diet. High-fat diet-induced upregulation of glucose-regulated protein-78, phosphorylation of eukaryotic initiation factor 2α and c-Jun NH2-terminal kinase-2 were significantly attenuated in the PTP1B knockout mice. Mice lacking PTP1B showed decreased expression of the autophagy related protein p62 and the unfolded protein response adaptor protein NCK1 (non-catalytic region of tyrosine kinase). Treatment of C2C12 myotubes with the ER-stressor tunicamycin resulted in the accumulation of reactive oxygen species (ROS), leading to the activation of protein expression of PTP1B. Furthermore, tunicamycin-induced ROS production activated nuclear translocation of NFκB p65 and was required for ER stress-mediated expression of PTP1B. Our data suggest that PTP1B is induced by ER stress via the activation of the ROS-NFκB axis which is causes unfolded protein response and mediates insulin resistance in the skeletal muscle under obese condition.
Highlights
Obesity has reached epidemic proportions worldwide and is associated with an increased risk of disability and morbidity [1]
Delibegovic and colleagues showed that mice with muscle-specific deletion of Protein tyrosine phosphatase 1B (PTP1B) had improved glucose uptake and insulin signaling in skeletal muscle after high-fat diet feeding [14]
Materials 2-Deoxy-[3H]-D-Glucose-1, propylene glycol and hematoxylin were from Sigma (St Lois, MO), tauroursodeoxycholic acid (TUDCA) and tunicamycin were from Calbiochem (Darmstadt, Germany); PTP1B siRNA sequences, non-target siRNA sequences and DharmaFECT transfection reagent were from Thermo Scientific (Rockford, IL); antibodies against-glucose-regulated protein 78 (GRP78), -CHOP, -GAPDH, -phospho-eIF2a, -phospho-JNK1/2, eIF2a, JNK1/2, -phospho-Akt, Akt, Beclin-1, p62, NFkB p65, lamin A, non-catalytic region of tyrosine kinase 1 (NCK1), LC-3B, ATG5, ATG7 and LumiGLO reagent were from Cell Signaling Technology (Boston, MA); antibodies against PTP1B were from Millipore (Billerica, MA, USA); antibodies against ATG5 were from Abgent (San Diego, CA)
Summary
Obesity has reached epidemic proportions worldwide and is associated with an increased risk of disability and morbidity [1]. Insulin resistance is a hallmark of obesity-associated metabolic syndrome and type 2 diabetes mellitus. It is characterized by impairment in glucose-uptake by insulin sensitive tissues [4]. Global knock out of PTP1B in mice exhibit a phenotype with low adiposity, elevated insulin sensitivity and increased energy expenditure [7,8]. Insulin resistant conditions, such as those seen with high-fat diet feeding, leptin deficiency, hyperglycemia or age-induced impairment in insulin signaling, are associated with increased expression of PTP1B in insulin-sensitive tissues [9,10,11]. Delibegovic and colleagues showed that mice with muscle-specific deletion of PTP1B had improved glucose uptake and insulin signaling in skeletal muscle after high-fat diet feeding [14]
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