Role of protein tyrosine phosphatase 1B and endoplasmic reticulum stress in obesity-induced insulin resistance

Obesity is a growing epidemic worldwide and is considered to be a major public health threat. Obesity underlies the development of metabolic syndrome and type 2 diabetes, which are the major risk factors for cardiovascular disease, the leading cause of death in developed countries. Insulin resistance is a fundamental aspect in the etiology of type 2 diabetes. 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 dissertation was to study the mechanism of the crosstalk between ER stress and PTP1B and its role in development of insulin resistance. The major finding of this dissertation is that ER stress can impair glucose uptake and insulin signaling in myotubes by upregulating expression of PTP1B. We also found that upregulation of ER stress markers in skeletal muscle of the high fat diet-fed mice was significantly attenuated by deletion of PTP1B. High fat diet-fed PTP1B knockout mice also had improved glucose uptake and Akt phosphorylation in the skeletal muscle. Mice lacking PTP1B also had decreased expression of unfolded protein response adaptor protein NCK1 (non-catalytic region of tyrosine kinase) indicating that PTP1B is required for full-range activation of ER stress pathway in mediating insulin resistance in skeletal muscle. Furthermore, in vitro treatment with tunicamycin induced ER stress-dependent accumulation of reactive oxygen species (ROS), which led to activation of protein expression of PTP1B. Our data indicates that PTP1B is induced by ER stress via ROS-dependent activation of transcription factor NFκB (Nuclear factor kappa-light-chain-enhancer of activated B cells) and is required for UPR activation in mediating insulin resistance in the skeletal muscle of obese mice. We also tested antidiabetic properties of a new curcuminoid compound CNB001, which showed ability to decrease adiposity and hepatic steatosis, to improve glucose intolerance and skeletal muscle insulin sensitivity in diet-induced obesity model in mice via inhibition of PTP1B and ER stress. Our data shows an important role of the crosstalk between ER stress and PTP1B in pathogenesis of obesity-induced insulin resistance.