Title: Integration of IKK and JNK signals in Insulin Resistance ABSTRACT The serine kinases IKK2 and JNK1 contribute to insulin resistance by phosphorylation of IRS-1. This activity has been widely used to explain insulin resistance from many risk factors including inflammation, free fatty acids or fatty acid derivatives (DAG or ceramide), ectopic fat (lipotoxicity), ER stress and oxidative stress. In addition to IRS-1, PPAR? is also a target of the two serine kinases in the regulation of glucose metabolism. In the last grant period, we investigated the mechanisms of signal integration for IKK2 and JNK1 in cellular and animal models. Our data suggests that IKK2 and JNK1 signals are integrated in activation of S6K1 in the cytoplasm, and S6K directly phosphorylates IRS-1 at four serine residues. In the nucleus, their signals are integrated in the regulation of histone deacetylases (HDACs) activities, and HDACs translate their signals into metabolism-related gene expression. Of the HDACs, IKK2 enhances HDAC3 through activation of NF-kB, and JNK1 inhibits SIRT1. Our data suggest that adipose tissue hypoxia may activate NF-kB for initiation of adipose chronic inflammation in obesity. Based on these observations, we hypothesize that S6K1 and HDACs may mediate IKK2 and JNK1 activities in the regulation of glucose metabolism. We will test the hypothesis in three specific aims:
AIM I : To test that IKK2 regulates the S6K activity through a post- translation mechanism;
AIM II : To characterize the molecular mechanisms by which hypoxia activates NF-kB and inhibits PPAR?;
AIM III : To test that JNK1 regulates SIRT1 activity. The results will support that S6K1 and HDACs are new targets of IKK2 and JNK1, and this mechanism may represent an epigenetic pathway for insulin resistance. We will take advantage of cellular and animal models that were developed in the last grant. The study will leads to identification of new drug target for prevention and treatment of metabolic syndrome.
Title: Integration of IKK and JNK signals in Insulin Resistance LAY ABSTRACT Type 2 diabetes has been a major health threat to the general public in US and developed countries. The treatment and prevention of the disease is limited by our understanding of the molecular mechanism of the diseases. In this study, we will investigate the molecular mechanism by focusing on two molecules IKK2 and JNK1. These two molecules are involved in the development of the diseases, but their targets are not clear. They play a role in progress of type 2 diabetes in many conditions including inflammation, free fatty acids or fatty acid derivatives, lipotoxicity, and oxidative stress. We have discovered new downstream signals of the two molecules in our early study that is supported by NIH. In the current study, we will obtain details about these signals, and test their role in type 2 diabetes. We will take advantage of cellular and animal models that were developed in the last study. The study will help us to understand molecular mechanism of type 2 diabetes, and to find new drug target for prevention and treatment of type 2 diabetes.
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