Lipids Inflammatory Pathways and Insulin Resistance

描述(由申请人提供)：慢性低度炎症与肥胖和II型糖尿病之间的关系现在已经得到了很好的证实。此外，大量证据现在表明，炎症状态升高与胰岛素抵抗的发病机制之间存在联系。因此，减少或预防特定炎症反应的干预措施可以改善胰岛素敏感性。基于它们对了解胰岛素抵抗的发病机制和治疗的重要性，我们目前正集中精力识别可能启动肥胖症炎症反应的机制。我们的工作集中在其中一个可能的机制上，即高脂血症。我们已经证实，骨骼肌中的饱和脂肪酸激活了主要的炎症通路之一(IKK/IkappaB/NF-kappaB)，并在初步数据中证明了脂肪酸对IKK/IkappaB/NF-kappaB(NF-kappaB)通路的作用机制之一是刺激Toll样受体(TLR)的活性。这项工作在脂质、炎症途径活动和天然免疫反应的近端介质(TLR‘s)之间建立了一种生化联系。目前的方案中要检验的假设很简单，即TLR在体内启动和维持肥胖的炎症反应和相关的胰岛素抵抗方面发挥作用，TLR激活的一个可能的驱动力是高脂血症。这些实验将加深我们对高脂血症在炎症通路激活中的作用，TLR在调节血脂效应中的作用，以及炎症反应升高与胰岛素抵抗发病机制之间的关系的理解。

DESCRIPTION (provided by applicant): The association of chronic low grade inflammation with obesity and type II diabetes is now well established. Moreover, substantial evidence now suggests a link between elevated inflammatory status and the pathogenesis of insulin resistance. Thus, interventions that decrease or prevent specific inflammatory responses improve insulin sensitivity. Based on their importance to understanding the pathogenesis and treatment of insulin resistance, we are currently concentrating our efforts on the identification of mechanisms that may initiate inflammatory responses in obesity. Our work has concentrated on one of these putative mechanisms, namely hyperlipidemia. We have established that one of the principal inflammatory pathways (IKK/IkappaB/NF-kappaB) is activated by saturated fatty acids in skeletal muscle and in preliminary data we demonstrate that one mechanism of action of fatty acids on the IKK/IkappaB/NF-kappaB (NF-kappaB) pathway is to stimulate toll-like receptor (TLR) activity. This work has established one biochemical link between lipids, inflammatory pathway activity and a proximal mediator of the innate immune response (TLR's). The hypothesis to be tested in the current proposal is simply that TLR's play a role in vivo in initiating and maintaining the inflammatory response and associated insulin resistance in obesity, and that one possible driving force of TLR activation is hyperlipidemia. These experiments will increase our understanding of the role of hyperlipidemia in activation of inflammatory pathways, the role of TLR's in mediating the effects of lipids, and the relationship between elevated inflammatory responses and the pathogenesis of insulin resistance.