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型糖尿病的关联现在已经得到了很好的证实。此外，现在有大量证据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，减少或预防特异性炎症反应的干预措施可改善胰岛素敏感性。基于它们对理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确定肥胖中可能引发炎症反应的机制。我们的工作集中在这些假定的机制之一，即高脂血症。我们已经确定，骨骼肌中的饱和脂肪酸可以激活主要的炎症通路（IKK/IkappaB/NF-kappaB），并且在初步数据中，我们证明脂肪酸对IKK/IkappaB/NF-kappaB （NF-kappaB）通路的一种作用机制是刺激toll样受体（TLR）活性。这项工作已经建立了脂质、炎症途径活性和先天免疫反应（TLR’s）的近端介质之间的生化联系。本研究拟验证的假设简单地说，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中发挥作用，而TLR激活的一个可能的驱动力是高脂血症。这些实验将增加我们对高脂血症在炎症通路激活中的作用，TLR在脂质介导作用中的作用，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.