Lipids, Inflammatory Pathways, and Insulin Resistance

脂质、炎症途径和胰岛素抵抗

• 批准号: 7632218
• 负责人: ROBERT M O'DOHERTY
• 金额: $ 26.85万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7632218
• 关键词: Acute; Address; Adipose tissue; Biochemical; Chronic; Data; Development; Fatty Acids; Gene Expression; Hyperlipidemia; I Kappa B-Alpha; Immune response; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Insulin Resistance; Insulin Resistance Pathway; Intervention; Ligands; Link; Lipids; Liver; Mediating; Mediator of activation protein; Muscle Fibers; NF-kappa B; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Palmitates; Pathogenesis; Pathway interactions; Pharmacologic Substance; Play; Rattus; Receptor Activation; Research Personnel; Role; Saturated Fatty Acids; Skeletal Muscle; Testing; Tissues; Toll-like receptors; Work; base; driving force; gene therapy; improved; in vivo; insulin sensitivity; prevent; programs; research study; toll-like receptor 4

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.

描述（由申请人提供）：慢性低度炎症与肥胖和II型糖尿病的相关性现已明确。此外，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鉴定可能引发肥胖炎症反应的机制。我们的工作集中在这些假定的机制之一，即高脂血症。我们已经建立了一个主要的炎症途径（IKK/IkappaB/NF-κ B）是由饱和脂肪酸在骨骼肌中激活，并在初步的数据中，我们证明了脂肪酸对IKK/IkappaB/NF-κ B（NF-κ B）途径的作用机制之一是刺激Toll样受体（TLR）的活性。这项工作已经建立了一个生物化学之间的联系脂质，炎症途径的活动和近端介质的先天性免疫反应（TLR的）。在当前提议中待测试的假设简单地是TLR在体内在引发和维持肥胖症中的炎症反应和相关的胰岛素抗性中起作用，并且TLR活化的一种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途径激活中的作用、TLR在介导脂质作用中的作用以及升高的炎症反应与胰岛素抵抗发病机制之间的关系的理解。

项目成果

Elevated metabolic rate and skeletal muscle oxidative metabolism contribute to the reduced susceptibility of NF-κB p50 null mice to obesity.

• DOI: 10.14814/phy2.13836
• 发表时间: 2018-09
• 期刊: Physiological reports
• 影响因子: 2.5
• 作者: Bhatt BA;Dedousis N;Sipula IJ;O'Doherty RM
• 通讯作者: O'Doherty RM

A modest glucokinase overexpression in the liver promotes fed expression levels of glycolytic and lipogenic enzyme genes in the fasted state without altering SREBP-1c expression.

肝脏中适度的葡萄糖激酶过度表达可促进禁食状态下糖酵解和脂肪生成酶基因的进食表达水平，而不改变 SREBP-1c 表达。

• DOI: 10.1023/a:1027306122336
• 发表时间: 2003
• 期刊: Molecular and cellular biochemistry
• 影响因子: 4.3
• 作者: Scott,DK;Collier,JJ;Doan,TTT;Bunnell,AS;Daniels,MC;Eckert,DT;O'Doherty,RM
• 通讯作者: O'Doherty,RM

Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance.

• DOI: 10.2337/db09-0016
• 发表时间: 2010-02
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Huang W;Metlakunta A;Dedousis N;Zhang P;Sipula I;Dube JJ;Scott DK;O'Doherty RM
• 通讯作者: O'Doherty RM

Mice lacking NKT cells but with a complete complement of CD8+ T-cells are not protected against the metabolic abnormalities of diet-induced obesity.

• DOI: 10.1371/journal.pone.0019831
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Mantell BS;Stefanovic-Racic M;Yang X;Dedousis N;Sipula IJ;O'Doherty RM
• 通讯作者: O'Doherty RM