The Impact of Heat Shock Protein Expression on Inflammation and Insulin Action

热激蛋白表达对炎症和胰岛素作用的影响

基本信息

批准号：
8244514
负责人：
Andrea L Hevener
金额：
$ 26.26万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-11 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8244514
关键词：
Ablation Adipose tissue American Biochemical Blood Body Composition Cell Fractionation Cell Respiration Cellular Stress Chronic Chronic Disease Clinical Data Development Diet Disease susceptibility Etiology Evaluation Family Fatty Acids Fatty acid glycerol esters Foundations Genes Genetic Glucose Clamp Technique Glucose Intolerance Glucose tolerance test HSP72 protein Health Healthcare Heat shock proteins Heat-Shock Response Heating Immunohistochemistry In Vitro Indirect Calorimetry Inflammation Inflammatory Insulin Insulin Resistance Laboratory Research Leptin Leptin deficiency Lipids Liver Measures Mediator of activation protein Metabolic Molecular Molecular Chaperones Mus Muscle N-terminal Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Pathogenesis Pathway interactions Patients Peripheral Phosphorylation Phosphotransferases Prediabetes syndrome Predisposition Protein Isoforms Protein-Serine-Threonine Kinases Proteins Public Health Publishing Research Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Skeletal Muscle Stress Techniques Testing Tissues Transcriptional Activation Transgenic Organisms United States Work base combat cytokine enzyme activity feeding heat shock transcription factor impaired glucose tolerance improved in vivo inflammatory marker insulin sensitivity insulin signaling macrophage male overexpression prevent protein expression response stress protein stress-activated protein kinase 1 therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Insulin resistance is a key metabolic abnormality of type 2 diabetes and is characterized by diminished insulin action in skeletal muscle, liver, and adipose tissue. While the precise mechanisms involved in the etiology of insulin resistance are not fully understood, many agree that inflammation and stress kinase activation are central mediators of impaired insulin signal transduction. A primary cellular defense against inflammatory insult includes the rapid synthesis of a family of chaperone proteins known as heat shock proteins (HSPs) through the induction of heat shock transcritpion factor (HSF)-1. Impaired heat shock protein induction in response to cellular stress may contribute to the development of insulin resistance as induction of HSF-1 and the inducible HSP (HSP72) are significantly diminished in patients with impaired glucose tolerance and type 2 diabetes compared with lean healthy subjects. To advance these clinical observations we propose to establish a causal relationship between HSP72 protein expression, inflammation and insulin action. We will achieve this in two specific aims employing experimental manipulations of HSP72 expression by genetic and pharmacologic means. In Aim 1 we hypothesize that pharmacologic or genetic overexpression of HSP72 will protect against inflammation, insulin resistance, and obesity induced by high fat diet (HFD) or leptin deficiency. In Aim 2 we hypothesize that genetic ablation of HSP72 or its transcription factor HSF-1 is causal for heightened inflammation, insulin resistance, and susceptibility to the deleterious effects of a HFD. Our preliminary findings show that muscle specific transgenic overexpression of HSP72 suppresses phosphorylation of a key inflammatory marker, c-Jun N-terminal kinase (JNK), and preserves insulin action in the face of HFD. These findings were recapitulated in genetically obese mice administered an HSF-1 co-inducer, BGP-15, which caused a marked increase in skeletal muscle HSP72 levels, blunted JNK activity, and improved insulin sensitivity (as measured by the glucose clamp technique). Furthermore we now provide evidence in this revised application that ablation of HSP72 causes JNK activation, glucose intolerance, insulin resistance and increased adiposity. Based upon these compelling preliminary data we anticipate that the studies outlined in these two aims will show that: (1) HSP72 expression is critical for normal insulin action, (2) HSP72 induction protects against metabolic insults known to cause insulin resistance, and (3) HSP72 is a promising therapeutic target that can be exploited to combat obesity and type 2 diabetes. PUBLIC HEALTH RELEVANCE: Type 2 diabetes afflicts over 24 million Americans and this poses a large healthcare and financial burden on the United States. We intend for our work to provide the foundation for a better understanding of the molecular underpinnings responsible for insulin resistance or "pre-diabetes." We find that an impaired stress protein induction in response to cellular stress is causal for insulin resistance and that pharmacologic strategies to restore stress protein levels can be used clinically to combat insulin resistance and type 2 diabetes.

描述（由申请人提供）：胰岛素抵抗是2型糖尿病的关键代谢异常，其特征是骨骼肌、肝脏和脂肪组织中的胰岛素作用减弱。虽然胰岛素抵抗病因学的确切机制尚不完全清楚，但许多人认为炎症和应激激酶激活是胰岛素信号转导受损的核心介质。针对炎症损伤的主要细胞防御包括通过诱导热休克转录因子 (HSF)-1 快速合成称为热休克蛋白 (HSP) 的伴侣蛋白家族。对细胞应激反应的热休克蛋白诱导受损可能会导致胰岛素抵抗的发展，因为与瘦健康受试者相比，糖耐量受损和 2 型糖尿病患者的 HSF-1 和诱导型 HSP (HSP72) 的诱导显着减少。为了推进这些临床观察，我们建议建立 HSP72 蛋白表达、炎症和胰岛素作用之间的因果关系。我们将通过遗传和药理学手段对 HSP72 表达进行实验操作，以实现两个具体目标。在目标 1 中，我们假设 HSP72 的药理学或遗传过度表达将预防由高脂肪饮食 (HFD) 或瘦素缺乏引起的炎症、胰岛素抵抗和肥胖。在目标 2 中，我们假设 HSP72 或其转录因子 HSF-1 的基因消除是导致炎症加剧、胰岛素抵抗和对 HFD 有害影响的敏感性的原因。我们的初步研究结果表明，HSP72 的肌肉特异性转基因过度表达可抑制关键炎症标记物 c-Jun N 末端激酶 (JNK) 的磷酸化，并在 HFD 时保持胰岛素作用。这些发现在给予 HSF-1 共诱导剂 BGP-15 的遗传性肥胖小鼠中得到了重现，该小鼠导致骨骼肌 HSP72 水平显着增加、JNK 活性减弱并改善胰岛素敏感性（通过葡萄糖钳技术测量）。此外，我们现在在这个修订后的申请中提供证据表明，HSP72 的消融会导致 JNK 激活、葡萄糖不耐受、胰岛素抵抗和肥胖增加。基于这些令人信服的初步数据，我们预计这两个目标中概述的研究将表明：(1) HSP72 表达对于正常胰岛素作用至关重要，(2) HSP72 诱导可防止已知导致胰岛素抵抗的代谢损伤，以及 (3) ) HSP72 是一个有前途的治疗靶点，可用于对抗肥胖和 2 型糖尿病。公共卫生相关性：2 型糖尿病困扰着超过 2400 万美国人，这给美国带来了巨大的医疗保健和财政负担。我们希望我们的工作能够为更好地理解导致胰岛素抵抗或“糖尿病前期”的分子基础奠定基础。我们发现，细胞应激反应中应激蛋白诱导受损是导致胰岛素抵抗的原因，并且恢复应激蛋白水平的药理学策略可在临床上用于对抗胰岛素抵抗和2型糖尿病。