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

• 批准号: 7655689
• 负责人: Andrea L Hevener
• 金额: $ 29.57万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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/7655689
• 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; Face; Family; Fatty Acids; Fatty acid glycerol esters; Foundations; Genes; Genetic; Glucose Clamp Technique; Glucose Intolerance; Glucose tolerance test; HSP72 protein; 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; 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; public health relevance; response; stress protein; stress-activated protein kinase 1; therapeutic target

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(申请人提供)：胰岛素抵抗是2型糖尿病的一种关键代谢异常，其特征是骨骼肌、肝脏和脂肪组织中胰岛素作用减弱。虽然胰岛素抵抗的确切发病机制尚不完全清楚，但许多人都认为炎症和应激性激酶激活是胰岛素信号转导受损的中心介质。对炎性损伤的主要细胞防御包括通过诱导热休克跨临界因子(HSF)-1快速合成被称为热休克蛋白(HSPs)的伴侣蛋白家族。在糖耐量受损和2型糖尿病患者中，由于HSF-1和可诱导的HSP(HSP72)的诱导与瘦的健康受试者相比显着减少，细胞应激反应中热休克蛋白的诱导受损可能有助于胰岛素抵抗的发生。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。我们将通过遗传学和药理学方法对HSP72的表达进行实验操作，通过两个具体的目标来实现这一点。在目标1中，我们假设HSP72的药物或遗传过表达将保护因高脂饮食(HFD)或瘦素缺乏而引起的炎症、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的遗传消融是导致炎症、胰岛素抵抗和对HFD有害影响的易感性的原因。我们的初步发现表明，肌肉特异的HSP72转基因过表达抑制了关键的炎症标志物c-jun氨基末端激酶(JNK)的磷酸化，并在面对HFD时保留了胰岛素的作用。这些发现在接受HSF-1联合诱导剂BGP-15的遗传性肥胖小鼠中重复，该诱导剂导致骨骼肌HSP72水平显著增加，JNK活性减弱，胰岛素敏感性改善(通过葡萄糖钳技术测量)。此外，我们现在在这项修订后的应用中提供了证据，证明切除HSP72会导致JNK激活、葡萄糖耐量异常、胰岛素抵抗和肥胖症增加。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的表达对正常的胰岛素作用至关重要，(2)HSP72的诱导可以保护已知的导致胰岛素抵抗的代谢损伤，以及(3)HSP72是一个有希望的治疗靶点，可用于治疗肥胖症和2型糖尿病。公共卫生相关性：2型糖尿病困扰着2400多万美国人，这给美国带来了巨大的医疗保健和经济负担。我们的工作旨在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，细胞应激反应中诱导的应激蛋白受损是导致胰岛素抵抗的原因，恢复应激蛋白水平的药物策略可以用于临床对抗胰岛素抵抗和2型糖尿病。