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: 8447593
• 负责人: Andrea L Hevener
• 金额: $ 25.34万
• 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/8447593
• 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; 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

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.

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，其特征在于骨骼肌、肝脏和脂肪组织中胰岛素作用减弱。虽然胰岛素抵抗病因学中涉及的确切机制尚未完全了解，但许多人认为炎症和应激激酶活化是胰岛素信号转导受损的中心介导物。针对炎性损伤的主要细胞防御包括通过诱导热休克转蛋白因子（HSF）-1快速合成称为热休克蛋白（HSP）的伴侣蛋白家族。响应于细胞应激的热休克蛋白诱导受损可能有助于胰岛素抵抗的发展，因为与瘦健康受试者相比，葡萄糖耐量受损和2型糖尿病患者中HSF-1和诱导型HSP（HSP 72）的诱导显著减少。为了推进这些临床观察，我们建议建立HSP 72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手段对HSP 72表达进行实验操作，实现两个特定目标。在目标1中，我们假设HSP 72的药理学或遗传过表达将防止由高脂饮食（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HSP 72或其转录因子HSF-1的基因消融是导致炎症加剧、胰岛素抵抗和对HFD有害作用的易感性的原因。我们的初步研究结果表明，肌肉特异性转基因HSP 72过表达抑制磷酸化的一个关键的炎症标志物，c-Jun N-末端激酶（JNK），并保留胰岛素的作用，在面对HFD。这些发现在给予HSF-1共诱导剂BGP-15的遗传性肥胖小鼠中重现，其引起骨骼肌HSP 72水平显著增加，JNK活性减弱，并且改善胰岛素敏感性（如通过葡萄糖钳夹技术测量的）。此外，我们现在提供的证据表明，在这个修改后的申请，热休克蛋白72的消融导致JNK激活，葡萄糖耐受不良，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）HSP 72表达对于正常的胰岛素作用至关重要，（2）HSP 72诱导可防止已知引起胰岛素抵抗的代谢损伤，（3）HSP 72是一种有前途的治疗靶点，可用于对抗肥胖和2型糖尿病。

项目成果

Membrane-lipid therapy in operation: the HSP co-inducer BGP-15 activates stress signal transduction pathways by remodeling plasma membrane rafts.

• DOI: 10.1371/journal.pone.0028818
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Gombos I;Crul T;Piotto S;Güngör B;Török Z;Balogh G;Péter M;Slotte JP;Campana F;Pilbat AM;Hunya A;Tóth N;Literati-Nagy Z;Vígh L Jr;Glatz A;Brameshuber M;Schütz GJ;Hevener A;Febbraio MA;Horváth I;Vígh L
• 通讯作者: Vígh L