Mechanistic studies on obesity-deteriorated glucose and lipid metabolisms

肥胖导致糖脂代谢恶化的机制研究

• 批准号: 8874215
• 负责人: Raju VS Rajala
• 金额: $ 32.19万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874215
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Ablation; Address; Animals; Biochemical; Biochemistry; Blood; Complex; Data; Defect; Development; Diabetes Mellitus; Diet; Disease; Dissociation; Energy Metabolism; Enhancers; Event; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Future; Genetic; Glucose; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Health; Homeostasis; Hormonal; Inflammatory; Insulin; Insulin Receptor; Insulin Resistance; Intracellular Accumulation of Lipids; Knockout Mice; Lead; Lipids; Lipolysis; Measures; Metabolic; Metabolic Diseases; Molecular; Mus; Muscle; Muscle Cells; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphatidylinositols; Phosphorylation; Phosphotransferases; Physiological; Process; Protein Kinase Interaction; Proteins; Receptor Activation; Regulation; Reporting; Research; Role; Signal Transduction; Skeletal Muscle; Therapeutic; Tissues; blood glucose regulation; cytokine; design; fatty acid oxidation; feeding; glucose metabolism; improved; in vivo; in vivo Model; insight; insulin receptor tyrosine kinase; insulin sensitivity; insulin signaling; lipid metabolism; novel; oxidation; prevent; protein complex; research study; sensor

DESCRIPTION (provided by applicant): Obesity is associated with impaired controls of glucose and lipid metabolisms. However, the molecular events leading to these metabolic defects are not well understood. In particular, it has been long recognized that both insulin receptor (IR) activity and fatty acid oxidation are impeded in the muscle of obese subjects by an indefinite mechanism. Our preliminary data show that IR interacts with a novel GTPase phosphoinositide 3- kinase enhancer-A (PIKE-A) to fully activate its kinase activity during insulin stimulation. This interaction is a metabolically regulated process as less IR/PIKE-A complex is founded in the skeletal muscle of obese mice and lipid-stimulated myotubes. We also found that genetic ablation of PIKE resulted in augmented AMP- activated protein kinase (AMPK) activation and lipolysis in muscle, thus protected the animals from diet- induced obesity and diabetes. Moreover, we observed an enhanced association between PIKE-A and AMPK in the skeletal muscle of diet-induced obese mice. Therefore, the interaction between PIKE-A, IR and AMPK may represent a novel regulation on lipid oxidation and insulin sensitivity, which is ravaged in the obese muscle. As a part of our long term goal to reveal the molecular mechanisms leading to various obesity-related disorders, we set forth the following studies to delineate the role of IR/PIKE-A/AMPK interaction in obesity-induced muscular insulin resistance and defective lipid oxidation. In this project, we will (1) characterize the molecular and functionl details of IR, PIKE-A and AMPK associations; (2) determine the mechanisms that regulate the IR/PIKE-A and PIKE-A/AMPK complexes formation with a special focus on lipotoxicity and inflammatory cytokines; and (3) study the obesity-induced pathology in muscle-specific PIKE knockout mice to demonstrate the critical role of IR/PIKE-A/AMPK interplay in energy and glucose homeostasis. Taken together, our proposed studies will provide a new mechanism to explain the alteration of insulin signaling and lipid metabolism in obese tissues, which is helpful to advance our understanding on the pathophysiology of obesity and improve the therapeutic design for its complications.

描述（由申请人提供）：肥胖与葡萄糖和脂质代谢控制受损有关。然而，导致这些代谢缺陷的分子事件尚不清楚。特别是，人们早已认识到肥胖受试者的肌肉中胰岛素受体（IR）活性和脂肪酸氧化均受到不确定机制的阻碍。我们的初步数据表明，IR 与新型 GTPase 磷酸肌醇 3-激酶增强剂-A (PIKE-A) 相互作用，在胰岛素作用期间完全激活其激酶活性 刺激。这种相互作用是一个代谢调节过程，因为肥胖小鼠的骨骼肌和脂质刺激的肌管中存在较少的 IR/PIKE-A 复合物。我们还发现，PIKE 的基因消除导致 AMP 激活蛋白激酶 (AMPK) 的激活和肌肉中的脂肪分解增强，从而保护动物免受饮食引起的肥胖和糖尿病。此外，我们观察到饮食诱导的肥胖小鼠骨骼肌中 PIKE-A 和 AMPK 之间的关联增强。因此，PIKE-A、IR 和 AMPK 之间的相互作用可能代表了对脂质氧化和胰岛素敏感性的新调节，而这在肥胖肌肉中受到破坏。作为揭示导致各种肥胖相关疾病的分子机制的长期目标的一部分，我们开展了以下研究来描述 IR/PIKE-A/AMPK 相互作用在肥胖引起的肌肉胰岛素抵抗和脂质缺陷中的作用氧化。在这个项目中，我们将 (1) 表征 IR、PIKE-A 和 AMPK 关联的分子和功能细节； (2) 确定调节 IR/PIKE-A 和 PIKE-A/AMPK 复合物形成的机制，特别关注脂毒性和炎症细胞因子； (3) 研究肌肉特异性 PIKE 敲除小鼠中肥胖引起的病理学，以证明 IR/PIKE-A/AMPK 相互作用在能量和葡萄糖稳态中的关键作用。总而言之，我们提出的研究将提供一种新机制来解释肥胖组织中胰岛素信号和脂质代谢的改变，这将有助于 增进我们对肥胖病理生理学的理解并改进其并发症的治疗设计。