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A Novel Role of IEX-1 in High Fat Diet-induced Obesity and Insulin Resistance

IEX-1 在高脂肪饮食引起的肥胖和胰岛素抵抗中的新作用

基本信息

批准号：
8805471
负责人：
Mohd Shahid
金额：
$ 15.74万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8805471
关键词：
ATP phosphohydrolase Adipocytes Adipose tissue Advocate American Anti-Inflammatory Agents Anti-inflammatory Apoptosis Atherosclerosis Bone Marrow Bone Marrow Involvement Bone Marrow Transplantation Cells Cessation of life Chronic Disease Coculture Techniques Consumption Development Diabetes Mellitus Diet Disease ERG gene Energy Metabolism Euglycemic Clamping Exhibits Fatty acid glycerol esters Future Genes Glucose Clamp Heart Diseases Hematopoietic Heterogeneity High Prevalence Homeostasis Human Hypertension Immune response In Vitro Indirect Calorimetry Individual Inflammation Inflammatory Inflammatory Response Insulin Resistance Investigation Link Measures Mediator of activation protein Mentored Research Scientist Development Award Metabolic Metabolic Diseases Mitochondria Modality Molecular Target Mus NF-kappa B National Institute of Diabetes and Digestive and Kidney Diseases Obesity Outcome Pathogenesis Pathology Pathway interactions Phenotype Play Process Proteins Public Health Regulation Research Proposals Resistance Respiration Risk Role Site Skeletal Muscle Staging Stress T-Lymphocyte Techniques Therapeutic Thermogenesis Tissues Weight Gain Wild Type Mouse attenuation base feeding glucose metabolism inhibitor/antagonist insight macrophage non-alcoholic fatty liver novel novel diagnostics novel therapeutic intervention novel therapeutics null mutation premature prevent public health relevance

项目摘要

DESCRIPTION (provided by applicant): The central theme of this application is to demonstrate how IEX-1 deficiency protects mice against HFD diet-induced obesity and insulin resistance. By employing a reciprocal adaptive transfer technique to specifically delete IEX-1 from hematopoietically derived cells, we will elucidate a decisive role of IEX-1 in regulation of macrophages phenotype and inflammation during high calorie consumption. This maneuver will help us delineate if IEX-1 in hematopoietically derived cells is important for development of obesity or insulin resistance. Furthermore, IEX-1 is highly expressed in mitochondria where it regulates mitochondrial respiration by promoting degradation of mitochondrial F1F0-ATPase inhibitor IF1 protein. Therefore, we suspect that IEX- 1 may have a direct role in metabolism and energy homeostasis. We will assess glucose metabolism in individual tissues and energy expenditure in the absence of IEX-1 using hyperinsulinemic-euglycemic clamp and indirect calorimetry, respectively. Lastly, to gain a mechanistic insight into how IEX-1 deficiency prevents diet-induced switch in ATM phenotype, we will employ an in-vitro forced M1 polarization techniques in bone marrow-derived macrophages co-cultured in the absence or presence of primary adipocytes. The study will provide novel insights into a mechanistic linkage between IEX-1 and metabolic function, and obesity.

描述(申请人提供)：本申请的中心主题是演示IEX-1缺陷如何保护小鼠免受HFD饮食诱导的肥胖和胰岛素抵抗的影响。通过使用相互适应转移技术从造血细胞中特异性地删除IEX-1，我们将阐明IEX-1在调节巨噬细胞表型和高热量消耗时的炎症中的决定性作用。这一操作将帮助我们描述造血细胞中的IEX-1是否在肥胖或胰岛素抵抗的发生中起重要作用。此外，IEX-1在线粒体中高表达，它通过促进线粒体F1F0-ATPase抑制剂IF1蛋白的降解来调节线粒体的呼吸。因此，我们推测IEX-1可能在新陈代谢和能量动态平衡中起直接作用。我们将分别使用高胰岛素-正常血糖钳和间接量热法评估单个组织中的葡萄糖代谢和在没有IEX-1的情况下的能量消耗。最后，为了从机制上了解IEX-1缺乏如何阻止饮食诱导的ATM表型转换，我们将在没有或存在原代脂肪细胞的情况下，对骨髓来源的巨噬细胞进行体外强制M1极化技术。这项研究将为IEX-1和代谢功能以及肥胖之间的机械联系提供新的见解。