Integrative Mechanisms of Adipose Tissue Dysfunction In obesity

肥胖症中脂肪组织功能障碍的综合机制

基本信息

批准号：
8584143
负责人：
Rosario G Scalia
金额：
$ 33.71万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-05 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8584143
关键词：
Accounting Acute Adhesives Adipocytes Adipose tissue Affect Animals Arthritis Binding Biochemical Biochemistry Blood Blood Vessels Blood capillaries Cardiovascular Diseases Cell Adhesion Molecules Cells Chronic Consumption Country Data Diabetes Mellitus Diet Dietary Fats Disease Disintegrins E-Selectin Endothelial Cells Endothelium Energy Intake Extravasation Family Fatty acid glycerol esters Food Food Energy Functional disorder Genetic Genetic Predisposition to Disease Glucose Intolerance Goals Health Histology Homeostasis Hyperglycemia Hypochlorous Acid Immunofluorescence Immunologic Immunohistochemistry In Vitro Incidence Individual Infiltration Inflammation Inflammatory Inflammatory Response Insulin Resistance Knockout Mice Lead Leukocytes Light Link Literature Lymphocyte Malignant Neoplasms Measurement Mediator of activation protein Mesentery Metabolic Diseases Metalloproteases Microcirculation Modeling Molecular Mus Neutrophil Activation Neutrophil Infiltration Nitric Oxide Nonesterified Fatty Acids Nutrient Obesity Organ Overweight Oxidants Pathogenesis Pathway interactions Peroxidases Phenotype Physical activity Physiology Play Population Principal Investigator Process Publishing Research Rodent Role Secondary to Selectins Signal Pathway Staging Surface TNF gene Techniques Technology Testing Therapeutic Intervention Tissues Transgenic Mice Trees Triglycerides Visceral Weight Gain Western Blotting Work adiponectin capillary chlorination cytokine experience feeding in vivo insight intravital microscopy lipoprotein lipase macrophage monocyte mouse model neutrophil novel novel therapeutics prevent public health relevance research study response subcutaneous theories trafficking

项目摘要

DESCRIPTION (provided by applicant): Even after accounting for lack of physical activity and genetic susceptibility, excessive food energy intake remains, probably, the most common cause of overweight and obesity in western countries. Unfortunately, the expanding adipose tissue experiences an abnormal infiltration of circulating leukocytes, a phenomenon that occurs in the microcirculation and it is associated with adipose tissue inflammation and insulin resistance. The precise cellular and molecular mechanisms that initiate and govern leukocyte extravasation in the microcirculation of expanding adipose depots remain undefined. Consequently, whether leukocyte infiltration is the cause or the effect of adipocyte dysfunction remains largely unknown, which hinders therapeutic interventions in the ever-growing obese population of the USA. Emerging information in the literature and new preliminary data presented in this application demonstrate that nutrients overload causes a postprandial infiltration of neutrophils in visceral fat depots. Obviously, this acute response to dietary nutrients occurs well before weight gain and insulin resistance. Accordingly, we propose to test the hypothesis that nutrients overload acutely activates leukocyte-endothelium interactions in the microcirculation of the visceral fat and that this process initiates adipocyte dysfunction. The overall goals of this projet are to study: a) the mechanisms by which nutrients overload triggers this rapid activation of neutrophils in the adipose tissue microcirculation; b) the cellular and molecular determinants that make the microcirculation of visceral fat depots highly responsive to nutrients overload; c) the impact of this phenomenon on adipocyte homeostasis. To implement these studies, we will utilize knockout and transgenic mouse technology along with the following biochemistry and physiology techniques: western blot analysis, immunohistochemistry and immunofluorescence, cells and tissue isolation techniques, intravital microscopy, nitric oxide measurements. We hope that the results of this work will advance our understanding of the integrated mechanisms that initiate and maintain adipose tissue inflammation and related metabolic disorders.

描述（由申请人提供）：即使考虑到缺乏体力活动和遗传易感性，过多的食物能量摄入仍然可能是西方国家超重和肥胖的最常见原因。不幸的是，扩张的脂肪组织会经历循环白细胞的异常浸润，这是微循环中发生的现象，与脂肪组织炎症和胰岛素抵抗有关。在扩张的脂肪库的微循环中启动和控制白细胞外渗的精确细胞和分子机制仍不清楚。因此，白细胞浸润是否是脂肪细胞功能障碍的原因或影响仍然很大程度上未知，这阻碍了对美国不断增长的肥胖人群的治疗干预。文献中的新信息和本申请中提出的新的初步数据表明，营养过剩会导致餐后中性粒细胞浸润内脏脂肪库。显然，这种对膳食营养素的急性反应早在体重增加和胰岛素抵抗之前就发生了。因此，我们建议检验以下假设：营养超载会急剧激活内脏脂肪微循环中的白细胞-内皮相互作用，并且该过程会引发脂肪细胞功能障碍。该项目的总体目标是研究：a）营养物质超载触发脂肪组织微循环中中性粒细胞快速激活的机制； b) 使内脏脂肪库的微循环对营养超载高度敏感的细胞和分子决定因素； c) 这种现象对脂肪细胞稳态的影响。为了实施这些研究，我们将利用基因敲除和转基因小鼠技术以及以下生物化学和生理学技术：蛋白质印迹分析、免疫组织化学和免疫荧光、细胞和组织分离技术、活体显微镜、一氧化氮测量。我们希望这项工作的结果将增进我们对引发和维持脂肪组织炎症和相关代谢紊乱的综合机制的理解。