Secretion from adipose cells

脂肪细胞的分泌

基本信息

批准号：
7369780
负责人：
Konstantin V Kandror
金额：
$ 29.71万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-03-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7369780
关键词：
Ablation Adaptor Signaling Protein Address Adipocytes Adipose tissue Affect Binding Proteins Biochemical Biogenesis Body Weight Body mass index Cell secretion Cells Condition Country Desire for food Ear Eating Elevation Energy Metabolism Fatty acid glycerol esters Funding Genetic Goals Golgi Apparatus Health Hormones Individual Insulin Resistance Intake Knock-out Laboratories Lead Leptin Life Life Expectancy Liver Localized Mediating Messenger RNA Molecular Nature Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Overweight Pathway interactions Peripheral Phosphatidylinositols Phosphotransferases Physiological Play Preparation Prevalence Production Protein Biosynthesis Protein Kinase Proteins RNA, Messenger, Stored Regulation Research Personnel Role Secretory Vesicles Signal Transduction Sirolimus Skeletal Muscle Testing Thinking Tissues Translations United States Vesicle Weight maintenance regimen Work World Health Organization base golgi associated, gamma adaptin homologous, ADP-ribosylation factor interacting protein hypertensive heart disease insulin signaling novel programs sensor

项目摘要

DESCRIPTION (provided by applicant): As the prevalence of obesity is rapidly growing in this country and throughout the world, understanding the mechanisms of weight control becomes an urgent biomedical problem. The adipose-derived hormone, leptin, plays a central role in regulation of body weight and energy expenditure. Food intake and accumulation of energy stores in adipocytes result in an increase in leptin production thus leading to inhibition of appetite and elevation of energy expenditure. Conversely, when fat stores decline, adipocytes reduce leptin production, and food intake is increased. However, the biochemical connection between nutrient intake/storage in adipocytes and the level of leptin secretion remains largely unknown. In the previous funding period, we found that production of leptin is regulated at the level of translation via the mTOR-mediated pathway as well as at the level of secretion. Since mTOR (mammalian target of rapamycin) represents a nutrient sensor in the cell, the first pathway may provide a long sought after physiological connection between food intake and leptin expression. Thus, our first goal for the next funding period is to determine how to manipulate expression levels of leptin mRNA stored in adipose cells using specific nutrient signals. For that, we propose to explore the mTOR-mediated mechanism of the translational control of leptin mRNA by various nutrients. This will give us the opportunity to maintain high levels of circulating endogenous leptin without increasing fat stores in adipocytes. Our second goal is to understand the molecular mechanisms of secretion from adipose cells. In particular, we will test the hypothesis that newly discovered Golgi-localized, gamma-ear-containing, Arf-binding proteins participate in the formation of secretory vesicles in adipocytes and regulate secretion from these cells. We will also determine whether or not Glut4-vesicles contain novel secreted proteins as their soluble cargo and continue our search for novel proteins secreted from adipocytes.

描述（由申请人提供）：随着肥胖症的患病率在这个国家和全世界迅速增长，了解体重控制机制成为一个紧迫的生物医学问题。脂肪源性激素瘦素在调节体重和能量消耗方面发挥着核心作用。食物摄入和脂肪细胞中能量储存的积累导致瘦素产生增加，从而导致食欲抑制和能量消耗增加。相反，当脂肪储存减少时，脂肪细胞会减少瘦素的产生，并且食物摄入量会增加。然而，脂肪细胞中营养物质的摄入/储存与瘦素分泌水平之间的生化联系仍然很大程度上未知。在之前的资助期间，我们发现瘦素的产生通过 mTOR 介导的途径在翻译水平以及分泌水平受到调节。由于 mTOR（雷帕霉素的哺乳动物靶标）代表细胞中的营养传感器，因此第一个途径可能提供食物摄入与瘦素表达之间长期寻求的生理联系。因此，我们下一个资助期的首要目标是确定如何使用特定的营养信号来操纵脂肪细胞中储存的瘦素 mRNA 的表达水平。为此，我们建议探索 mTOR 介导的各种营养素对瘦素 mRNA 翻译控制的机制。这将使我们有机会维持高水平的循环内源性瘦素，而不增加脂肪细胞中的脂肪储存。我们的第二个目标是了解脂肪细胞分泌的分子机制。特别是，我们将测试以下假设：新发现的高尔基体定位的、包含伽马耳的 Arf 结合蛋白参与脂肪细胞中分泌囊泡的形成并调节这些细胞的分泌。我们还将确定 Glut4 囊泡是否含有新的分泌蛋白作为其可溶性货物，并继续寻找脂肪细胞分泌的新蛋白。