Role of caveolae in signaling in fat cells

小窝在脂肪细胞信号传导中的作用

• 批准号: 6613742
• 负责人: PAUL F PILCH
• 金额: $ 32.6万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-15 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6613742
• 关键词: adipocytes; biological signal transduction; caveolas; cell component structure /function; cell differentiation; cell membrane; chemical kinetics; cryoelectron microscopy; fatty acid binding protein; gene expression; glucose transporter; high performance liquid chromatography; hormone regulation /control mechanism; insulin; intermolecular interaction; laboratory rat; lipid metabolism; lipid transport; mass spectrometry; molecular site; protein purification; protein sequence; protein structure function; proteomics; tissue /cell culture; transport proteins

DESCRIPTION: (provided by applicant) Obesity is the major factor predisposing people to insulin resistance and type II diabetes, despite the fact that it is the failure of skeletal muscle to respond to insulin which prevents glucose uptake and results in hyperglycemia and diabetes. From a mechanistic viewpoint, it is the availability of lipids (fatty acids) from fat stores that produces muscle insulin resistance, in part if not entirely. Insulin resistant skeletal muscles contain more fat than normal muscle, and acute perfusion of fatty acids into muscle will rapidly produce this resistance. Indeed, Richard Bergman and colleagues have postulated that inhibition of lipid release from fat cells is rate limiting with respect to insulin's organismal actions (the so-called single gateway hypothesis to explain the rate limiting step of insulin action). Dennis MeGarry has also emphasized the role of free fatty acids in muscle insulin resistance and the failure, in diabetes, of insulin to suppress fatty acid release from adipocytes. Moreover, the recent discovery of the role of the adipocyte with regard to leptin secretion has added further to the importance of this cell in the regulation of metabolic homeostasis. Thus, while there remains incomplete agreement about cause and effect in type II diabetes, no one would argue that obesity and fat cell metabolism are not critically relevant. The mechanism(s) by which fatty acids are taken up (and released) by adipocytes is not clear. Published data as well as data in this application suggest that structures abundant in adipocytes, called caveolae, may be the Site of lipid (fatty acid) entry and egress in these cells and may play a role in regulating lipid flux. Caveolae (little caves) are sac like structures that protrude into the cell interior from the cell surface. They are an anatomical feature of most cells whose overall physiological role is still unclear and controversial. It has been shown that caveolae bind fatty acids, and caveolae have been postulated as the site of cholesterol release from cells. We have raised a novel monoclonal antibody with which we can irnmuno-isolate caveolae. We are using this new tool to characterize the composition and physiological function of caveolae. In support of a role for caveolae in lipid metabolism, we have identified a putative fatty acid Lransporter (FAT/CD36) as a major protein component. We propose three specific aims: 1. to further characterize the protein constituents of caveolae in primary and cultured adipocytes. 2. to determine the physiological function of these proteins. 3. to modulate the expression of caveolae and determine the effects of this on the function of specific proteins as weU as on overall fat cell metabolism. Such studies address fundamental questions concemin2 insulin resistance as well as the cell biologv of caveolae.

描述：（申请人提供）肥胖是易诱发胰岛素抵抗和II型糖尿病的主要因素，尽管事实是 骨骼肌无法反应胰岛素，以防止葡萄糖 吸收并导致高血糖和糖尿病。从机械角度来看 脂肪储存的脂质（脂肪酸）的可用性产生 肌肉胰岛素抵抗，部分甚至不是完全。抗胰岛素的骨骼 肌肉含有比正常肌肉更多的脂肪，脂肪酸的急性灌注 进入肌肉将迅速产生这种阻力。确实，理查德·伯格曼（Richard Bergman）和 同事认为从脂肪细胞中抑制脂质释放为 相对于胰岛素的有机作用的速率限制（所谓的 单门通道假设解释了胰岛素作用的速率限制步骤）。 丹尼斯·梅加里（Dennis Megarry）还强调了游离脂肪酸在肌肉中的作用 胰岛素抵抗和糖尿病中胰岛素的衰竭抑制脂肪 从脂肪细胞释放酸。而且，最近发现的角色 关于瘦素分泌的脂肪细胞已进一步增加了重要性 该细胞的代谢稳态调节。因此，在那里 关于II型糖尿病的因果和影响仍然不完整，没有人 会认为肥胖和脂肪细胞代谢无关紧要。 脂肪细胞吸收（并释放）脂肪酸的机制 不清楚。在本应用程序中发布的数据以及数据表明 脂肪细胞中丰富的结构称为小窝，可能是脂质的位置 （脂肪酸）进入这些细胞中并出口，并可能在调节中发挥作用 脂质通量。小窝（小洞穴）是囊的类似于伸入的结构 细胞从细胞表面内部。它们是大多数的解剖学特征 整体生理作用的细胞仍然不清楚且有争议。它 已显示小窝结合脂肪酸，而小窝是 假定是从细胞释放的胆固醇部位。我们已经提出了 新型的单克隆抗体，我们可以通过这些抗体来脱离小窝。我们是 使用此新工具来表征组成和生理功能 小屋。为了支持小窝在脂质代谢中的作用，我们有 鉴定出推定的脂肪酸lanansporter（脂肪/CD36）为主要蛋白 成分。我们提出了三个具体目标：1。进一步表征 小窝脂肪细胞和培养的脂肪细胞中小窝的蛋白质成分。 2 确定这些蛋白质的生理功能。 3。调制 表达小窝，并确定此对​​此的影响 特定的蛋白质与WEU一样，如整体脂肪细胞代谢。这样的研究 解决基本问题，即胰岛素抵抗以及细胞 小屋的生物学。