Role of caveolae in signaling in fat cells

描述：(申请人提供)肥胖是导致胰岛素抵抗和II型糖尿病的主要因素，尽管事实是 骨骼肌对阻止葡萄糖的胰岛素反应失败 摄取并导致高血糖和糖尿病。从机械论的观点来看， 正是脂肪储存中的脂肪(脂肪酸)的可用性产生了 肌肉胰岛素抵抗，部分如果不是完全的话。胰岛素抵抗骨骼 肌肉比正常肌肉含有更多的脂肪，而且脂肪酸的急性灌流 会迅速产生这种抵抗力。事实上，理查德·伯格曼和 同事们推测，抑制脂肪细胞的脂质释放是 对胰岛素的机体作用的速率限制(所谓的 解释胰岛素作用的限速步骤的单一通道假说)。 丹尼斯·梅加里也强调了游离脂肪酸在肌肉中的作用 胰岛素抵抗与糖尿病患者胰岛素抑制脂肪的失败 脂肪细胞的酸释放量。此外，最近发现的该基因的作用 脂肪细胞在瘦素分泌方面的重要性进一步增加 这种细胞在调节代谢动态平衡方面的作用。因此，虽然在那里 关于II型糖尿病的因果关系仍未达成一致，没有人 认为肥胖和脂肪细胞新陈代谢并不是关键的相关。 脂肪细胞吸收(和释放)脂肪酸的机制(S) 目前还不清楚。已公布的数据以及本申请中的数据表明 脂肪细胞中丰富的结构，称为小凹，可能是脂肪的位置。 (脂肪酸)在这些细胞中的进出，可能起到调节作用 脂流。洞穴(小洞穴)是一种囊状结构，突出到 从细胞表面到细胞内部。它们是大多数人的解剖特征 细胞的整体生理作用仍不清楚，也存在争议。它 已经证明小窝结合脂肪酸，小窝已经被 被认为是细胞释放胆固醇的场所。我们已经筹集了一个 我们可以用来免疫分离小窝的新型单抗。我们是 利用这一新的工具来表征其组成和生理功能 洞穴中的。为了支持小窝在脂质代谢中的作用，我们有 确定一种可能的脂肪酸转运蛋白(FAT/CD36)是一种主要蛋白质 组件。我们提出了三个具体目标：1.进一步描述 原代和培养脂肪细胞小凹的蛋白质组分。2.至 确定这些蛋白质的生理功能。3.调节 小窝的表达，并确定这对小窝功能的影响 特定的蛋白质如WEU一样对脂肪细胞的整体新陈代谢有影响。这类研究 解决与胰岛素抵抗和细胞有关的基本问题 小窝的生物学。

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.