REGULATION OF ADIPOCYTE PROTEIN SYNTHESIS BY AMINO ACIDS

本申请中描述的研究的长期目标是 为肥胖症的治疗提供新的治疗策略。大 脂肪细胞的大小增加（肥大性生长）发生在 正常发育和衰老。肥大性生长不仅涉及 单室脂滴的大小增加，但 脂肪细胞的蛋白质含量也是如此。在肥胖症中， 被夸大了营养素被认为在 调节脂肪细胞的肥大生长。但不 完全知道暴饮暴食是如何转化为 脂肪细胞的结构，以适应不断增长的脂滴。 胰岛素参与了这一过程;它既可以调节蛋白质， 脂肪细胞中的合成，也促进脂质合成和储存。 因此，营养素的促生长作用可能作用于强迫 有证据表明，一些营养素有直接的作用，调节脂肪 肥胖的组织生长。例如，本文提供的初步数据 先前的研究清楚地表明，氨基酸具有直接的代谢作用， 对分离的脂肪细胞的影响。这些效应模拟并与 尤其是在蛋白质合成方面。的 初步研究中受氨基酸影响的信号通路 也可被胰岛素用于增加脂质的合成和储存， 脂肪细胞所以私家侦探。假设氨基酸具有直接的 脂肪蛋白合成和脂质积累的调节作用。 这些作用可能在调节肥大性生长中起重要作用。 脂肪组织 这个项目的目标是了解氨基酸 刺激脂肪组织中蛋白质和脂质代谢并描绘 所涉及的分子机制。提案的具体目标 主要是：1）鉴定能够刺激蛋白质的氨基酸 （2）确定TOR激酶的激活机制; 3)研究其他细胞信号级联在细胞凋亡中的作用， 刺激蛋白质合成，4）确定步骤， 翻译的氨基酸刺激;和，5）检查 氨基酸对中性脂质合成的影响。这些研究 将进一步深入了解氨基 酸调节脂肪蛋白质和脂质代谢， 肥大生长从这些研究中获得的信息可能 确定肥胖症治疗干预的新靶点。

The long-term goals of the studies describes in this application are to fund new therapeutic strategies for the treatment of obesity. Large increases in the size of adipocytes (hypertrophic growth) occur during normal development and aging. Hypertrophic growth involves not only an increase in the size the unilocular lipid droplet, but an increase in the protein content of the adipocytes as well. In obesity, this growth is exaggerated. Nutrients are thought to play an important role in regulating the hypertrophic growth of adipocytes. However, it is not entirely known how overeating translates into changes in the architecture of adipocytes that accommodate the growing lipid droplet. Insulin is involved in this process; it can both regulate protein synthesis in adipocytes and also promote lipid synthesis and storage. Thus the growth promoting actions of nutrients may act on compelling evidence that some nutrients have direct effects that regulate adipose tissue growth in obesity. For example, preliminary data presented herein and previous studies clearly show that amino acids have direct metabolic effects on isolated fat cells. These effects mimic and are additive with those of insulin especially in regard to protein synthesis. The signaling pathways affected by the amino acids in preliminary studies may also be used by insulin to increase lipid synthesis and storage in adipocytes. Therefore the P.I. hypothesizes that amino acids have direct regulatory effects of adipose protein synthesis and lipid accumulation. These effects may be important in regulating hypertrophic growth of adipose tissue. The objectives of this project are to understand how amino acids stimulate protein and lipid metabolism in adipose tissue and delineate the molecular mechanisms involved. The specific aims of the proposal are: 1) to identify the amino acids capable of stimulating protein synthesis; 2) to determine the mechanisms use to stimulate TOR kinase; 3) to investigate the role of other cell signaling cascades in the stimulation of protein synthesis, 4) to determine the steps in translation that are stimulated by amino acids; and, 5) to examine the effect of amino acids on the synthesis of neutral lipids. These studies will provide further insight into the mechanism through which amino acids regulate adipose protein and lipid metabolism leading to hypertrophic growth. The information gained from these studies may identify new targets for therapeutic intervention in obesity.