Adipose Tissue Branched-Chain Amino Acid Metabolism and Glucose Homeostasis

描述（由申请人提供）： 在胰岛素抵抗状态如肥胖和2型糖尿病中，胰岛素应答性Glut4葡萄糖转运蛋白的表达在脂肪组织中下调，但在肌肉中不下调。Glut4的表达也下调，特别是在脂肪组织禁食后，这种表达迅速恢复后再喂养。由于脂肪组织仅占胰岛素刺激的葡萄糖处置的一小部分，因此Glut4调节的生理意义尚不确定。为了研究脂肪组织中改变的Glut4表达的生理意义，Kahn实验室开发了在脂肪组织中选择性地组成性过表达或敲除Glut4的转基因模型。这些模型显示出相互的代谢表型，由于Glut4过表达而具有改善的葡萄糖耐量，并且由于Glut4敲除而具有全身胰岛素抵抗。值得注意的是，脂肪特异性过表达Glut4（AG4OX）导致小鼠对禁食诱导的低血糖症极其敏感。脂肪特异性修饰Glut4表达导致全身葡萄糖稳态变化的生理机制仍不确定。 来自这些转基因模型的脂肪组织的基因表达微阵列的分析表明，过量表达或敲除Glut4导致支链氨基酸（BCAA）代谢酶表达的相互和协调变化。实验表明，在AG4OX小鼠模型中，BCAA酶表达的协同下调与循环BCAA水平的增加有关。支链氨基酸以前被认为是葡萄糖稳态的调节剂。 这项建议的主要目的是确定支链氨基酸对葡萄糖稳态的影响。目的1将定义禁食期间维持正常所需的生理机制。目的2将确定支链氨基酸代谢的改变是否会引起葡萄糖稳态的变化。目的3探讨Glut4过表达导致支链氨基酸代谢改变的机制。 该提案旨在促进申请人在糖尿病和代谢领域的培训和职业发展。职业发展计划包括主要研究项目、实验室技术培训、会议和数据展示以及教学研讨会。拟议的研究将在Beth Israel Deaconess Medical Center的内分泌、糖尿病和代谢科进行，在那里可以随时获得开展拟议研究的所有资源。最终目标是让申请人成为独立的调查员。

DESCRIPTION (provided by applicant): In insulin resistant states such as obesity and type 2 diabetes, expression of the insulin-responsive Glut4 glucose transporter is down-regulated in adipose tissue, but not in muscle. Glut4 expression is also down-regulated specifically in adipose tissue after fasting and this expression quickly recovers after refeeding. The physiologic significance of Glut4 regulation is uncertain as adipose tissue accounts for only a small fraction of insulin-stimulated glucose disposal. To study the physiologic significance of altered Glut4 expression in adipose tissue, the Kahn lab has developed transgenic models with constitutive overexpression or knockout of Glut4 selectively in adipose tissue. These models display reciprocal metabolic phenotypes with improved glucose tolerance as a result of Glut4 overexpression and whole-body insulin resistance as a result of Glut4 knockout. Notably, the adipose-specific overexpression of Glut4 (AG4OX) results in a mouse extremely susceptible to fasting-induced hypoglycemia. The physiologic mechanisms by which the adipose-specific modifications of Glut4 expression result in changes in systemic glucose homeostasis remain uncertain. Analysis of gene expression microarrays derived from adipose tissue from these transgenic models has revealed that overexpression or knockout of Glut4 results in reciprocal and coordinate changes in the expression of enzymes of branched-chain amino acid (BCAA) metabolism. Experiments have demonstrated that in the AG4OX mouse model, the coordinate down-regulation of BCAA enzyme expression is associated with increased levels of circulating BCAAs. BCAAs have previously been implicated as regulators of glucose homeostasis. The central aim of this proposal is to determine the impact of BCAAs on glucose homeostasis. Aim 1 will define physiologic mechanisms necessary for the maintenance of euglycemia during fasting. Aim 2 will determine whether alterations in BCAA metabolism cause changes in glucose homeostasis. Aim 3 investigates the mechanisms by which Glut4 overexpression results in altered BCAA metabolism. The proposal is designed to facilitate the training and career development of the applicant in the field of diabetes and metabolism. The career development plan includes the main research project, laboratory technique training, meetings and data presentation, and didactic seminars. The proposed research will take place in the Division of Endocrinology, Diabetes, and Metabolism at Beth Israel Deaconess Medical Center where all the resources to carry out the proposed research are readily available. The ultimate goal is for the applicant to become an independent investigator.