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，胰岛素反应性GLUT4葡萄糖转运体在脂肪组织中表达下调，但在肌肉中不表达。禁食后，GLUT4在脂肪组织中的表达也明显下调，重新进食后该表达迅速恢复。GLUT4调节的生理意义尚不确定，因为脂肪组织只占胰岛素刺激的葡萄糖处置的一小部分。为了研究GLUT4在脂肪组织中表达变化的生理学意义，Kahn实验室建立了选择性地在脂肪组织中结构性过表达或敲除GLUT4的转基因模型。这些模型显示了相互的代谢表型，由于GLUT4过表达而改善了葡萄糖耐量，而由于GLUT4基因敲除而导致全身胰岛素抵抗。值得注意的是，脂肪特异性的GLUT4(AG4OX)的过度表达导致小鼠极易受到禁食诱导的低血糖的影响。脂肪特异性修饰GLUT4表达导致全身葡萄糖稳态改变的生理机制仍不确定。 对来自这些转基因模型的脂肪组织的基因表达芯片的分析表明，GLUT4的过度表达或敲除导致支链氨基酸(BCAA)代谢酶的相互和协调变化。实验证明，在AG4OX小鼠模型中，支链氨基酸酶表达的协同下调与循环支链氨基酸水平的增加有关。支链氨基酸此前被认为是葡萄糖动态平衡的调节剂。 这项建议的中心目标是确定支链氨基酸对血糖稳态的影响。目标1将确定禁食期间维持正常血糖所必需的生理机制。目标2将确定支链氨基酸代谢的改变是否会导致葡萄糖稳态的改变。目的3研究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者在糖尿病和新陈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、会议和数据演示以及教学研讨会。拟议的研究将在贝丝以色列女执事医学中心的内分泌学、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。最终目标是让申请者成为一名独立的调查员。

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.