Adipose Tissue Branched-Chain Amino Acid Metabolism and Glucose Homeostasis

脂肪组织支链氨基酸代谢和葡萄糖稳态

• 批准号: 7183845
• 负责人: MARK A HERMAN
• 金额: $ 12.97万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-20 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7183845
• 关键词: adipose tissue; aminoacid metabolism; biological signal transduction; branched chain aminoacid; enzyme activity; fasting; genetically modified animals; glucose; glucose metabolism; glycogen; homeostasis; insulin; laboratory mouse; pathogenic diet; phenotype; radiotracer; transplantation

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.

描述（由申请人提供）： 在肥胖和 2 型糖尿病等胰岛素抵抗状态下，胰岛素反应性 Glut4 葡萄糖转运蛋白的表达在脂肪组织中下调，但在肌肉中则不然。禁食后，Glut4 表达在脂肪组织中也特异性下调，并且这种表达在重新进食后迅速恢复。 Glut4 调节的生理意义尚不确定，因为脂肪组织仅占胰岛素刺激的葡萄糖处理的一小部分。为了研究脂肪组织中 Glut4 表达改变的生理意义，Kahn 实验室开发了在脂肪组织中选择性过度表达或敲除 Glut4 的转基因模型。这些模型显示出相互的代谢表型，其中 Glut4 过度表达导致葡萄糖耐量改善，Glut4 敲除导致全身胰岛素抵抗。值得注意的是，Glut4 (AG4OX) 的脂肪特异性过度表达导致小鼠极易发生空腹引起的低血糖。 Glut4 表达的脂肪特异性修饰导致全身葡萄糖稳态变化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微阵列的分析表明，Glut4的过度表达或敲除会导致支链氨基酸（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 酶表达的协调下调与循环 BCAA 水平的增加相关。 BCAA 此前曾被认为是葡萄糖稳态的调节剂。 该提案的中心目标是确定支链氨基酸对葡萄糖稳态的影响。目标 1 将定义禁食期间维持血糖正常所需的生理机制。目标 2 将确定 BCAA 代谢的改变是否会导致葡萄糖稳态的变化。目标 3 研究 Glut4 过度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、会议和数据演示以及教学研讨会。拟议的研究将在贝斯以色列女执事医疗中心的内分泌、糖尿病和代谢科进行，该中心拥有进行拟议研究的所有资源。最终目标是申请人成为一名独立调查员。