FoxO6 in Glucose Metabolism

FoxO6 在葡萄糖代谢中的作用

基本信息

批准号：
8310118
负责人：
HENGJIANG HENRY DONG
金额：
$ 31.12万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-24 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8310118
关键词：
Ablation Address Alleles Attenuated Binding Blood Glucose Boxing DNA Binding Data Diabetes Mellitus Diet Disease Erythrocytes Exclusion Family Fasting Forehead Gene Expression Gene Silencing Gene Transfer Gluconeogenesis Glucose Goals Health Hepatic Hepatocyte Human Hyperglycemia Hyperinsulinism Insulin Insulin Resistance Knockout Mice Life Link Liver Mediating Metabolic Pathway Metabolism Morbid Obesity Mus Nuclear Obese Mice Obesity Output Pathogenesis Pathway interactions Phosphorylation Physiological Play Process Production Regulation Regulatory Pathway Research Rodent Role Site Small Interfering RNA Source Starvation Testis Brain Therapeutic Transgenic Mice Transgenic Organisms db/db mouse diabetes control diabetic feeding gain of function glucose metabolism glucose output glucose production glycemic control hepatic gluconeogenesis improved insight insulin signaling knockout gene loss of function member new therapeutic target nucleocytoplasmic transport overexpression promoter public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Gluconeogenesis is a life-sustaining process for providing the sole fuel source for brain, testes and erythrocytes during starvation or prolonged fasting. Gluconeogenesis takes place mainly in liver in a metabolic pathway that is tightly regulated by insulin. When hepatic insulin signaling goes awry, gluconeogenesis becomes unabated, resulting in excessive glucose production and contributing to fasting hyperglycemia in diabetes. Our long-term goal is to characterize factors that link impaired insulin action to unrestrained gluconeogenesis. Our research identified FoxO6 as an important player in gluconeogenesis. FoxO6 is a new member of the forehead box O family, with unassigned function in metabolism. We show that hepatic FoxO6 activity is maintained at low basal levels in fed states, but is markedly unregulated in response to fasting. Augmented FoxO6 activity is detectable in insulin resistant livers, correlating with unrestrained gluconeogenesis in obesity and diabetes. FoxO6 stimulates gluconeogenesis in cultured hepatocytes and this effect is counteracted by insulin. Insulin inhibits FoxO6 activity via site-specific phosphorylation without altering its subcellular distribution, a distinct mechanism that distinguishes FoxO6 from other members of FoxO family. Our data underscore the importance of FoxO6 in glucose metabolism; spurring the hypothesis that FoxO6 dysregulation may contribute to the pathogenesis of fasting hyperglycemia in insulin resistant subjects. To address this hypothesis, we propose three specific aims: 1) To characterize the role of FoxO6 in gluconeogenesis and determine its contribution to blood glucose metabolism; 2) To investigate the distinct mechanism by which FoxO6 integrates insulin signaling to gluconeogenesis in liver; and 3) To determine the functional contribution of FoxO6 to the pathogenesis of fasting hyperglycemia in obesity and diabetes. To achieve these goals, we will employ gene transfer, transgenic overexpression, gene knockout and siRNA- mediated gene-silencing approaches to achieve FoxO6 gain- vs. loss-of-function in normal mice and mice with altered glucose metabolism. We have provided proof-of-principle and demonstrated the feasibility for the proposal. Accomplishing this project will deepen our understanding of insulin-dependent regulation of hepatic gluconeogenesis, by revealing a new regulatory pathway for fine-tuning the rate of hepatic glucose production between fasting and receding states. While the gluconeogenic pathway has been a major target for anti- hyperglycemia therapies, revelation of FoxO6-dependent gluconeogenic pathway will provide a potential therapeutic avenue for improving glycemic control in diabetes. PUBLIC HEALTH RELEVANCE: Excessive glucose production in liver is attributable to fasting hyperglycemia, a pathological condition that is commonly seen in subjects with morbid obesity or poorly controlled diabetes. The underlying mechanism is poorly understood. Our goal is to characterize factors that couple impaired insulin action to unrestrained glucose production for identifying novel therapeutic targets for improving glycemic control in diabetes.

描述（由申请人提供）：糖异生是一种维持生命的过程，用于在饥饿或长时间禁食期间提供唯一的脑，睾丸和红细胞的燃料来源。糖异生主要发生在肝脏中的肝脏中，该途径受胰岛素严格调节。当肝胰岛素信号传导出现问题时，糖异生就不会减弱，导致葡萄糖产生过多，并导致糖尿病中禁食性高血糖。我们的长期目标是表征将胰岛素作用受损的因素与不受约束的糖异生联系起来。我们的研究将FOXO6确定为糖异生的重要参与者。 FOXO6是额头盒O家族的新成员，在代谢中具有未分配的功能。我们表明，肝FOXO6活性保持在FED状态下的基础水平低，但在禁食中明显不受监管。增强的FOXO6活性在胰岛素抗性肝脏中可检测到，与肥胖症和糖尿病中不受约束的糖异生有关。 FOXO6刺激培养的肝细胞中的糖异生，这种作用被胰岛素抵消。胰岛素通过位点特异性磷酸化抑制FOXO6活性而不会改变其亚细胞分布，这是一种将FOXO6与Foxo家族其他成员区分开的独特机制。我们的数据强调了FOXO6在葡萄糖代谢中的重要性；刺激了FOXO6失调可能有助于胰岛素抵抗受试者禁食高血糖的发病机理的假设。为了解决这一假设，我们提出了三个特定的目的：1）表征FoxO6在糖异生中的作用并确定其对血糖代谢的贡献； 2）研究FOXO6将胰岛素信号传导与肝脏中的糖异生相结合的独特机制； 3）确定FOXO6对肥胖和糖尿病中禁食高血糖的发病机理的功能贡献。为了实现这些目标，我们将采用基因转移，转基因的过表达，基因敲除和siRNA介导的基因计算方法来实现FOXO6增益 - 正常小鼠和葡萄糖代谢改变的正常小鼠和小鼠的功能丧失。我们提供了原则证明，并证明了该提案的可行性。完成该项目将通过揭示一种新的调节途径来加深我们对胰岛素依赖性肝糖异生的调节的理解，以微调禁食和恢复状态之间肝葡萄糖产生速率。虽然糖原途径一直是抗血糖疗法的主要靶点，但FOXO6依赖性糖原途径的启示将为改善糖尿病血糖控制的潜在治疗途径提供潜在的治疗途径。公共卫生相关性：肝脏中过量的葡萄糖产生归因于禁食性高血糖，这种病理状况通常在病态肥胖症患者或控制不良的糖尿病患者中被发现。基本机制知之甚少。我们的目标是表征将胰岛素作用损害到不受约束的葡萄糖产生的因素，以鉴定新的治疗靶标，以改善糖尿病的血糖控制。