FoxO6 in Glucose Metabolism

描述（由申请人提供）：葡萄糖异生是一种维持生命的过程，在饥饿或长期禁食期间为大脑、睾丸和红细胞提供唯一的燃料来源。葡萄糖异生主要发生在肝脏中，其代谢途径受到胰岛素的严格调节。当肝脏胰岛素信号传导出错时，胰岛素生成变得不减弱，导致过量葡萄糖产生并导致糖尿病的空腹高血糖症。我们的长期目标是描述胰岛素作用受损与无限制的胰岛素生成之间的联系。我们的研究确定FoxO 6是胚胎发生的重要参与者。FoxO 6是前额O盒家族的新成员，在代谢中具有未指定的功能。我们发现，肝脏FoxO 6活性维持在低基础水平，在进食状态，但明显不受管制的响应空腹。在胰岛素抵抗的肝脏中可检测到增强的FoxO 6活性，这与肥胖和糖尿病中不受限制的肝脏生成有关。FoxO 6刺激培养的肝细胞中的肝细胞生成，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FoxO 6活性而不改变其亚细胞分布，这是FoxO 6与FoxO家族其他成员区别开来的独特机制。我们的数据强调了FoxO 6在葡萄糖代谢中的重要性;刺激了FoxO 6失调可能导致胰岛素抵抗受试者空腹高血糖症发病机制的假设。为了解决这一假设，我们提出了三个具体的目标：1）描述FoxO 6在糖尿病新生中的作用，并确定其对血糖代谢的贡献; 2）研究FoxO 6整合胰岛素信号传导到肝脏中糖尿病新生的独特机制; 3）确定FoxO 6对肥胖和糖尿病空腹高血糖发病机制的功能贡献。为了实现这些目标，我们将采用基因转移、转基因过表达、基因敲除和siRNA介导的基因沉默方法，在正常小鼠和葡萄糖代谢改变的小鼠中实现FoxO 6功能的获得与丧失。我们已经提供了原则证明，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微调空腹和消退状态之间的肝脏葡萄糖产生速率，加深我们对肝脏糖异生的胰岛素依赖性调节的理解。虽然促血糖途径一直是抗高血糖治疗的主要靶点，但FoxO 6依赖性促血糖途径的揭示将为改善糖尿病的血糖控制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可归因于空腹高血糖症，这是一种常见于病态肥胖或糖尿病控制不佳的受试者中的病理状况。其基本机制尚不清楚。我们的目标是表征将受损的胰岛素作用与不受限制的葡萄糖产生耦合的因素，以确定改善糖尿病血糖控制的新治疗靶点。

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.