FoxO6 in Glucose Metabolism

FoxO6 在葡萄糖代谢中的作用

• 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
• 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

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，为饥饿或长时间禁食期间的大脑、睾丸和红细胞提供唯一的燃料来源。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现问题时，糖异生作用有增无减，导致葡萄糖产生过多，并导致糖尿病的空腹高血糖。我们的长期目标是确定将胰岛素作用受损与不受限制的糖异生联系起来的因素。我们的研究确定 FoxO6 是糖异生的重要参与者。 FoxO6是额框O家族的新成员，在新陈代谢方面具有未指定的功能。我们发现，在进食状态下，肝脏 FoxO6 活性维持在较低的基础水平，但在禁食时明显不受调节。在胰岛素抵抗肝脏中可检测到 FoxO6 活性增强，这与肥胖和糖尿病中不受限制的糖异生有关。 FoxO6 刺激培养的肝细胞中的糖异生，并且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，而不改变其亚细胞分布，这是 FoxO6 与 FoxO 家族其他成员的独特机制。我们的数据强调了 FoxO6 在葡萄糖代谢中的重要性；激发了这样的假设：FoxO6 失调可能导致胰岛素抵抗受试者空腹高血糖的发病机制。为了解决这一假设，我们提出了三个具体目标：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将胰岛素信号整合到肝脏糖异生的独特机制； 3) 确定 FoxO6 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 FoxO6 功能的增强与功能丧失。我们提供了原理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禁食状态和减量状态之间肝葡萄糖生成速率，从而加深我们对肝脏糖异生的胰岛素依赖性调节的理解。虽然糖异生途径一直是抗高血糖治疗的主要目标，但FoxO6依赖性糖异生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：肝脏中葡萄糖产生过多可归因于空腹高血糖，这是一种常见于病态肥胖或糖尿病控制不佳的受试者的病理状况。其基本机制尚不清楚。我们的目标是描述胰岛素作用受损与葡萄糖产生不受限制之间的耦合因素，以确定改善糖尿病血糖控制的新治疗靶点。