Role of Forkhead Proteins in Insulin Action

叉头蛋白在胰岛素作用中的作用

• 批准号: 8237006
• 负责人: DOMENICO ACCILI
• 金额: $ 42.09万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8237006
• 关键词: 1-Phosphatidylinositol 3-Kinase; Ablation; Accounting; Acetylation; Adenoviruses; Admixture; Anatomy; Biochemical; Biological; Body Weight decreased; Brain; Cancer Immunology Science; Cell Differentiation process; Cells; Complex; Consensus; Cues; Data; Development; Diabetes Mellitus; Drug Delivery Systems; Eating; Endocrine; Energy Metabolism; Family; Food Intake Regulation; Functional disorder; Gene Expression; Glucose; Goals; Grant; Hepatic; Home environment; Hormonal; Hormone Receptor; Hormones; Hypothalamic structure; Immune Sera; Insulin; Insulin Receptor; Insulin Resistance; Investigation; Knock-in Mouse; Knowledge; Laboratories; Leptin; Link; Lipids; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolism; Mus; Mutant Strains Mice; Neuroanatomy; Neurons; Neuropeptides; Neurotransmitters; Nutrient; Obesity; Organism; Paper; Pathogenesis; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phenotype; Physiology; Population; Property; Publishing; Reagent; Receptor Activation; Regulation; Research; Rest; Role; Signal Transduction; Structure of nucleus infundibularis hypothalami; Susceptibility Gene; Testing; Therapeutic; Time; Tissues; Work; Yawning; base; cDNA Expression; carboxypeptidase H; detection of nutrient; energy balance; expression vector; forkhead protein; glucose metabolism; glucose production; hormone regulation; inhibitor/antagonist; insight; insulin sensitivity/resistance; insulin signaling; loss of function mutation; mutant; notch protein; novel; public health relevance; recidivism; response; sensor; tool; transcription factor

DESCRIPTION (provided by applicant): The identification of forkhead transcription factors of the Foxo sub-family as effectors of insulin action on gene expression has filled a yawning gap in our knowledge of insulin signaling, and has identified a cellular biological mechanism linking Insulin Receptor activation to regulation of the cell's transcriptional response through sub-cellular redistribution of transcription factors. Key advances supported by this grant in the past cycle have been: i, demonstration of a key role of Foxo1 in hormonal regulation of hepatic glucose production and lipid synthesis; ii, identification of novel roles of Foxo1 in the hypothalamic arcuate nucleus, linking insulin and leptin signaling with neuropeptide synthesis and action; iii, identification of the obesity susceptibility gene Carboxypeptidase E (Cpe) as a Foxo1 target, providing insight into the pathophysiology of the recidivism of obesity following weight loss; iv, identification of acetylation-based mechanisms of regulation of Foxo1 function by nutrients, and their integration in the pathogenesis of insulin resistance; v, discovery of non-transcriptional functions of Foxo1 as a coregulator of gene expression; vi, demonstration of a functional interaction between Foxo and Notch, establishing a mechanistic link between a major developmental pathway and the nutrient- sensing pathway. We seek to continue our studies with the following aims: in Aim 1, we propose to investigate whether Foxo1 is a transcriptional sensor of nutrient and neurotransmitter levels, linking food intake with energy expenditure and hepatic glucose production in Npy/AgRP neurons. Acetylation- defective Foxo1 mutant mice developed during the past cycle will be instrumental in a critical test of this hypothesis. In Aim 2, we will use Foxo1 mutants to probe the neuroanatomy of hormone and nutrient signaling. While a budding consensus highlights the role of the CNS in diabetes and obesity, the complexity of brain endocrine signaling has thus far thwarted efforts to develop CNS-targeted medications for either condition. The central role of Foxo1 in hormone signaling, and its regulation by nutrients make it an attractive tool to probe the neuroanatomy of insulin and leptin signaling using gain- and loss-of-function mutations in mice. We propose to establish anatomic-functional relationships between sub-phenotypes engendered by Foxo1 manipulations and specific neuron subsets. In Aim 3, we will investigate metabolic functions of the Foxo/Notch axis. We have shown that Foxo1 regulates cell differentiation by interacting with the Notch pathway. The Notch pathway is generally thought of as a developmental pathway, and its metabolic functions have not been explored. We show in preliminary data that Notch1 and Foxo1 cooperate to regulate hepatic glucose metabolism. We propose to explore the mechanism of this observation, with the ultimate goal of applying Notch inhibitors to diabetes treatment. PUBLIC HEALTH RELEVANCE: Transcription factor Foxo1 is a key sensor of the organism's metabolic and hormonal status, and can induce changes in gene expression that account for the protean manifestations of insulin resistance, and its progression to overt diabetes. Based on a body of work developed during the past decade, we will endeavor to understand the integrated physiology of Foxo1 function in specific tissues, and its biochemical underpinnings. The ultimate goal of this work is to find therapeutic approaches to modify Foxo1 function. Indeed, while Foxo1 is an attractive biological target to reverse diabetes and metabolic diseases, it is largely intractable as a drug target. Therefore, it is hoped that by parsing its modes of action and interacting partners, new ways to modulate its function can be found.

描述（由申请人提供）：鉴定Foxo亚家族的叉状转录因子作为胰岛素作用对基因表达的效应因子，在我们对胰岛素信号传导的知识中弥补了打哈欠的差距，并且已经确定了将胰岛素受体激活与细胞转录反应的转录反应的转录因子的转录反应的调节的细胞生物学机制。在过去的周期中，这笔赠款支持的主要进步是：I，表明FOXO1在肝葡萄糖产生和脂质合成的激素调节中的关键作用； II，鉴定FOXO1在下丘脑弧形核中的新作用，将胰岛素和瘦素信号传导与神经肽合成和作用联系起来； iii，将肥胖易感性基因羧肽酶E（CPE）鉴定为FOXO1靶标，从而深入了解体重减轻后肥胖症累犯的病理生理学； iv，鉴定营养素对FOXO1功能调节的基于乙酰化的机制，以及它们在胰岛素抵抗的发病机理中的整合； V，发现FOXO1作为基因表达的核心测量剂的非转录功能； VI，表明FOXO和Notch之间的功能相互作用，建立了主要的发育途径与营养感应途径之间的机械联系。我们试图以以下目的继续进行研究：在AIM 1中，我们建议FOXO1是否是营养和神经递质水平的转录传感器，将食物摄入与能量消耗和NPY/AGRP神经元中的肝葡萄糖产生联系起来。过去周期中开发的乙酰化缺陷FOXO1突变小鼠将在对该假设的批判性检验中发挥作用。在AIM 2中，我们将使用FOXO1突变体来探测激素和养分信号的神经解剖学。虽然出现的共识突出了中枢神经系统在糖尿病和肥胖症中的作用，但迄今为止，脑内分泌信号传导的复杂性却妨碍了针对任何一种疾病开发针对CNS的药物的努力。 FOXO1在激素信号传导中的中心作用及其对营养的调节使其成为使用小鼠中功能障碍和功能丧失突变探测胰岛素和瘦素信号传导神经解剖学的有吸引力的工具。我们建议在FOXO1操纵和特定神经元子集产生的子表型之间建立解剖功能关系。在AIM 3中，我们将研究FOXO/Notch轴的代谢功能。我们已经表明，FOXO1通过与Notch途径相互作用来调节细胞分化。通常认为Notch途径是一种发展途径，并且尚未探索其代谢功能。我们在初步数据中表明，Notch1和FoxO1合作调节肝葡萄糖代谢。我们建议探索该观察结果的机制，其最终目的是将缺口抑制剂应用于糖尿病治疗。 公共卫生相关性：转录因子FOXO1是该生物体代谢和激素状态的关键传感器，可以诱导基因表达的变化，以解释胰岛素抵抗的蛋白质表现及其发展为明显的糖尿病。基于过去十年中开发的一系列工作，我们将努力了解特定组织中FOXO1功能的综合生理学及其生化基础。这项工作的最终目标是找到修改FOXO1功能的治疗方法。确实，尽管FOXO1是逆转糖尿病和代谢性疾病的有吸引力的生物学靶标，但它在很大程度上是棘手的。因此，希望通过解析其动作模式和互动合作伙伴，可以找到调节其功能的新方法。