Mechanistically Linking Insulin Action and the Thermic Effect of Food

胰岛素作用与食物热效应的机制联系

• 批准号: 9769720
• 负责人: Don Tianmu Li
• 金额: $ 5万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-16 至 2020-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769720
• 关键词: 3T3-L1 Cells; Adipose tissue; Adrenergic Agents; Adult; Affect; Age; Aging; Binding; Biological Assay; C-terminal; Cell Line; Cell Nucleus; Cells; Central obesity; ChIP-seq; Chimeric Proteins; Cost of Illness; DNA; Data; Deposition; Development; Diabetes Mellitus; Disease; Energy Metabolism; Exhibits; Fatty acid glycerol esters; Food; Futile Cycling; Gene Expression; Genes; Genetic Transcription; Goals; Half-Life; Healthcare Systems; Hypertension; Immunofluorescence Immunologic; In Vitro; Insulin; Insulin Resistance; Intake; Intervention; Knock-out; Knockout Mice; Knowledge; Learning; Light; Link; Luciferases; Mediating; Metabolic; Metabolic syndrome; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mouse Cell Line; Mouse Strains; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nutrient; Obesity; Oxygen Consumption; Pathogenesis; Pathway interactions; Pharmacology; Physicians; Play; Process; Proteins; Regulation; Regulatory Pathway; Research; Response Elements; Role; Sarcoplasmic Reticulum; Scientist; Signal Transduction; Site; Small Interfering RNA; Testing; Thermogenesis; Time; Tissues; Training; Transgenic Mice; Transgenic Organisms; United States; Vasopressins; Work; basal insulin; base; clinically relevant; cost; diabetes mellitus therapy; energy balance; experience; glucose uptake; in vivo; insulin signaling; mouse model; novel; obesity prevention; total energy expenditure; transcriptome; transcriptome sequencing

Project Summary: Mechanistically Linking Insulin Action and the Thermic Effect of Food Positive energy balance leading to ectopic fat deposition has been shown to play a major role in the pathogenesis of insulin resistance and type 2 diabetes, a disease that costs the United States healthcare system over 300 billion dollars a year. One important component of energy expenditure is the thermic effect of food (TEF), which represents the increase in heat production and oxygen consumption following nutrient intake. However, the mechanistic link between nutrient intake and energy expenditure remains poorly understood. Insulin stimulated cleavage of the TUG protein has been shown to regulate glucose uptake and vasopressin inactivation in vitro and in vivo. Unexpectedly, mice with constitutive and unregulated cleavage of TUG proteins exhibit significantly increased energy expenditure that is associated with transcriptional induction of proteins that mediate futile cycles of metabolic substrates. Conversely, mice with muscle specific deletion of TUG have decreased expression of thermogenic proteins. This proposal will test the hypothesis that the TUG C-terminal cleavage product regulates energy expenditure by localizing to the nucleus and modulating gene expression. The first aim is to study the mechanism of increased energy expenditure in transgenic mice with constitutive TUG cleavage. The dynamics of TUG C-terminal product localization and how it is affected in insulin resistant tissues will be studied in complementary mouse strains. Interaction partners of the TUG C-terminus within the nucleus will be identified using unbiased screens and verified in both mice and cell lines. The second aim is to understand how degradation of the TUG C-terminus is regulated by the N-end rule, which is well described to regulate the half-life of cleavage products. Tagged fusion proteins, siRNA, and in vivo characterization will be used to determine how the abundance of TUG may be regulated. Overall, this proposal will elucidate a novel link between insulin signaling and energy expenditure and provide the groundwork for further studies on how this process may be regulated. Such studies will also allow for the identification of potential sites of pharmacologic intervention. Finally, the proposal includes a comprehensive training plan that will provide important new learning experiences to support the applicant’s development as a physician-scientist who is able to integrate scientific work and knowledge of diabetes with novel clinically relevant research.

项目摘要：机械师将胰岛素作用和食物的热效应联系起来 积极的能量平衡导致生态脂肪沉积已显示在发病机理中起主要作用 胰岛素抵抗和2型糖尿病的疾病，这种疾病使美国的医疗保健系统超过3000亿 一年的美元。能量消耗的一个重要组成部分是食物的热效应（TEF）， 代表养分摄入后的热量产量和氧气消耗的增加。但是， 营养摄入量和能量消耗之间的机械联系仍然很少了解。胰岛素刺激 已显示拖离蛋白的切割可调节体外葡萄糖摄取和加压素失活的诱导 体内。出乎意料的是，具有匹配和不受管制的拖线蛋白切割的小鼠显着暴露 增加了与介导徒劳周期的蛋白质转录诱导相关的能量消耗 代谢底物。相反，肌肉特异性缺失的小鼠的表达提高了 热蛋白。该提案将检验以下假设：拖线C末端裂解产品调节 通过将核定位并调节基因表达来消耗能量。第一个目的是研究 具有组成型拖线裂解的转基因小鼠能量消耗增加的机制。动态 TUG C末端产品定位及其在胰岛素抵抗时机中的影响将在 完全鼠标应变。将鉴定出细胞核内拖线C末端的相互作用伙伴 使用公正的屏幕，并在小鼠和细胞系中进行了验证。第二个目的是了解如何退化 拖船C末端的n端规则调节，该规则很好地描述了裂解的半衰期 产品。标记的融合蛋白，siRNA和体内表征将用于确定如何 可以调节拖船的抽象。总体而言，该建议将阐明胰岛素信号之间的新联系 和能源支出，并为如何调节这一过程提供进一步研究的基础。 这些研究还将允许鉴定药理学干预的潜在部位。最后， 建议包括一项全面的培训计划，该计划将提供重要的新学习经验以支持 申请人作为身体科学家的发展，能够整合科学工作和知识 具有新型临床相关研究的糖尿病。