Exercise and Fuel Metabolism

运动和燃料代谢

• 批准号: 8006764
• 负责人: DAVID H WASSERMAN
• 金额: $ 14.47万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-04 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8006764
• 关键词: 5' -AMP-activated protein kinase; ATP Hydrolysis; Acute; Address; Adenine Nucleotides; Adopted; Arts; Blood Glucose; Catheterization; Cells; Charge; Chronic; Conscious; Couples; Development; Diabetes Mellitus; Diet; Dyslipidemias; Effectiveness; Epidemic; Exercise; Fasting; Fatty acid glycerol esters; Functional disorder; Genetic; Genetic Models; Glucagon; Glucagon Receptor; Gluconeogenesis; Glucose Clamp Technique; Grant; Health; Healthcare Systems; Hepatic; Hormones; Infusion procedures; Insulin Resistance; Life Style; Lipids; Liver; Metabolic; Metabolic Control; Metabolic Pathway; Metabolic syndrome; Metabolism; Methods; Modeling; Modification; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Obesity; Operative Surgical Procedures; Pathogenesis; Phenotype; Phosphoenolpyruvate Carboxylase; Physical activity; Physiological; Physiological Adaptation; Procedures; Protocols documentation; Quality of life; Regulation; Risk; Role; Running; Severities; Shapes; Signal Transduction; Site; Symptoms; Techniques; Testing; Texas; Tissues; Universities; base; blood glucose regulation; design; energy balance; fascinate; feeding; improved; in vivo; intrahepatic; knockout gene; liver metabolism; mouse model; oxidation; public health relevance; research study; tool

DESCRIPTION (provided by applicant): Metabolic syndrome is devastating our health care system and compromising the quality of life for millions. Understanding the pathogenesis of this condition is paramount to eliminating it. The metabolic syndrome is an epidemic because people have adopted a diet for which they are poorly adapted and a lifestyle that is largely inactive. Hepatic metabolic dysfunction associated with inadequate substrate oxidation, lipid accumulation, and dyslipidemia is a hallmark of metabolic syndrome as it is evident early in its development and is associated with the severity of other symptoms. It has been speculated that liver metabolic dysfunction is a causative step in the natural progression to metabolic syndrome. Despite the central role of liver metabolism to overall "metabolic health," the mechanism for its effectiveness in healthy physically active states, the factors responsible for dysfunction, and the means to correct dysfunction are poorly understood. The protocols that comprise this proposal are designed to define mechanisms that control (i) intra-hepatic energy balance during acute perturbations and (ii) intra-hepatic and whole body energy balance by modifications in diet and physical activity. The finding from the present grant cycle that shapes the aims of this proposal is based on an observation so fundamental to metabolism that it will influence flux control at the most basic level. What we have shown is that the energy state of the "healthy liver" undergoes dramatic deviations. Cellular energy status is tightly controlled in most tissues of the body, so that cells are in a highly charged state (low AMP:ATP). However, physiological conditions such as exercise and fasting can trigger a five- to tenfold increase in the AMP:ATP in liver. We will test whether (a) the increase in hepatic AMP:ATP during glucagon stimulation and exercise is due to ATP hydrolysis associated with the energetics of gluconeogenesis; (b) the nucleotide monophosphates signal the stimulation of hepatic substrate oxidation through the activation of AMPK11 and AMPK12 subunits; and (c) the hepatic adaptations to high fat feeding and physical activity are AMPK-dependent. The regulation of hepatic metabolism will be studied using surgical and experimental tools that allow well-controlled experiments to be carried out in vivo. Glucagon infusion, treadmill exercise, wheel running and high fat feeding will be used as tools to amplify physiological signals and as a means of perturbing hepatic metabolic control. Mechanisms of action and sites of dysfunction will be delineated using well-defined genetic mouse models. Hepatic substrate metabolism will be quantified using sophisticated isotopic approaches employing 2H and 13C NMR analytical techniques. These studies will define how liver substrate fluxes are regulated in the healthy liver and where sites of dysfunction lie in the pathogenesis of metabolic syndrome and hepatic insulin resistance. PUBLIC HEALTH RELEVANCE. Metabolic syndrome and Type II diabetes are an enormous burden on our health care system. The physiological adaptations to exercise decrease the risk of developing these conditions, at least in part by improving liver metabolic function. The aim of this proposal is to elucidate the mechanism by which exercise improves metabolic regulation by the liver.

描述（由申请人提供）：代谢综合征正在破坏我们的医疗保健系统，并损害数百万人的生活质量。了解这种情况的发病机制对于消除它至关重要。代谢综合征是一种流行病，因为人们采用了不适应的饮食习惯和缺乏运动的生活方式。与底物氧化不足、脂质积累和血脂异常相关的肝代谢功能障碍是代谢综合征的一个标志，因为它在其发展的早期就很明显，并且与其他症状的严重程度相关。据推测，肝脏代谢功能障碍是自然进展为代谢综合征的一个致病步骤。尽管肝脏代谢在整体“代谢健康”中发挥着核心作用，但其在健康身体活动状态下的有效性机制、导致功能障碍的因素以及纠正功能障碍的方法却知之甚少。构成该提案的协议旨在定义控制（i）急性扰动期间肝内能量平衡和（ii）通过改变饮食和身体活动来控制肝内和全身能量平衡的机制。当前拨款周期的发现决定了该提案的目标，其基础是对新陈代谢如此重要的观察，它将在最基本的层面上影响流量控制。我们已经证明，“健康肝脏”的能量状态发生了巨大的偏差。身体大多数组织中的细胞能量状态受到严格控制，因此细胞处于高电荷状态（低 AMP:ATP）。然而，运动和禁食等生理条件可能会导致肝脏中的 AMP:ATP 增加五到十倍。我们将测试 (a) 胰高血糖素刺激和运动期间肝脏 AMP:ATP 的增加是否是由于与糖异生能量相关的 ATP 水解所致； (b) 单磷酸核苷酸通过激活 AMPK11 和 AMPK12 亚基发出刺激肝底物氧化的信号； (c) 肝脏对高脂肪喂养和体力活动的适应是 AMPK 依赖性的。将使用手术和实验工具来研究肝脏代谢的调节，以便在体内进行良好控制的实验。胰高血糖素输注、跑步机运动、轮跑和高脂肪喂养将被用作放大生理信号的工具和扰乱肝脏代谢控制的手段。将使用明确的遗传小鼠模型来描述作用机制和功能障碍部位。肝脏底物代谢将通过采用 2H 和 13C NMR 分析技术的复杂同位素方法进行量化。这些研究将确定健康肝脏中肝脏底物通量的调节方式以及代谢综合征和肝脏胰岛素抵抗的发病机制中功能障碍的部位。公共卫生相关性。 代谢综合征和二型糖尿病给我们的医疗保健系统带来了巨大的负担。对运动的生理适应可以降低患这些疾病的风险，至少部分是通过改善肝脏代谢功能来实现的。该提案的目的是阐明运动改善肝脏代谢调节的机制。