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）：代谢综合征正在毁灭我们的医疗保健系统，并损害了数百万的生活质量。了解这种情况的发病机理对于消除它至关重要。代谢综合征是一种流行病，因为人们采取了一种饮食，其适应不良的饮食和一种在很大程度上不活跃的生活方式。与底物氧化，脂质积累和血脂异常不足有关的肝代谢功能障碍是代谢综合征的标志，因为它在发育的早期很明显，并且与其他症状的严重程度有关。据推测，肝脏代谢功能障碍是自然发展对代谢综合征的原因。尽管肝脏代谢在整体“代谢健康”，其在健康身体活跃状态下的有效性的机制，但导致功能障碍的因素以及纠正功能障碍的手段知之甚少。构成该提案的协议旨在定义控制（i）在急性扰动过程中控制（i）肝内能平衡的机制，以及（ii）通过修改饮食和体育活动中的肝内和全身能量平衡。从当前赠款周期中塑造该提案目的的发现是基于对代谢至关重要的观察，以至于它将影响最基本的水平的助焊剂控制。我们表明的是，“健康肝脏”的能量状态发生了巨大的偏差。细胞能量状态在人体的大多数组织中受到严格控制，因此细胞处于高电荷状态（低AMP：ATP）。但是，诸如运动和禁食等生理状况会触发AMP：ATP肝脏中的五到十倍。我们将测试（a）在胰高血糖素刺激和运动过程中肝AMP：ATP的增加是否是由于与糖异生能量相关的ATP水解引起的； （b）核苷酸单磷酸盐通过AMPK11和AMPK12亚基的激活来刺激肝底物氧化； （c）对高脂肪进食和体育活动的肝适应是AMPK依赖性的。将使用手术和实验工具研究肝代谢的调节，这些工具可以在体内进行良好控制的实验。胰高血糖素输注，跑步机运动，车轮跑步和高脂肪进食将被用作放大生理信号的工具，并用作扰动肝代谢控制的一种手段。使用明确定义的遗传小鼠模型将描绘作用机理和功能障碍位点。将使用采用2H和13C NMR分析技术的复杂同位素方法来量化肝底物代谢。这些研究将定义如何在健康肝脏中调节肝脏底物通量以及功能障碍部位在代谢综合征和肝胰岛素抵抗的发病机理中。公共卫生相关性。 代谢综合征和II型糖尿病是我们医疗保健系统的巨大负担。行使的生理适应性降低了发展这些疾病的风险，至少部分通过改善肝脏代谢功能。该提案的目的是阐明运动改善肝脏代谢调节的机制。