Exercise and Fuel Metabolism

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。了解代谢综合征的发病机制对消除它至关重要。代谢综合征是一种流行病，因为人们采用了一种他们不适应的饮食和一种基本上不活动的生活方式。与底物氧化不足、脂质蓄积和血脂异常相关的肝代谢功能障碍是代谢综合征的标志，因为它在其发展早期就很明显，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代谢综合征自然进展的一个致病步骤。尽管肝脏代谢对整体“代谢健康”具有核心作用，但其在健康体力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仍知之甚少。构成本提案的方案旨在定义控制（i）急性扰动期间肝内能量平衡和（ii）通过调整饮食和体力活动控制肝内和全身能量平衡的机制。从目前的资助周期中发现的，形成了这个建议的目标，是基于一个观察，这是新陈代谢的基础，它将影响流量控制在最基本的水平。我们所展示的是“健康肝脏”的能量状态经历了戏剧性的偏差。细胞能量状态在身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）。然而，运动和禁食等生理条件可以引发肝脏中AMP：ATP增加5至10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肝脏再生能量学相关的ATP水解;（B）核苷酸单磷酸通过AMPK 11和AMPK 12亚基的激活发出刺激肝脏底物氧化的信号;以及（c）肝脏对高脂喂养和体力活动的适应是否是AMPK依赖性的。将使用允许在体内进行良好对照实验的手术和实验工具来研究肝脏代谢的调节。胰高血糖素输注、踏车运动、轮跑和高脂肪喂养将用作放大生理信号的工具和干扰肝脏代谢控制的手段。将使用定义明确的遗传小鼠模型来描述作用机制和功能障碍部位。将采用2 H和13 C NMR分析技术，使用复杂的同位素方法定量肝脏底物代谢。这些研究将确定如何在健康肝脏中调节肝脏底物通量，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II型糖尿病是我们卫生保健系统的巨大负担。运动的生理适应性降低了发展这些疾病的风险，至少部分是通过改善肝脏代谢功能。这项建议的目的是阐明运动改善肝脏代谢调节的机制。

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.