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，并危及数百万人的生活质量。了解这种疾病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太适应的饮食和一种基本上不运动的生活方式。与底物氧化不足、脂质积累和血脂异常相关的肝脏代谢功能障碍是代谢综合征的标志，因为它在发展早期就很明显，并与其他症状的严重程度有关。据推测，肝脏代谢功能障碍是代谢综合征自然发展过程中的一个致病步骤。尽管肝脏代谢在整体“代谢健康”中起着核心作用，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。包含本提案的方案旨在定义控制(i)急性摄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。从目前的拨款周期得出的结论决定了本提案的目标，这一发现是基于对新陈代谢如此重要的观察，它将影响最基本水平上的通量控制。我们所展示的是，“健康肝脏”的能量状态经历了巨大的偏差。在身体的大多数组织中，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会导致肝脏中AMP:ATP增加5到10倍。我们将测试(a)胰高血糖素刺激和运动期间肝脏AMP:ATP的增加是否由于ATP水解与糖异生的能量学相关；(b)单磷酸核苷酸信号通过激活AMPK11和AMPK12亚基刺激肝脏底物氧化；(c)肝脏对高脂肪喂养和体力活动的适应依赖于ampk。肝脏代谢的调节将使用外科和实验工具进行研究，这些工具允许在体内进行良好控制的实验。胰高血糖素输注、跑步机运动、轮式跑步和高脂肪喂养将被用作放大生理信号的工具和干扰肝脏代谢控制的手段。作用机制和功能障碍的地点将描述使用定义良好的遗传小鼠模型。肝脏底物代谢将使用复杂的同位素方法，采用2H和13C核磁共振分析技术进行量化。这些研究将确定健康肝脏中肝脏底物通量是如何调节的，以及代谢综合征和肝脏胰岛素抵抗发病机制中功能障碍的位置。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。对运动的生理适应降低了患这些疾病的风险，至少部分是通过改善肝脏代谢功能来实现的。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.