Free Fatty Acid Metabolism in Different Types of Human Obesity

描述(申请人提供)：游离脂肪酸(FFA)对许多细胞系统有重要影响。血浆游离脂肪酸浓度升高会刺激内源性葡萄糖的产生，导致极低密度脂蛋白的异常分泌，抑制肌肉对葡萄糖的摄取和氧化，并改变血管的反应性。肥胖症，特别是上半身肥胖症患者的血浆游离脂肪酸浓度升高，被认为在肥胖相关健康问题的病理生理学中起着重要作用。我们使用同位素稀释技术测量循环中FFA的出现(Ra)和消失(Rd)，以了解维持或改变血浆FFA浓度的机制，并将能量可获得性与能量需求联系起来。然而，细胞本身很可能无法检测到FFA“通量”，而是对它们所暴露的细胞外FFA浓度做出反应。由这笔赠款支持的研究结果使我们得出了意想不到的结论，即FFA摄取的差异可以对全身FFA浓度产生实质性影响。我们发现，在相同的FFA浓度和脂肪酸氧化速率下，女性的FFA摄取率和释放率大约高出40%。这只能通过更多的非氧化性FFA处置来解释。我们还发现，在高胰岛素血症期间，对上身肥胖成年人进行吡格列酮治疗可导致更大的FFA清除(较低的浓度而不是较低的脂肪分解)。非氧化性FFA处置的主要部位/机制包括直接重新摄取脂肪组织、通过极低密度脂蛋白-甘油三酯循环或摄取到心肌细胞内的甘油三酯。这些途径中的每一条都参与了非氧化性FFA的处理，但每条途径的相对贡献尚不清楚。我们的初步数据表明，在男性和女性之间，在下半身肥胖和上半身肥胖女性和肥胖男性之间，非氧化性FFA处置的途径/机制是不同的。我们已经开发或调整了一些方法，允许将FFA直接和间接地分配到脂肪组织中，直接分配到肌肉中，并通过极低密度脂蛋白池跟随FFA。我们将确定在日常生活中通常遇到的条件下，瘦和肥胖男性和女性的非氧化性FFA处置的组织和机制是什么：休息、餐后和体力活动。这项建议的具体目的是确定：1.直接进入脂肪组织的非氧化性FFA在夜间吸收后条件下、在进食条件下和在体力活动中的男性和女性之间是否存在差异。2.在过夜吸收后状态、摄食状态和体力活动状态下，直接进入心肌细胞内甘油三酯的非氧化性FFA处置方式不同于男性和女性。3.通过VLDL-甘油三酯的非氧化性FFA处置在吸收后过夜、摄食和体力活动条件下的男性和女性有所不同。4.肥胖和体脂分布改变了在过夜吸收后和喂养条件下以及在体力活动期间非氧化性FFA处置的途径/机制。5.FFA利用率或体脂百分比决定非氧化性FFA处置的相对处置，而不是性别。这些研究的结果应该为人类血浆FFA浓度的决定因素提供新的见解，这反过来应该使对基本机制的重点和富有成效的研究成为可能。了解这些机制可能会导致肥胖症的新治疗方法。拟议的研究代表了我们努力确定FFA代谢在肥胖的不利健康后果中的作用的合乎逻辑的延伸。

DESCRIPTION (provided by applicant): Free fatty acids (FFA) have important effects on many cell systems. Elevated plasma FFA concentrations stimulate endogenous glucose production, cause abnormal VLDL secretion, inhibit muscle glucose uptake and oxidation, and alter vascular responsiveness. The elevated plasma FFA concentrations found in obesity and specifically upper body obesity are thought to play a significant role in the pathophysiology of obesity-related health problems. We measure FFA appearance (Ra) and disappearance (Rd) from the circulation using isotope dilution techniques to understand the mechanisms by which plasma FFA concentrations are maintained or altered and to relate energy availability to energy needs. Cells, however, most likely cannot detect FFA "flux" per se, but instead respond to the extracellular FFA concentrations to which they are exposed. The results of studies supported by this grant have led us to the unexpected conclusion that differences in FFA uptake can have substantial effects on systemic FFA concentrations. We found that at the same FFA concentrations and rates of fatty acid oxidation women have approximately 40% greater rates of FFA uptake and release. This can only be accounted for by greater non-oxidative FFA disposal. We also found that pioglitazone treatment of upper body obese adults resulted in greater FFA clearance (lower concentrations without lower lipolysis) during hyperinsulinemia. The major sites/mechanisms for non-oxidative FFA disposal include direct reuptake into adipose tissue, recycling via VLDL-triglyceride or uptake into intramyocellular triglyceride. Each of these pathways participates in non-oxidative FFA disposal, but the relative contribution of each pathway is unknown. Our preliminary data suggests that the pathways/mechanisms of non-oxidative FFA disposal are different in men and women and between lower body obese and upper body obese women and obese men. We have developed or adapted methods that allow partitioning of FFA disposal directly and indirectly into adipose tissue, directly into muscle and to follow FFA through the VLDL pool. We will determine what tissues and mechanisms account for non-oxidative FFA disposal in lean and obese men and women under the conditions typically encounter in daily life: resting, postprandial and during physical activity. The Specific Aims of this proposal are to determine whether: 1. Non-oxidative FFA disposal directly into adipose tissue differs between men and women in the overnight postabsorptive condition, under fed conditions and during physical activity. 2. Non-oxidative FFA disposal directly into intramyocellular triglyceride differs between men and women in the overnight postabsorptive condition, under fed conditions and during physical activity. 3. Non-oxidative FFA disposal via VLDL-triglyceride differs between men and women in the overnight postabsorptive condition, under fed conditions and during physical activity. 4. Obesity and body fat distribution alter the pathways/mechanisms of non-oxidative FFA disposal under overnight postabsorptive and fed conditions as well as during physical activity. 5. FFA availability or percent body fat, rather than sex determine the relative disposition of non-oxidative FFA disposal. The results of these studies should provide new insights into the determinants of plasma FFA concentrations in humans, which should in turn allow focused and productive studies of the basic mechanisms. Understanding these mechanisms may lead to new treatment approaches for obesity. The proposed studies represent a logical extension of our efforts to define the role of FFA metabolism in the adverse health consequences of obesity.