Free Fatty Acid Metabolism in Different Types of Human Obesity

不同类型人类肥胖中的游离脂肪酸代谢

• 批准号: 7269471
• 负责人: MICHAEL D. JENSEN
• 金额: $ 37.79万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7269471
• 关键词: Accounting; Address; Adipose tissue; Adult; Appearance; Blood Circulation; Blood Vessels; Body fat; Cells; Condition; Daily; Data; Dilution Techniques; Functional disorder; Grant; Health; Human; Hyperinsulinism; In Vitro; Isotopes; Lead; Life; Lipolysis; Measures; Methods; Muscle; Nonesterified Fatty Acids; Obesity; Pathway interactions; Physical activity; Pioglitazone; Plasma; Play; Process; Rate; Recycling; Relative (related person); Research Design; Rest; Role; Site; System; Testing; Thinking; Tissues; Triglycerides; Very low density lipoprotein; Woman; extracellular; fatty acid metabolism; fatty acid oxidation; feeding; glucose production; glucose uptake; insight; men; oxidation; response; reuptake; sex; uptake; very low density lipoprotein triglyceride; volunteer

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.

描述（由申请人提供）：游离脂肪酸（FFA）对许多细胞系统具有重要作用。升高的血浆FFA浓度刺激内源性葡萄糖产生，引起异常VLDL分泌，抑制肌肉葡萄糖摄取和氧化，并改变血管反应性。在肥胖症，特别是上身肥胖症中发现的血浆FFA浓度升高被认为在肥胖相关健康问题的病理生理学中起重要作用。我们测量FFA的出现（Ra）和消失（Rd）的循环使用同位素稀释技术，以了解血浆FFA浓度的维持或改变的机制，并与能源供应的能源需求。然而，细胞很可能不能检测FFA“通量”本身，而是对它们所暴露的细胞外FFA浓度作出反应。这项资助支持的研究结果使我们得出了一个意想不到的结论，即FFA摄取的差异可能对全身FFA浓度产生重大影响。我们发现，在相同的FFA浓度和脂肪酸氧化率下，女性的FFA摄取和释放率高出约40%。这只能通过更多的非氧化FFA处置来解释。我们还发现，在高胰岛素血症期间，吡格列酮治疗上身肥胖成人导致FFA清除率更高（浓度更低，但脂解作用更低）。非氧化FFA处置的主要位点/机制包括直接重摄取到脂肪组织中、通过VLDL-甘油三酯再循环或摄取到肌细胞内甘油三酯中。这些途径中的每一个都参与非氧化FFA处置，但每个途径的相对贡献是未知的。我们的初步数据表明，非氧化FFA处置的途径/机制在男性和女性以及下身肥胖和上身肥胖的女性和肥胖男性之间是不同的。我们已经开发或调整了方法，允许FFA直接或间接进入脂肪组织，直接进入肌肉，并通过VLDL池跟踪FFA。我们将确定在日常生活中通常遇到的条件下（休息、餐后和体力活动期间），瘦型和肥胖男性和女性的非氧化性FFA处置是由哪些组织和机制引起的。本提案的具体目的是确定：1.非氧化FFA处置直接进入脂肪组织的男性和女性之间的不同，在夜间吸收后的条件下，在进食条件下，并在体力活动。2.非氧化FFA处置直接进入肌细胞内甘油三酯在夜间吸收后条件下，在进食条件下和体力活动期间，男性和女性之间存在差异。3.在过夜吸收后条件下、进食条件下和体力活动期间，男性和女性通过VLDL-甘油三酸酯的非氧化FFA处置存在差异。4.肥胖和体脂分布改变了在吸收后过夜和进食条件下以及体力活动期间非氧化FFA处置的途径/机制。5. FFA可用性或体脂百分比，而不是性别决定非氧化FFA处置的相对处置。这些研究的结果应该提供新的见解，在人类血浆FFA浓度的决定因素，这反过来又应该允许集中和生产性的研究的基本机制。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代谢在肥胖不良健康后果中的作用的逻辑延伸。