FFA Production From Triglyceride-Rich Lipoproteins

描述（由申请人提供）：拟进行的研究将继续我们在脂质燃料代谢调节领域的工作。脂质能量以多种形式在血液中运输，包括乳糜微粒和游离脂肪酸（FFA）。乳糜微粒是膳食脂肪吸收和储存的关键因素，也通过产生残余颗粒在动脉粥样硬化的发病机制中发挥作用，但其作为直接燃料来源的作用尚未得到广泛研究。游离脂肪酸是体内主要的脂质燃料，其浓度的增加已被证明会导致胰岛素抵抗、内皮功能障碍和极低密度脂蛋白的产生增加。脂肪酸通过激素敏感脂肪酶对脂肪细胞中储存的甘油三酯的作用释放到血液中。乳糜微粒在FFA代谢中的作用知之甚少，但乳糜微粒对FFA的潜在贡献是相当大的，特别是在食用高脂肪饮食的人群中。最初的研究表明，除了乳糜微粒在脂肪储存中的作用外，一部分乳糜微粒脂肪酸在一个称为“溢出”的过程中以FFA的形式释放。一项关于内脏床溢出的研究发现，超重和肥胖的高甘油三酯血症患者的内脏溢出率非常高。随后的研究表明，静脉输注烟酸（一种已知可抑制游离脂肪酸释放的药物）可显著减少部分溢出，而胰岛素输注则没有效果。此外，在2型糖尿病患者中，外溢与腿部脂肪呈负相关，即腿部脂肪量大，外溢较低（表明脂肪储存效率更高），而腿部脂肪量少的人外溢较高，表明脂肪储存效率较低。没有关于下体脂肪组织溢出的信息，也没有关于其与内脏床（包括内脏脂肪）溢出的关系的信息。研究者已经开发了非常准确和精确的方法来测量血浆中游离脂肪酸和乳糜微粒甘油三酯脂肪酸的浓度和比活性。此外，还开发了一种准确测定乳糜微粒动力学的示踪方法。在拟议的研究中，示踪技术将用于系统地研究乳糜微粒对总FFA有效性的贡献。这项技术将应用于瘦弱和肥胖的受试者，包括接受过胃分流手术的人。具体而言，这些研究将：1)确定胃旁路术后体重减轻是否会减少乳糜微粒的溢出；2)确定烟酸输注急性降低FFA是否能减少超重和肥胖人群的溢出效应；3)确定上半身肥胖的女性是否比下半身肥胖的女性有更大的系统性溢出，以及身体脂肪分布是否决定了乳糜微粒甘油三酯在腿部和内脏脂肪的摄取和溢出。4)确定上半身肥胖的女性在监督过度喂养期间是否比下半身肥胖的女性体重增加更少。

DESCRIPTION (provided by applicant): The proposed research will continue our work in the area of the regulation of lipid fuel metabolism. Lipid energy is transported in the blood in severa forms, including chylomicrons and free fatty acids (FFA). Chylomicrons are key elements in the absorption and storage of dietary fat, and also play a role in the pathogenesis of atherosclerosis via the production of remnant particles, but their role as a direct fuel source has not been extensively investigated. FFAs are the major lipid fuel in the body, and increases in their concentration have been shown to cause insulin resistance, endothelial dysfunction and increases in the production of very low density lipoproteins. FFAs are released into the blood through the action of hormone sensitive lipase on triglyceride stores in fat cells. Very little is known about the role of chylomicrons in FFA metabolism, but the potential contribution of chylomicrons to FFA is considerable, especially in people who consume high fat diets. Initial studies indicate that in addition to the role of chylomicrons in fat storage, a portion of chylomicron fatty acids are released as FFA in a process called "spillover". A study of spillover in the splanchnic bed found very high rates of splanchnic spillover in overweight and obese individuals with hypertriglyceridemia. Subsequent studies have shown that intravenous infusion of niacin, a drug known to suppress FFA release, produced a significant reduction in fractional spillover, whereas insulin infusion had no effect. Furthermore, in people with type 2 diabetes spillover correlated negatively with leg fat - that is, individuals with a large amount of leg fat ad lower spillover (an indication of more efficient fat storage), while those with small amounts of le fat had higher spillover, indicating less efficient storage. No information is available on spillovr in lower body fat tissue, nor on its relationship with spillover in the splanchnic bed (which includes visceral fat). Extremely accurate and precise methods have been developed by the investigator for the measurement of the concentration and specific activity of FFA and chylomicron triglyceride fatty acids in plasma. In addition, a tracer method for accurately determining the kinetics of chylomicrons has been developed. In the proposed studies, the tracer technique will be used to systematically investigate the contribution of chylomicrons to total FFA availability. The technique will be applied to lean and obese subjects, including people who have undergone gastric bypass surgery. Specifically, these studies will: 1) determine whether weight loss after gastric bypass reduces spillover from chylomicrons; 2) determine whether acute lowering of FFA with niacin infusion reduces spillover in overweight and obese people; 3) determine whether women with upper body obesity have greater systemic spillover than women with lower body obesity, and whether body fat distribution determines chylomicron triglyceride uptake and spillover in leg and splanchnic fat and 4) determine whether women with upper body obesity gain less weight during supervised overfeeding than women with lower body obesity.