High fat feeding and intramyocellular lipid abnormality

高脂肪喂养与肌细胞内脂质异常

• 批准号: 6613332
• 负责人: ZENGKUI GUO
• 金额: $ 14.3万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6613332
• 关键词: biopsy; dietary lipid; gas chromatography mass spectrometry; glucose metabolism; glucose transport; glycogen; glycolysis; hyperinsulinism; hyperlipidemia; insulin; laboratory rat; lipid biosynthesis; lipid disorder; lipid metabolism; muscle disorders; muscle metabolism; nuclear magnetic resonance spectroscopy; nutrition related tag; triglycerides

It is now known that intramyocellular triglycerides (imcTG) content in skeletal muscle of obese adults is increased and this abnormality is associated with impaired glucose metabolism in the muscle. However, the pathways responsible for the increase and the link between the increased imcTG and insulin resistance have not been studied in detail. The objective of this application is to determine the factors and pathways that are responsible for the imcTG accumulation, and to determine whether the oxidation of imcTG fatty acids is also increased and, if so, whether it directly affects glucose metabolism. It is hypothesized that elevated plasma insulin and fatty acid levels, as commonly seen in human obesity, independently stimulate imcTG synthesis and synthesis is the primary pathway leading to the increased imcTG accumulation; and that a larger imcTG pool leads to accelerated imcTG oxidation thereby interfering with muscle glucose metabolism. To test the hypotheses, three specific aims will be pursued to answer following questions: 1) Is insulin an anabolic hormone stimulating imcTG synthesis? 2) Does elevated plasma fatty acid concentration increase imcTG synthesis by providing abundant precursors? 3) Is a larger imcTG pool associated with accelerated oxidation of imcTG fatty acids, and if so, how this affects muscle glucose metabolism? A new one-pool model will be applied to determine the rates of imcTG synthesis, turnover and oxidation directly (muscle biopsy) at controlled insulin and fatty acid levels in rats made obese by high fat feeding. The oxidation of imcTG fatty acids and muscle glucose uptake, glycolysis and glycogen synthesis will be determined using multiple tracers to determine the effect of imcTG oxidation on glucose metabolism. Stable isotopic tracers (13C) and mass spectrometry (GC/MS and isotope ratio MS) will be used to quantitate the kinetics. These studies are designed to answer the questions whether an enlarged imcTG is a chemical entity that imposes a negative effect on glucose metabolism, and whether plasma insulin and fatty acids are responsible for the increased imcTG, and if so, how. Thus, the proposed research will improve the understanding of the mechanism of insulin resistance and imcTG abnormalities in the obese rat that will benefit investigation of human obesity.

现在已知，肥胖成人骨骼肌中肌细胞内甘油三酯（imcTG）含量增加，这种异常与肌肉中葡萄糖代谢受损有关。 然而，尚未详细研究导致 imcTG 增加的途径以及增加的 imcTG 与胰岛素抵抗之间的联系。 本应用的目的是确定导致 imcTG 积累的因素和途径，并确定 imcTG 脂肪酸的氧化是否也增加，如果是，是否直接影响葡萄糖代谢。据推测，血浆胰岛素和脂肪酸水平升高（如人类肥胖症中常见）独立刺激 imcTG 合成，并且合成是导致 imcTG 积累增加的主要途径；并且较大的 imcTG 池会导致 imcTG 氧化加速，从而干扰肌肉葡萄糖代谢。 为了检验这些假设，将追求三个具体目标来回答以下问题：1）胰岛素是刺激 imcTG 合成的合成代谢激素吗？ 2) 血浆脂肪酸浓度升高是否会通过提供丰富的前体来增加 imcTG 的合成？ 3) 较大的 imcTG 库是否与 imcTG 脂肪酸的加速氧化相关，如果是，这如何影响肌肉葡萄糖代谢？一种新的单池模型将用于在控制胰岛素和脂肪酸水平的情况下，直接确定因高脂肪喂养而肥胖的大鼠的 imcTG 合成、周转和氧化速率（肌肉活检）。将使用多种示踪剂测定imcTG脂肪酸的氧化和肌肉葡萄糖摄取、糖酵解和糖原合成，以确定imcTG氧化对葡萄糖代谢的影响。 稳定同位素示踪剂 (13C) 和质谱（GC/MS 和同位素比 MS）将用于定量动力学。 这些研究旨在回答以下问题：增大的 imcTG 是否是一种对葡萄糖代谢产生负面影响的化学实体，以及血浆胰岛素和脂肪酸是否与 imcTG 增加有关，如果是，又是如何造成的。 因此，拟议的研究将增进对肥胖大鼠胰岛素抵抗和 imcTG 异常机制的理解，这将有利于人类肥胖的研究。