Regional Fatty Acid Metabolism In Humans

人类的区域脂肪酸代谢

• 批准号: 8755927
• 负责人: MICHAEL D. JENSEN
• 金额: $ 56.09万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8755927
• 关键词: 1,2-diacylglycerol; Acute; Acyl Coenzyme A; Address; Adipocytes; Adipose tissue; Adult; Affect; Burn injury; CD36 gene; Carnitine; Cell Size; Central obesity; Ceramides; Clinical Trials; Defect; Diglycerides; Disease; Emulsions; Family; Family member; Fat emulsion; Fatty Acids; Fatty acid glycerol esters; Funding; Health; Homozygote; Human; Infusion procedures; Insulin; Insulin Resistance; Insulin Signaling Pathway; Intravenous; Knock-out; Link; Lipids; Lipolysis; Liquid Chromatography; Liver; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Methods; Mitochondria; Monitor; Mono-S; Muscle; Muscle Cells; Muscle function; Mutation; Nicotinic Acids; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Palmitates; Pathway interactions; Phenotype; Physiological; Plasma; Positron-Emission Tomography; Proteins; Reporting; Research; Signal Transduction; Signaling Molecule; Techniques; Testing; Tissues; Tracer; Triglycerides; Variant; acylcarnitine; base; fatty acid metabolism; fatty acid transport; glucose disposal; glucose metabolism; glucose uptake; improved; in vivo; insight; insulin sensitivity; insulin signaling; interest; liquid chromatography mass spectrometry; novel; novel strategies; oxidation; palm oil; public health relevance; response; stable isotope; sugar; tandem mass spectrometry; trafficking; uptake; volunteer

DESCRIPTION (provided by applicant): The long-term objective of our research is to understand the mechanisms by which obesity, and specifically upper body obesity, causes insulin resistance and the other health problems such as Type 2 Diabetes. Our focus has been on regional adipose tissue lipolysis and fat storage, as well as FFA released as a result of lipolysis affect the functioning of other tissues (lipotoxicity). The specific aims of this proposa are to: 1) assess the contribution of plasma FFA and muscle FFA uptake to the intramyocellular lipid metabolites (ceramides and diacylglycerols - DG) most closely linked to impaired activation of insulin signaling pathways in muscle and reduced glucose uptake; 2) define the improvements in muscle FFA uptake and FFA incorporation into intramyocellular lipid metabolites associated with improved activation of insulin signaling pathways and muscle glucose uptake following overnight suppression of FFA with intravenous niacin in UBO and T2DM; 3) measure the effects of sub-acute, moderate elevations of physiological FFA on muscle lipid metabolite trafficking, insulin signaling and muscle glucose uptake in healthy, non-obese adults. We will measure insulin stimulated glucose disposal (muscle glucose uptake) and muscle insulin signaling in obese humans with widely varying degrees of insulin resistance. We will also measure muscle FFA uptake as a function of FFA concentrations using 11C-palmitate PET scan approaches to understand if variations in muscle FFA uptake beyond those predicted by concentration contributes to greater lipotoxicity. We also measure muscle FFA trafficking using will use stable isotope/mass spectrometry approaches to determine how FFA are trafficked into long chain acyl-CoA, DG, TG, ceramides and long chain acyl-carnitines in muscle of these same volunteers. Our hypothesis is that trafficking of FFA into ceramides and/or DG, specifically subsarcolemmal lipids, is more closely linked with muscle insulin resistance. We will also test how lowering of FFA by an overnight, intravenous niacin infusion alters intramyocellular FFA trafficking and insulin action. Finally, by raising FFA via a duodenal infusion of palm oil vs. Intralipid(R), we will test whether a physiological elevation of FFA (as opposed to isolated increases in polyunsaturated FFA) mimics the muscle trafficking profile of insulin resistant obesity. Combined, we believe these studies will offer insights as to why some obesity phenotypes have even more variability in muscle insulin action than would be predicted based solely upon plasma FFA concentrations.

描述（由申请人提供）：我们研究的长期目标是了解肥胖，尤其是上身肥胖的机制，会引起胰岛素抵抗和其他健康问题，例如2型糖尿病。我们的重点一直放在区域脂肪组织脂解和脂肪储存上，以及脂肪分解释放的FFA会影响其他组织的功能（脂肪毒性）。该提议的具体目的是：1）评估血浆FFA和肌肉FFA摄取对肌肉和减少肌肉和减少胰岛素胰岛素信号途径激活的胰岛素信号途径的激活最密切相关的血浆中细胞内脂质代谢物（Ceramides和dicyl -Glycerols -DG）的贡献； 2）定义肌肉FFA吸收和FFA掺入中的肌肉内脂质代谢产物的改善，与改善胰岛素信号通路和肌肉葡萄糖在UBO和T2DM中用静脉NIAICIN NIACIN的抗体抑制后，胰岛素信号通路和肌肉葡萄糖吸收的激活相关； 3）测量急性，生理FFA中等升高对健康的非肥胖成年人中肌肉脂质代谢物运输，胰岛素信号传导和肌肉葡萄糖摄取的影响。我们将测量胰岛素刺激的葡萄糖处置（肌肉葡萄糖摄取）和肥胖人的肌肉胰岛素信号传导，胰岛素抵抗程度差异很大。我们还将使用11C-膜酸PET扫描方法测量肌肉FFA摄取作为FFA浓度的函数，以了解超出浓度预测的肌肉FFA摄取的变化是否有助于更大的脂肪毒性。我们还使用稳定的同位素/质谱方法来测量肌肉FFA运输，以确定如何将FFA投入长链酰基-COA，DG，TG，TG，CERAMIDES和长链酰基carnitines中的肌肉中。我们的假设是，将FFA运输到神经酰胺和/或DG，特别是肾小球脂质中，与肌肉胰岛素抵抗更加紧密相关。我们还将测试通过一夜之间的静脉烟酸输注来降低FFA的降低，从而改变了细胞内FFA的运输和胰岛素作用。最后，通过通过十二指肠输注棕榈油与脂质内（R）提高FFA，我们将测试FFA的生理升高（与多不饱和FFA的孤立增加相反）是否模仿了胰岛素耐药性肥胖的肌肉贩运曲线。结合在一起，我们认为这些研究将提供有关为什么某些肥胖表型在肌肉胰岛素作用中具有比仅基于血浆FFA浓度预测的更可变性的见解。