Dietary fat, lipoproteins, and lipopolysaccharide: role in insulin resistance

膳食脂肪、脂蛋白和脂多糖：在胰岛素抵抗中的作用

• 批准号: 8835108
• 负责人: Philip A Kern
• 金额: $ 18.8万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835108
• 关键词: Abbreviations; Adipose tissue; Aftercare; Antibiotic Therapy; Antibiotics; Area Under Curve; Bacteria; Binding; Biopsy; Chronic; Chylomicrons; Diabetes Mellitus; Diet; Dietary Fats; Endotoxins; Euglycemic Clamping; Exposure to; Extracellular Matrix; Fasting; Fatty acid glycerol esters; Germ-Free; Glucose Clamp; Health; Hepatic; Human; Immune system; Inflammation; Inflammatory; Infusion procedures; Insulin; Insulin Resistance; Intervention; Limulus; Link; Lipids; Lipolysis; Lipopolysaccharides; Lipoproteins; Literature; Liver; Measures; Metabolic syndrome; Methods; Mus; Muscle; Nonesterified Fatty Acids; OGTT; Obesity; Peripheral; Plasma; Play; Process; Reaction; Research; Rodent; Role; Safety; Serum amyloid A protein; Techniques; Testing; Tissues; Transplantation; Triglycerides; bacterial resistance; gut microbiota; immunoregulation; improved; insulin sensitivity; lipopolysaccharide-binding protein; lipoprotein lipase; particle; research study; rifaximin

DESCRIPTION (provided by applicant): Obesity is associated with insulin resistance and chronic inflammation in adipose tissue, muscle and liver and the mechanisms underlying this inflammation is not well understood. Endotoxin (lipopolysaccharide, LPS) is carried on gut-derived lipoproteins (chylomicrons) and provides a link between dietary fat and inflammation. During chylomicrons assembly, LPS and LPS binding protein (LBP) are attached to the particle. Plasma LPS in the chylomicron fraction transiently increases following a fatty meal. Chylomicron triglyceride is cleared from plasma by adipose and muscle lipoprotein lipase (LpL); remnant lipoproteins are then cleared by the liver. Strong associations between insulin resistance/diabetes and plasma LPS have been found. Further links between gut bacteria and insulin resistance are illustrated by many experiments in germ-free mice or in mice with microbiota transplants, which show changes in diet-induced obesity and insulin resistance. We hypothesize that the LPS on chylomicrons is delivered to adipose tissue, muscle and liver during chylomicron TG lipolysis, and the released LPS initiates a low-grade inflammatory reaction in these tissues that contributes to tissue inflammation and insulin resistance. A slow process of chylomicron lipolysis, with persistent remnant lipoproteinemia, may be associated with high exposure to LPS and consequent tissue inflammation. There is already an extensive literature in rodents demonstrating alterations in obesity, inflammation and insulin resistance with various immune modulations or manipulations of microbiota. These questions have not been well tested in humans. This study is intended to determine whether alteration of gut microbiota can impact human lipoprotein associated LPS and insulin resistance. Specific Aim 1. We will determine whether an alteration in the gut microbiota achieved with rifaximin will decrease circulating LPS. We will measure plasma LPS both in the fasting state and after a lipid-rich meal in obese MetS subjects. The subjects will then be treated with the antibiotic rifaximin for 8 weeks to substantially reduce gut bacteria, which can be detected by current techniques. Specific Aim 2. We will determine whether a change in the gut microbiota from rifaximin treatment will decrease adipose inflammation and improve insulin resistance. Subjects will undergo a baseline fat biopsy and a euglycemic clamp to measure peripheral and hepatic insulin sensitivity. They will then be treated with rifaximin and the insulin sensitivity testing ad biopsies will be repeated to determine if disruption of the microbiota reduces tissue inflammation and improves insulin sensitivity.

描述(申请人提供)：肥胖与胰岛素抵抗和脂肪组织、肌肉和肝脏的慢性炎症有关，这种炎症的机制尚不清楚。内毒素(脂多糖，LPS)由肠道来源的脂蛋白(乳糜粒)携带，在饮食脂肪和炎症之间提供联系。在乳胶粒的组装过程中，脂多糖和脂多糖结合蛋白(LBP)被附着在颗粒上。在吃了一顿肥胖餐后，乳糜粒部分的血浆内毒素会短暂升高。乳糜米隆甘油三酯被脂肪和肌肉脂蛋白脂酶(LPL)从血浆中清除；残留的脂蛋白随后被肝脏清除。胰岛素抵抗/糖尿病与血浆内毒素之间有很强的相关性。肠道细菌和胰岛素抵抗之间的进一步联系被在无菌小鼠或有微生物区系移植的小鼠身上的许多实验所阐明，这些实验表明饮食诱导的肥胖和胰岛素抵抗发生了变化。我们假设乳糜微粒上的内毒素在乳糜微粒甘油三酯脂解过程中被传递到脂肪组织、肌肉和肝脏，释放的内毒素在这些组织中启动了一种低级别的炎症反应，从而导致组织炎症和胰岛素抵抗。乳糜粒脂肪分解的缓慢过程，伴随着持续的残余脂蛋白血症，可能与高暴露于脂多糖和随后的组织炎症有关。已经有大量关于啮齿动物的文献表明，通过各种免疫调节或微生物区系的操纵，肥胖、炎症和胰岛素抵抗会发生变化。这些问题还没有在人类身上得到很好的测试。本研究旨在确定肠道微生物区系的改变是否会影响人类脂蛋白相关的内毒素和胰岛素抵抗。具体目标1。我们将确定利福昔明对肠道微生物区系的改变是否会减少循环中的内毒素。我们将测定肥胖的METS受试者在空腹状态和高脂饮食后的血浆内毒素水平。然后，受试者将接受为期8周的抗生素利福昔明治疗，以大幅减少肠道细菌，目前的技术可以检测到这种细菌。具体目的2。我们将确定利福昔明治疗后肠道微生物区系的改变是否会减少脂肪炎症和改善胰岛素抵抗。受试者将接受基线脂肪活检和正常血糖钳夹以测量外周和肝脏的胰岛素敏感性。然后他们将接受利福昔明治疗，胰岛素敏感性测试和活组织检查将重复，以确定破坏微生物区系是否减少组织炎症并改善胰岛素敏感性。