Metabolic Actions of Omega-3 Fatty Acids on Inflammation

Omega-3 脂肪酸对炎症的代谢作用

• 批准号: 8275681
• 负责人: ANDREW P GOLDBERG
• 金额: $ 15.62万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8275681
• 关键词: Abdomen; Abdominal Muscles; Acids; Acute-Phase Proteins; Adipocytes; Adipose tissue; Adult; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Biological Markers; Blood Pressure; Body Composition; Cardiovascular Diseases; Central obesity; Characteristics; Cholesterol Esters; Clinical; Clinical Research; Collaborations; Comparative Study; Deposition; Dual-Energy X-Ray Absorptiometry; Epidemic; Epidemiologic Studies; Fasting; Fatty acid glycerol esters; Fish Oils; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Hip region structure; Human; Hypertriglyceridemia; Impaired fasting glycaemia; Inflammation; Inflammatory; Insulin; Insulin Resistance; Intra-abdominal; Investigation; Life Style; Linolenic Acids; Lipids; Lipolysis; Lipoproteins; Liver; Macronutrients Nutrition; Marines; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolic syndrome; Metabolism; Methodology; Muscle; National Institute of Diabetes and Digestive and Kidney Diseases; Nonesterified Fatty Acids; Nutraceutical; Nutritional Biochemistry; Obesity; Oils; Omega-3 Fatty Acids; Outcome; Outcome Study; Overweight; Patients; Pharmaceutical Preparations; Physiological; Plasma; Polyunsaturated Fatty Acids; Research; Research Design; Research Personnel; Risk; Supplementation; Therapeutic; Therapeutic Uses; Therapy Clinical Trials; Tissues; Translating; Triglycerides; Viscera; Visceral; Weight; Woman; X-Ray Computed Tomography; abdominal fat; adipocyte biology; alpha-Linolenic Acid; basal insulin; cardiovascular disorder risk; cytokine; efficacy testing; eicosapentanoic acid; experience; glucose tolerance; glycerol-insulin; heart disease risk; improved; insight; insulin sensitivity; lipid biosynthesis; lipid metabolism; macrophage; men; novel; novel strategies; nutrition; paracrine; particle; programs; randomized trial; response; subcutaneous; treatment planning; uptake

DESCRIPTION (provided by applicant): Clinical studies suggest that the marine-derived omega-3 polyunsaturated fatty acids (PUFAs), eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) improve high triglyceride (TG) and blood pressure (BP) constituents of the metabolic syndrome (MetS) , and also reduce cytokines; however, we are not aware of any studies that have examined the mechanisms underlying these effects in overweight men and women with MetS. Of the few human studies evaluating EPA/DHA supplementation on lipid metabolism, most were conducted for short periods in normal weight or non-hyperTG subjects and did not measure effects on adipocyte lipolysis, adipokine secretion, lipogenesis or visceral fat. We hypothesize that EPA/DHA supplementation will not only reduce plasma TG, but also decrease systemic and tissue inflammation, insulin resistance (HOMA-IR), adipose tissue lipolysis and cytokine release to enhance the TG storage capacity of adipose tissue. The reduction in inflammation and increase in insulin sensitivity will remodel adipose tissue to function more efficiently in TG uptake and storage, thus reducing circulating FFAs and cytokines. We further postulate that these metabolic effects may decrease ectopic fat deposition in viscera (intra-abdominal fat and muscle), an intriguing, novel outcome that provides rationale for the 9-month treatment plan. The Aims of this R21 proposal are to conduct a pilot, 9 month randomized trial in adults with MetS comparing the effects of EPA/DHA vs. ALA supplementation on 1) Metabolic (e.g., lipoproteins, inflammatory cytokines, acute phase reactants, glucose tolerance/insulin resistance) and adipose tissue metabolism (basal and insulin suppressed lipolysis (ED50), cytokine release and lipogenesis), and 2) Regional fat distribution quantified as, visceral and subcutaneous adipose volumes and muscle lipid accumulation by CT-scan and body composition (total and regional fat mass) by dual energy absorptiometry (DXA). This proposal capitalizes on collaboration among experienced investigators in lipoprotein metabolism, nutritional biochemistry and adipocyte biology in a NIDDK-Nutrition Obesity Research Center to examine a clinical/therapeutic question using a novel study design and methodologies that will determine the mechanisms by which omega-3 PUFA (EPA, DHA and ALA) supplementation affect adipocyte biology to reduce inflammation, lipolysis, TG and ectopic fat accumulation in adults with MetS. Favorable outcomes could translate into therapeutic trials to test the efficacy of EPA/DHA supplements, either singly or in combination with other drugs to reduce TG, systemic inflammation, insulin resistance and CVD risk. PUBLIC HEALTH RELEVANCE: The metabolic syndrome raises the risk of heart disease and is currently at epidemic proportions in the U.S. It consists of 3 of the following components: central obesity, high triglycerides, low HDL, abnormal blood pressure and impaired fasting glucose levels. Previous studies have suggested that omega-3 fish oil may influence some of these components but the mechanisms involved are not well understood. Therefore, this proposal will investigate how omega-3 fish oils affect inflammation, lipids and fat breakdown by comparing it to a non-fish oil omega-3 supplement (linolenic acid). Favorable outcomes from this study could translate into a new approach to improve heart disease risk in men and women with the metabolic syndrome.

临床研究表明，海洋来源的omega-3多不饱和脂肪酸（PUFAs）、二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）可改善代谢综合征（MetS）的高甘油三酯（TG）和血压（BP）成分，并降低细胞因子；然而，我们不知道有任何研究已经检查了这些影响在患有MetS的超重男性和女性中的潜在机制。在少数评估补充EPA/DHA对脂质代谢影响的人体研究中，大多数是在正常体重或非高tg受试者中进行的短期研究，并没有测量对脂肪细胞脂解、脂肪因子分泌、脂肪生成或内脏脂肪的影响。我们假设补充EPA/DHA不仅可以降低血浆TG，还可以减少全身和组织炎症、胰岛素抵抗（HOMA-IR）、脂肪组织脂解和细胞因子释放，从而增强脂肪组织的TG储存能力。炎症的减少和胰岛素敏感性的增加将重塑脂肪组织，使其在TG摄取和储存方面更有效地发挥作用，从而减少循环中的FFAs和细胞因子。我们进一步假设，这些代谢作用可能会减少内脏（腹内脂肪和肌肉）的异位脂肪沉积，这是一个有趣的新结果，为9个月的治疗计划提供了理论依据。该R21提案的目的是在成年met患者中进行一项为期9个月的随机试验，比较EPA/DHA和ALA补充对以下方面的影响：1)代谢（如脂蛋白、炎症细胞因子、急性期反应物、葡萄糖耐量/胰岛素抵抗）和脂肪组织代谢（基础和胰岛素抑制的脂肪分解（ED50）、细胞因子释放和脂肪生成），2)区域脂肪分布量化为：通过ct扫描测量内脏和皮下脂肪体积和肌肉脂质积累，通过双能量吸收仪（DXA）测量身体成分（总脂肪量和局部脂肪量）。该提案利用niddk营养肥胖研究中心在脂蛋白代谢、营养生物化学和脂肪细胞生物学方面经验丰富的研究人员之间的合作，利用一种新的研究设计和方法来研究一个临床/治疗问题，该研究将确定omega-3 PUFA （EPA、DHA和ALA）补充影响脂肪细胞生物学的机制，以减少成人met患者的炎症、脂肪分解、TG和异位脂肪积累。有利的结果可以转化为治疗试验，以测试EPA/DHA补充剂的功效，无论是单独使用还是与其他药物联合使用，都可以降低TG、全身炎症、胰岛素抵抗和心血管疾病的风险。