Metabolic Actions of Omega-3 Fatty Acids on Inflammation

描述(申请人提供)：临床研究表明，海洋衍生的omega-3多不饱和脂肪酸(PUFAs)、二十碳五酸(EPA)和二十二碳六烯酸(DHA)可以改善代谢综合征(METS)的高甘油三酯(TG)和血压(BP)成分，并减少细胞因子；然而，我们还不知道有任何研究探讨了患有METS的超重男性和女性产生这些影响的机制。在少数评估EPA/DHA补充剂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，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。我们推测，补充EPA/DHA不仅可以降低血浆甘油三酯，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，从而提高脂肪组织的甘油三酯储存能力。炎症的减轻和胰岛素敏感性的增加将重塑脂肪组织，使其更有效地吸收和储存甘油三酯，从而减少循环中的游离脂肪酸和细胞因子。我们进一步推测，这些代谢效应可能会减少内脏(腹内脂肪和肌肉)中的异位脂肪沉积，这是一个有趣的、新的结果，为9个月的治疗计划提供了理论基础。该R21建议的目的是在患有蛋氨酸的成年人中进行一项为期9个月的试验性随机试验，比较EPA/DHA和ALA对1)代谢(例如脂蛋白、炎性细胞因子、急性时相反应物、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解(ED50)、细胞因子释放和脂肪生成)和2)区域脂肪分布(CT扫描定量为内脏和皮下脂肪体积，肌肉脂肪堆积)和身体组成(总脂肪质量和局部脂肪质量)的影响。这项建议利用NIDDK-营养性肥胖研究中心脂蛋白代谢、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的合作，利用一项新颖的研究设计和方法来研究临床/治疗问题，该研究将确定补充omega-3多不饱和脂肪酸(EPA、DHA和ALA)影响脂肪细胞生物学以减少炎症、脂肪分解、甘油三酯和异位脂肪堆积的机制。有利的结果可能转化为治疗试验，以测试EPA/DHA补充剂的有效性，无论是单独使用还是与其他药物联合使用，以降低甘油三酯、全身炎症、胰岛素抵抗和心血管疾病风险。 与公共健康相关：代谢综合征增加了心脏病的风险，目前在美国处于流行状态。它由以下3个组成部分组成：中心性肥胖、高甘油三酯、低高密度脂蛋白、异常血压和空腹血糖水平受损。以前的研究表明，omega-3鱼油可能会影响其中一些成分，但涉及的机制尚不清楚。因此，这项建议将通过将omega-3鱼油与非鱼油omega-3补充剂(亚麻酸)进行比较来研究omega-3鱼油如何影响炎症、血脂和脂肪分解。这项研究的有利结果可能转化为一种新的方法来改善患有代谢综合征的男性和女性的心脏病风险。

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.