Metabolic Actions of Omega-3 Fatty Acids on Inflammation

描述（申请人提供）：临床研究表明，海洋来源的ω-3多不饱和脂肪酸（PUFA）、二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）改善代谢综合征（MetS）的高甘油三酯（TG）和血压（BP）成分，还减少细胞因子;然而，我们并不知道有任何研究已经检查了超重男性和女性代谢综合征患者这些影响的潜在机制。在评估EPA/DHA补充剂对脂质代谢的少数人体研究中，大多数是在正常体重或非高TG受试者中进行的短期研究，并且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，EPA/DHA补充不仅会降低血浆TG，而且会降低全身和组织炎症、胰岛素抵抗（HOMA-IR）、脂肪组织脂解和细胞因子释放，以增强脂肪组织的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摄取和储存中更有效地发挥作用，从而减少循环FFA和细胞因子。我们进一步假设，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，这是一种有趣的新结果，为9个月治疗计划提供了依据。这项R21提案的目的是在患有代谢综合征的成年人中进行一项为期9个月的试点随机试验，比较EPA/DHA与ALA补充剂对1）代谢（例如，脂蛋白、炎性细胞因子、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解（ED 50）、细胞因子释放和脂肪生成），和2）局部脂肪分布，其通过CT扫描定量为内脏和皮下脂肪体积和肌肉脂质积累，通过双能吸收测定法（DXA）定量为身体组成（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，使用新的研究设计和方法来检查临床/治疗问题，这些研究设计和方法将确定omega-3 PUFA（EPA，DHA和ALA）补充剂影响脂肪细胞生物学，以减少MetS成人中的炎症，脂解，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补充剂的疗效，无论是单独使用还是与其他药物联合使用，以降低TG，全身炎症，胰岛素抵抗和CVD风险。 公共卫生相关性：代谢综合征增加了心脏病的风险，目前在美国处于流行病的比例。它由以下3个组成：中心性肥胖、高甘油三酯、低HDL、血压异常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，但所涉及的机制还不清楚。因此，该提案将通过将其与非鱼油omega-3补充剂（亚麻酸）进行比较，研究omega-3鱼油如何影响炎症，脂质和脂肪分解。这项研究的有利结果可以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.