Nutritional Effects On Essential Fatty Acid Composition

营养对必需脂肪酸组成的影响

• 批准号: 8746462
• 负责人: Joseph Hibbeln
• 金额: $ 97.19万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8746462
• 关键词: 7 year old; 8 year old; Acids; Adipose tissue; Aging; Alcohol abuse; Alcoholism; Alcohols; Alleles; American Heart Association; Animal Model; Animals; Arachidonic Acids; Attention deficit hyperactivity disorder; Attenuated; Biological Process; Birth; Blood specimen; Brain; Breast; Breast Feeding; CRH gene; Cannabinoids; Carbon; Cardiovascular system; Cessation of life; Characteristics; Child; Chronic; Chronic Daily Headaches; Clinical; Clinical Trials; Collaborations; Complex; Consumption; Coronary heart disease; Data; Data Set; Desire for food; Development; Diet; Dietary Supplementation; Dietary intake; Disease; Disease model; Docosahexaenoate; Docosahexaenoic Acids; Domestic Fowls; Eicosapentaenoic Acid; Endocannabinoids; Erythrocytes; Essential Fatty Acids; Evaluation; Fat-Restricted Diet; Fatty Acids; Fatty acid glycerol esters; Feeding Methods; Food; Fortified Food; Genes; Genetic Polymorphism; Genotype; Headache; Health; Health Benefit; Heart; Human; Human Milk; Infant formula; Infusion procedures; Intake; Intervention; Investigation; Lead; Linear Regressions; Linoleic Acids; Meat; Meta-Analysis; Metabolism; Minor; Modeling; Mothers; Myocardial Infarction; N-3 polyunsaturated fatty acid; Nervous system structure; Neurophysiology - biologic function; Newborn Infant; Nutrient; Nutritional; Nutritional Study; Obesity; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Organ; Outcome; Overweight; Pathology; Phospholipids; Polyunsaturated Fatty Acids; Population; Pregnancy; Pregnant Women; Production; Protocols documentation; Psyche structure; Randomized Controlled Trials; Recipe; Reporting; Residual state; Risk; Risk Reduction; Satiation; Saturated Fatty Acids; Serum; Severities; Substance abuse problem; Supplementation; Time; Tissues; Translating; Umbilical cord structure; United States National Institutes of Health; Unsaturated Fats; Unsaturated Fatty Acids; Vascular blood supply; Weight; Woman; addiction; alpha-Linolenic Acid; base; egg; fatty acid metabolism; feeding; genetic variant; improved; interest; mortality; neonate; neurodevelopment; neuropsychiatry; neurotransmission; nutrition; obesity risk; offspring; polyunsaturated fat; prevent; saturated fat; statistics; text searching

Our past studies have indicated that alcohol abuse leads to a loss of docosahexaenoate (DHA), the major polyunsaturate in the nervous system. These losses contribute to deficits in dopaminergic neurotransmission and likely to excesses in CRH neurotransmission which are characteristic of states of chronic addiction. Nutritional inadequacies, particularly during early development, may also lead to such losses in this essential fatty acid. Residual developmental deficits include lower IQ, risk for ADHD and conduct disorders. This phenotypic profile is characteristic of an adverse developmental trajectory towards increased risk of substance abuse. However, tissue deficits of omega-3 highly unsaturated fats (n-3 HUFAs) may also be caused by excess dietary intakes of omega-6 fats, in particular linoleic acid. In a portfolio of animal and human trials, we have evaluated the effects of lowering dietary intakes of the omega-6 fatty acid linoleic acid on elevating endogenous production of the long chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid. During the 20th century dietary intakes of omega-6 fats increased dramatically. Linoleic acid increased from approximately 1 % of energy to more than 8 % of energy. We modeled these changes in animal studies and found that lowering linoleic acid intakes reduced excessive levels of endogenous cannabinoid like molecules. Reducing the linoleic acid intake reversed obesity, despite animals consuming a high fat diet (60 %en) and was able to induce obesity even in low fat diets (212% en). This study provides a critical framework for reducing excessive endocannabinoid activity by reducing dietary intake of their precursor molecules. Thus, lowering the omega-6 fatty acid linoleic acid, is being evaluated in three human clinical trials. 1)Among subjects with chronic daily headache, selective lowering of linoleic acid, and linoleic acid lowering in conjunction with elevating EPA and DHA intakes, reduced arachidonic acid in phospholipids and elevated EPA and DHA in serum. These changes caused a 50% reduction in headache severity and duration. 2) The Optimal Omega-3 trial is a collaboration with the DOD nutrition directorate, USARIEM. First we have translated the principle of linoleic lowering to the production of poultry meat (and eggs) enriched in omega-3 fats with significantly reduced omega-6 fats. These highly enriched food stuffs will replace standard commodity foods in recipes used in the US garrison food lines. 3) A third human protocol is active within the NIH Clinical Center to evaluate the effects of selective linoleic acid lowering on reducing adiposity among overweight women. The protocolwill selectively lowering intake to approximately 1 en%. These dietary changes are expected to reduce excessive endocannabinoid levels, improve satiety and results in weight and adipose loss. Elongation and desaturation of the omega-3 alpha linolenic acid (d5) to EPA and DHA will be quantified using steady state infusion and GC- MS/MS/MS quantification. Since linoleic acid is a polyunsaturated fat, it has been critical to determine if advice to reduce intake might be harmful or beneficial. The American Heart Association has specifically advised consumption of at least 5 to 10% of energy as omega-6 PUFAs substantially based on randomized controlled trials (RCTs) of mixed n-3/n-6 PUFAs and meta-analyses of their CHD outcomes. To better evaluate these studies we: conducted an extensive literature search and performed a meta-analysis. For non-fatal myocardial infarction (MI) + CHD death, the pooled risk reduction for mixed n-3/n-6 PUFA diets was 22% (RR=0.78 95%CI 0.65-0.93), compared to an increased risk of 13% for n-6 specific PUFA diets (RR=1.13 95%CI 0.84-1.53). Risk of non-fatal MI + CHD death was significantly higher in n-6 specific PUFA compared to mixed n-3/n-6 diets (Q-statistic=5.44, df =1, p=0.02). RCTs that substituted n-6 PUFAs for trans and saturated fatty acids without simultaneously increasing n-3 PUFAs produced an increase in risk of death that approached statistical significance (RR=1.16 95%CI 0.95-1.42). We found that advice to specifically increase n-6 PUFA intake, based on mixed n-3/n-6 RCT data, is likely to increase CHD risk. The Sydney Diet Heart Study, conducted from 1966-1973 was unique as it was an intervention specifically with the n-6 polyunsaturated fat linoleic acid (LA) in place of saturated fats. Careful evaluation of recovered data from the Sydney Diet Heart Study show no indication of cardiovascular benefit from elevating dietary intake of LA above 6 en%. By contrast, there was a significant increased risk of death from coronary heart disease and all-cause mortality in the Sydney Diet Heart Study. Thus, from the available RCT data, increasing LA intakes above 6 en% appears likely to increase the risk of coronary heart disease and death. A separate but related line of investigation has been to evaluate the impact of genetic variants in the metabolism of essential fatty cid precursors to their highly unsaturated products. Genetic variants in the FADS 1-2 gene complex are thought to influence the ability to desaturate 18 carbon fats, ALA and LA to their respective products AA and EPA/DHA. A study by Caspi et al has suggested that rs174575 within the FADS2 gene moderates this effect so that children homozygous in the minor allele (GG genotype) have similar IQs irrespective of breast or feeding method. Breast milk contains preformed DHA whereas infant formula did not. In our study of 5934 children aged 8 years, an interaction with this polymorphism was observed such that breastfed GG children performed better than their formula fed counterparts by an additional 5.8 points 1.4, 10.1 (interaction p 0.0091). Interaction results were attenuated by about 10% after adjustment for 7 factors. We evaluated data from blood samples for 4342 pregnant women, 3343 umbilical cords reflecting the newborns blood supply and 5240 children aged 7 years to investigate the associations of polyunsaturated fatty acids with rs1535 and rs174575 two polymorphisms in the FADS2 gene. We compared the effect of two polymorphisms in the FADS2 gene on fatty acid profiles at three time points: during pregnancy for the mother, at birth for the neonate and at 7 years old for the child. In all three datasets, the two genetic variants had strong associations with most of the polyunsaturated FAs reported in this study. These results were consistent with the minor allele being associated with lower activity leading to reduced amounts of the products but increased amounts of the unmetabolised precursors. In this population we also investigated associations between erythrocyte maternal fatty acids in pregnancy and child IQ at 8y amongst 2839 mother-child pairs. The strongest association was comparing the highest quartile of osbond acid (22:5n-6) and lower verbal IQ, -2.26 points 95% CI -3.72, -0.8; p<0.003 and the lowest quartile of DHA (22:6n-3) with lower full scale IQ, -1.6 points 95% CI -3.0, -0.1; p<0.033. using linear regression. These findings are consistent with the interpretation that during DHA insufficiency, with reciprocal replacement with osbond acid is suboptimal for neural development.

我们过去的研究表明，酗酒会导致二十二碳六烯酸 (DHA) 的损失，二十二碳六烯酸 (DHA) 是神经系统中主要的多不饱和脂肪酸。这些损失导致多巴胺能神经传递缺陷，并可能导致 CRH 神经传递过度，这是慢性成瘾状态的特征。营养不足，特别是在早期发育期间，也可能导致这种必需脂肪酸的损失。残余发育缺陷包括智商较低、多动症风险和品行障碍。这种表型特征是药物滥用风险增加的不利发育轨迹的特征。 然而，Omega-3 高度不饱和脂肪 (n-3 HUFA) 的组织缺陷也可能是由于饮食中过量摄入 Omega-6 脂肪（特别是亚油酸）造成的。 在一系列动物和人体试验中，我们评估了降低 omega-6 脂肪酸亚油酸饮食摄入量对提高长链 omega-3 脂肪酸二十碳五烯酸和二十二碳六烯酸内源性产量的影响。 20 世纪，膳食中 omega-6 脂肪的摄入量急剧增加。亚油酸从约 1% 的能量增加到超过 8% 的能量。我们在动物研究中模拟了这些变化，发现降低亚油酸摄入量可以减少内源性大麻素样分子的过量水平。 尽管动物食用高脂肪饮食（60%en），但减少亚油酸摄入量可以逆转肥胖，并且即使在低脂肪饮食中也能诱发肥胖（212%en）。这项研究为通过减少膳食中前体分子的摄入量来减少过度的内源性大麻素活性提供了一个关键框架。 因此，三项人体临床试验正在评估降低 omega-6 脂肪酸亚油酸的效果。 1)在患有慢性每日头痛的受试者中，选择性降低亚油酸，以及降低亚油酸与增加EPA和DHA摄入量相结合，导致磷脂中花生四烯酸减少，血清中EPA和DHA升高。 这些变化使头痛的严重程度和持续时间减少了 50%。 2) Optimal Omega-3 试验是与国防部营养局 USARIEM 合作进行的。 首先，我们将降低亚油酸的原理转化为富含 omega-3 脂肪且显着减少 omega-6 脂肪的家禽肉（和蛋）的生产。 这些高度浓缩的食品将取代美国驻军食品生产线中使用的食谱中的标准商品食品。 3) NIH 临床中心正在开展第三项人类方案，以评估选择性降低亚油酸对减少超重女性肥胖的影响。 该方案将选择性地将摄入量降低至约 1 en%。 这些饮食变化预计将减少过量的内源性大麻素水平，提高饱腹感，并导致体重和脂肪减少。 omega-3 α 亚麻酸 (d5) 向 EPA 和 DHA 的伸长和去饱和将使用稳态输注和 GC-MS/MS/MS 定量进行定量。 由于亚油酸是一种多不饱和脂肪，因此确定减少摄入量的建议是否有害或有益至关重要。美国心脏协会特别建议摄入至少 5% 至 10% 的 omega-6 PUFA 能量，主要基于混合 n-3/n-6 PUFA 的随机对照试验 (RCT) 及其 CHD 结局的荟萃分析。 为了更好地评估这些研究，我们：进行了广泛的文献检索并进行了荟萃分析。 对于非致命性心肌梗死 (MI) + CHD 死亡，混合 n-3/n-6 PUFA 饮食的汇总风险降低了 22% (RR=0.78 95%CI 0.65-0.93)，而风险增加了 13% n-6 特定 PUFA 饮食的百分比 (RR=1.13 95%CI 0.84-1.53​​)。 与混合 n-3/n-6 饮食相比，n-6 特定 PUFA 的非致命性 MI + CHD 死亡风险显着更高（Q 统计量 = 5.44，df = 1，p = 0.02）。 用 n-6 PUFA 替代反式和饱和脂肪酸而不同时增加 n-3 PUFA 的随机对照试验导致死亡风险增加，达到统计学显着性 (RR=1.16 95%CI 0.95-1.42)。 我们发现，根据混合 n-3/n-6 RCT 数据，专门增加 n-6 PUFA 摄入量的建议可能会增加冠心病风险。 1966 年至 1973 年进行的悉尼饮食心脏研究是独一无二的，因为它是专门用 n-6 多不饱和脂肪亚油酸 (LA) 代替饱和脂肪的干预措施。对悉尼饮食心脏研究恢复数据的仔细评估表明，没有迹象表明将 LA 的饮食摄入量提高到 6 en% 以上对心血管有益。 相比之下，悉尼饮食心脏研究显示，冠心病死亡风险和全因死亡率显着增加。因此，从现有的 RCT 数据来看，将 LA 摄入量增加到 6 en% 以上似乎可能会增加冠心病和死亡的风险。 一项单独但相关的研究路线是评估遗传变异对必需脂肪酸前体代谢为其高度不饱和产物的影响。 FADS 1-2 基因复合体中的遗传变异被认为影响将 18 碳脂肪、ALA 和 LA 去饱和为其各自产物 AA 和 EPA/DHA 的能力。 Caspi 等人的一项研究表明，FADS2 基因内的 rs174575 可以缓和这种效应，因此，无论母乳或喂养方式如何，次要等位基因（GG 基因型）纯合子的儿童都具有相似的智商。母乳含有预先形成的 DHA，而婴儿配方奶粉则不含。 在我们对 5934 名 8 岁儿童的研究中，观察到与这种多态性的相互作用，使得母乳喂养的 GG 儿童的表现比配方奶喂养的儿童多出 5.8 分 1.4, 10.1（交互作用 p = 0.0091）。调整7个因素后，交互结果衰减了约10%。 我们评估了 4342 名孕妇的血液样本、3343 条反映新生儿血液供应的脐带和 5240 名 7 岁儿童的血液样本数据，以研究多不饱和脂肪酸与 FADS2 基因中 rs1535 和 rs174575 两个多态性的关联。我们比较了 FADS2 基因中的两种多态性对三个时间点脂肪酸谱的影响：母亲怀孕期间、新生儿出生时和孩子 7 岁时。在所有三个数据集中，这两种遗传变异与本研究中报告的大多数多不饱和 FA 都有很强的相关性。这些结果与次要等位基因与较低的活性相关，导致产物的量减少，但未代谢的前体的量增加。 在这个人群中，我们还研究了 2839 对母子对妊娠期红细胞母体脂肪酸与 8 岁时儿童智商之间的关联。最强的关联是比较 Osbond 酸的最高四分位数 (22:5n-6) 和较低的语言智商，-2.26 分 95% CI -3.72，-0.8； p<0.003，DHA 的最低四分位数 (22:6n-3) 具有较低的满量程 IQ，-1.6 点 95% CI -3.0，-0.1； p<0.033。 使用线性回归。这些发现与以下解释一致：在 DHA 不足期间，用奥斯邦德酸相互替代对于神经发育来说不是最理想的。