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，酗酒会导致神经系统中主要多不饱和的二十六烯酸酯（DHA）损失。这些损失导致多巴胺能神经传递的缺陷，并且可能导致CRH神经传递中的过量，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。残留的发育缺陷包括较低的智商，多动症风险和行为障碍。这种表型的特征是不利发展轨迹的特征，以增加滥用药物的风险。 但是，omega-3高度不饱和脂肪（N-3 HUFA）的组织缺陷也可能是由欧米茄6脂肪（特别是亚油酸）饮食摄入过量引起的。 在动物和人类试验的投资组合中，我们评估了降低omega-6脂肪酸亚油酸饮食摄入量对升高长链omega-3脂肪酸eicosapentaenoic eicososapentaenoic and docosahecosahecahecaenoic酸的饮食摄入量的影响。 在20世纪，Omega-6脂肪的饮食摄入量急剧增加。亚油酸从大约1％的能量增加到超过8％的能量。我们在动物研究中对这些变化进行了建模，发现降低亚油酸摄入量会降低过度水平的内源性大麻素（例如分子）。 尽管动物消耗了高脂肪饮食（60％EN），但减少亚油酸摄入量也逆转了肥胖，即使在低脂肪饮食中也能够诱导肥胖症（212％EN）。这项研究提供了一个关键的框架，可通过减少其前体分子的饮食摄入来减少内源性大麻素活性。 因此，在三项人类临床试验中评估了降低omega-6脂肪酸亚油酸。 1）在患有慢性每日头痛的受试者中，选择性降低亚油酸和亚油酸与升高EPA和DHA摄入量的降低，磷脂中的蛛网膜含量降低，血清中的EPA和DHA升高。 这些变化导致头痛的严重程度和持续时间降低了50％。 2）最佳Omega-3试验是与DOD营养局USARIEM的合作。 首先，我们将降低亚油酸的原理转化为富含omega-3脂肪的家禽肉（和鸡蛋）的产生，并具有明显降低的omega-6脂肪。 这些高度丰富的食品将取代美国驻军食品产品中使用的食谱中的标准商品食品。 3）第三个人类方案在NIH临床中心内是活跃的，以评估选择性亚油酸降低对降低超重女性肥胖的影响。 该协议将选择性地将摄入量降低到大约1 en％。 这些饮食变化有望降低过度的内源性大麻素水平，改善饱腹感并导致体重和脂肪损失。 Omega-3α亚麻酸（D5）对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有害还是有益。美国心脏协会特别建议消耗至少5％至10％的能源作为Omega-6 PUFA，基于将N-3/N-6 PUFA混合的随机对照试验（RCT）和其CHD结果的荟萃分析的随机对照试验（RCT）。 为了更好地评估这些研究，我们：进行了广泛的文献搜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为22％（RR = 0.78 95％CI 0.65-0.93），而N-6特定PUFA饮食的风险增加了13％（RR = 1.13 95％CI 0.84-1.53​​）。 与混合N-3/N-6饮食相比，N-6特异性PUFA中非致命MI + CHD死亡的风险明显更高（Q-Statistic = 5.44，DF = 1，P = 0.02）。 将N-6 PUFA代替反式和饱和脂肪酸而不同时增加N-3 PUFA的RCT产生的死亡风险增加了统计学意义（RR = 1.16 95％CI 0.95-1.42）。 我们发现，基于混合N-3/N-6 RCT数据，特别增加N-6 PUFA摄入量的建议可能会增加CHD风险。 1966 - 1973年进行的悉尼饮食心脏研究是独一无二的，因为它是针对N-6多不饱和脂肪亚油酸（LA）而不是饱和脂肪的干预措施。从悉尼饮食心脏研究中仔细评估恢复的数据表明，没有迹象表明升高LA摄入量高于6 EN％的心血管益处。 相比之下，悉尼饮食心脏研究中，冠心病和全因死亡率死亡的风险显着增加。因此，从可用的RCT数据中，将LA摄入量的增加到6％以上似乎可能会增加冠心病和死亡的风险。 一个单独的但相关的研究线是评估遗传变异对基本脂肪CID前体代谢对其高度不饱和产物的代谢的影响。 FADS 1-2基因复合物中的遗传变异被认为会影响18种碳脂肪，ALA和LA对其各自的产物AA和EPA/DHA的能力。 Caspi等人的一项研究表明，FADS2基因内的RS174575 rs174575调节了这种效果，因此在次要等位基因（GG基因型）中纯合子（GG基因型）具有相似的智商，而与乳腺癌或喂养方法无关。母乳含有预制的DHA，而婴儿配方则没有。 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，使母乳喂养的GG儿童的表现要比其配方奶粉喂的更好的对应物的5.8点1.4、10.1（相互作用p 0.0091）。调整了7个因素后，相互作用的结果减弱了约10％。 我们评估了来自4342名孕妇的血液样本数据，3343条脐带反映了新生儿血液供应和5240名7岁儿童，以调查多不饱和脂肪酸与Rs1535和Rs174575的多不饱和脂肪酸的关联。我们比较了FADS2基因对三个时间点的脂肪酸谱的两种多态性的影响：母亲怀孕期间，新生儿出生时，在7岁时对孩子。在所有三个数据集中，这两个遗传变异与本研究中报告的大多数多不饱和FA都有很强的关联。这些结果与次要等位基因与较低的活性相关，导致产品量减少，但无代谢前体的量增加。 在这一人群中，我们还研究了2839年母子对之间的红细胞孕产妇脂肪酸与8岁的儿童智商之间的关联。最强的关联是比较了奥斯本酸（22：5n -6）和较低的言语智商的最高四分位数，-2.26点95％CI -3.72，-0.8; p <0.003和DHA（22：6n-3）的最低四分位数，较低的全尺度IQ，-1.6分95％CI -3.0，-0.1; p <0.033。 使用线性回归。这些发现与这样的解释是一致的：在DHA功能不全期间，互相替代了Osbond Acid，对于神经发育而言是最佳的。