Nutritional Effects On Essential Fatty Acid Composition

营养对必需脂肪酸组成的影响

基本信息

批准号：
10267512
负责人：
Joseph Hibbeln
金额：
$ 33.47万
依托单位：
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
依托单位国家：
美国
项目类别：
财政年份：
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/10267512
关键词：
Adipose tissue Aging Alcohol abuse Alcoholism American Heart Association Animal Feed Animals Arachidonic Acids Attention deficit hyperactivity disorder Autopsy Brain CRH gene Cardiovascular system Cessation of life Characteristics Chickens Cholesterol Chronic Chronic Daily Headaches Clinical Clinical Trials Collaborations Consumption Corn Oil Coronary Coronary Arteriosclerosis Coronary heart disease Data Development Diet Dietary Supplementation Dietary intake Disease Disease model Docosahexaenoic Acids Domestic Fowls Eicosapentaenoic Acid Endocannabinoids Essential Fatty Acids Evaluation Exposure to Fat-Restricted Diet Fatty Acids Fatty acid glycerol esters Food Fortified Food Goals Graph Headache Health Benefit Heart High Fat Diet Human Hyperactive behavior Infusion procedures Intake Intervention Intervention Trial Lead Link Linoleic Acids Major Depressive Disorder Margarine Mass Fragmentography Measures Meat Mental disorders Meta-Analysis Military Personnel Minnesota Modeling Mothers Myocardial Infarction Nervous system structure Neurodevelopmental Deficit Neurophysiology - biologic function Nutrient Nutritional Nutritional Study Obesity Omega-3 Fatty Acids Omega-6 Fatty Acids Organ Outcome Outcome Measure Overweight Pain Participant Pathology Phenotype Phospholipids Polyunsaturated Fatty Acids Production Protocols documentation Publications Publishing Randomized Randomized Controlled Trials Recipe Recommendation Residual state Risk Satiation Serum Severities Source Specific qualifier value Subgroup Substance abuse problem Testing Tissues Translating United States National Institutes of Health Unsaturated Fats Unsaturated Fatty Acids Update Vegetable Oils Weight Woman addiction aged alpha-Linolenic Acid base cardiovascular disorder risk clinical center cohort design dietary excess egg experimental study fatty acid metabolism food consumption group intervention hazard high risk improved interest men mortality mortality risk neurotransmission nutrition offspring polyunsaturated fat prevent saturated fat suicidal behavior suicidal risk trial design unpublished documents

项目摘要

Our past studies have indicated that alcohol abuse leads to a loss of docosahexaenoic acid (DHA), the major polyunsaturated fat in the nervous system. These losses contribute to deficits in dopaminergic neurotransmission, excesses in CRH neurotransmission and endocannabinoid hyperactivity, 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 posited that elevations in this omega-6 fat would elevate endogenous cannabinoids and induce obesity. We modeled these changes in animal studies and found that lowering linoleic acid intakes elevated omega-3 levels and reduced excessive levels of endogenous cannabinoid like molecules. We reversed obesity by reducing the linoleic acid intake to levels common in the US early in the 20th century, despite animals consuming a high fat diet (60 % en). In a separate study, we were able to induce obesity even in low fat diets (12% en) by raising linoleic acid intakes. This study provides a critical framework for reducing excessive endocannabinoid activity by reducing dietary intake of their precursor omega-6 molecules as a means to both prevent and treat obesity. The efficacy of lowering dietary linoleic acid to below 2 en% is being evaluated in three human clinical intervention 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 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 protocol will selectively lower intake to approximately 1 en%. These dietary changes are expected to reduce excessive endocannabinoid levels, improve satiety and result 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 recommendations we recovered data from two large randomized controlled trials conducted in the late 1060's to early 1970's that had not been fully published. 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. The Minnesota Coronary Experiment (MCE), an RCT designed to test whether replacement of saturated fat (SFA) with vegetable oil rich in linoleic acid (LA) reduces coronary heart disease and death by lowering serum cholesterol. We recovered (1) unpublished documents with completed analyses for the randomized cohort of 9,423 institutionalized women and men aged 20-97; (2) longitudinal serum cholesterol data for the 2,355 participants exposed to the study diets for 1 year; and (3) 149 completed autopsy files. The intervention was designed to lower serum cholesterol by replacing saturated fats with linoleic acid (LA, from corn oil and corn oil polyunsaturated margarine). Control participants consumed a diet high in SFA from animal fats, common margarines and shortenings. Outcome measures included (1) death from all causes; (2) association between changes in serum cholesterol and death; and (3) coronary atherosclerosis and myocardial infarcts at autopsy. We found that the intervention group had significant reductions in serum cholesterol compared to controls (mean change from baseline -13.8% v -1.0%; p<0.001). (1) We present unpublished Kaplan Meier graphs showing no mortality benefit for the intervention group in the full randomized cohort or any pre-specified subgroup. (2) There was a 22% higher risk of death for each 30 mg/dL reduction in serum cholesterol in covariate-adjusted Cox regression models (hazard ratio (HR) 1.22; 95% CI 1.14, 1.32; p<0.001). (3) The intervention group had no evidence of benefit for coronary atherosclerosis or myocardial infarcts. An updated meta-analysis of RCTs that lowered serum cholesterol by providing vegetable oils rich in LA in place of SFA showed no evidence of coronary (HR 1.12 (0.85 to 1.46)) or all-cause mortality benefit (HR 1.07 (0.92 to 1.23)). In meta-regression, there was no association between cholesterol lowering and coronary or all-cause mortality. MCE results do not provide support for the traditional diet-heart hypothesis. These findings add to growing evidence that incomplete publication has contributed to an overestimation of the benefits, and underestimation of the potential risks, of replacing SFA with vegetable oils rich in LA.

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。这些损失导致多巴胺能神经传递缺陷、CRH 神经传递过度和内源性大麻素过度活跃，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。我们推测，这种 omega-6 脂肪的升高会增加内源性大麻素并诱发肥胖。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提高 omega-3 水平，并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），但我们通过将亚油酸摄入量减少到 20 世纪初美国常见的水平来逆转肥胖。在另一项研究中，即使在低脂饮食（12% en）中，我们也能够通过增加亚油酸的摄入量来诱发肥胖。这项研究提供了一个关键框架，通过减少前体 omega-6 分子的饮食摄入量来减少过度的内源性大麻素活性，作为预防和治疗肥胖的一种手段。三项人体临床干预试验正在评估将膳食亚油酸降低至 2 en% 以下的功效。 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大约 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建议，我们从 1060 年代末到 1970 年代初进行的两项大型随机对照试验中恢复了尚未完全发表的数据。 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。明尼苏达冠心病实验 (MCE) 是一项随机对照试验，旨在测试用富含亚油酸 (LA) 的植物油替代饱和脂肪 (SFA) 是否可以通过降低血清胆固醇来减少冠心病和死亡。我们恢复了 (1) 未发表的文件，其中包含对 9,423 名 20-97 岁住院女性和男性的随机队列的完整分析； (2) 接受研究饮食 1 年的 2,355 名参与者的纵向血清胆固醇数据； (3) 149份完整的尸检档案。该干预措施旨在通过用亚油酸（LA，来自玉米油和玉米油多不饱和人造黄油）替代饱和脂肪来降低血清胆固醇。对照组参与者食用富含动物脂肪、普通人造黄油和起酥油的 SFA 饮食。结果指标包括 (1) 所有原因导致的死亡； (2)血清胆固醇变化与死亡的关系； (3)尸检时冠状动脉粥样硬化和心肌梗塞。我们发现，与对照组相比，干预组的血清胆固醇显着降低（相对于基线的平均变化为 -13.8% vs -1.0%；p<0.001）。 (1) 我们提供了未发表的 Kaplan Meier 图，显示在完全随机队列或任何预先指定的亚组中，干预组没有死亡率获益。 (2) 在协变量调整的 Cox 回归模型中，血清胆固醇每降低 30 mg/dL，死亡风险就会增加 22%（风险比 (HR) 1.22；95% CI 1.14, 1.32；p<0.001）。 (3)没有证据表明干预组对冠状动脉粥样硬化或心肌梗塞有益处。通过提供富含 LA 的植物油代替 SFA 来降低血清胆固醇的随机对照试验的最新荟萃分析显示，没有证据表明冠状动脉（HR 1.12（0.85 至 1.46））或全因死亡率（HR 1.07（0.92 至 1.23）有益处。）。在荟萃回归中，胆固醇降低与冠心病或全因死亡率之间没有关联。 MCE 结果并没有为传统的饮食-心脏假说提供支持。这些发现进一步证明，不完整的发表导致人们高估了用富含洛杉矶植物油替代 SFA 的好处，并低估了潜在风险。