Lipid Nutrition and the Brain

脂质营养与大脑

• 批准号: 8931542
• 负责人: Stanley I. Rapoport
• 金额: $ 72.89万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 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/8931542
• 关键词: Address; Adolescence; Adolescent; Adolescent Behavior; Adult; Affect; Affective; Age; Aging; Antipsychotic Agents; Arachidonic Acids; Behavioral; Brain; Brain-Derived Neurotrophic Factor; Cardiovascular system; Chemicals; Chronic; Clinical Research; Coenzyme A; Cognitive; Conscious; Consumption; Corpus striatum structure; Data; Diabetes Mellitus; Diet; Docosahexaenoic Acids; Docosapentaenoic Acid n-6; Dopamine; Dorsal; Dose; Eicosapentaenoic Acid; Environmental Risk Factor; Enzymes; Fatty Acids; Fish Oils; Generations; Glial Fibrillary Acidic Protein; Goals; Health; Heart; Hepatic; Impairment; Individual; Inflammation; Interleukin-1; Kinetics; Label; Linoleic Acids; Lipids; Liver; Liver diseases; Malnutrition; Measures; Mental disorders; Messenger RNA; Metabolic syndrome; Metabolism; Methods; Modality; Modeling; Mood Disorders; N-3 polyunsaturated fatty acid; N-Methylaspartate; Nutritional; Obesity; Omega-3 Fatty Acids; Organ; Parents; Performance; Peripheral; Pharmaceutical Preparations; Phospholipids; Plasma; Polyunsaturated Fatty Acids; Prevention strategy; Proteins; Rat Protein; Rattus; Risk; Rodent; Saline; Schizophrenia; Supplementation; Techniques; Tissues; Tyrosine 3-Monooxygenase; Weaning; age group; alpha-Linolenic Acid; behavioral health; deacylation; deprivation; emerging adult; excitotoxicity; fat nutrition study; fatty acid metabolism; feeding; in vivo; lipid metabolism; male; mathematical model; microwave electromagnetic radiation; motivated behavior; neuropathology; neurotransmission; oxidation; response; trend; uptake

ADOLESCENT BEHAVIOR AND DOPAMINE AVAILABILITY ARE SENSITIVE TO DIETARY N-3 FATTY ACID CONTENT. Understanding environmental factors that contribute to behavioral health is critical for successful prevention strategies in individuals at risk for psychiatric disorders. Dietary deficiency of N-3 polyunsaturated fatty acids (PUFAs) has been implicated in schizophrenia and mood disorders, which typically occur during adolescence to early adulthood. Thus, adolescence might be the critical age range for the negative impact of diet as an environmental insult. A rat model involving consecutive generations of n-3 PUFA deficiency was developed on the assumption that dietary trends toward decreased consumption of these PUFAS began 4-5 decades ago when parents of current adolescents were born. Behavioral performance in a range of tasks as well as markers of dopamine-related neurotransmission were compared in adolescents and adult rats fed n-3 PUFA adequate and deficient diets. In adolescents, n-3 PUFA deficiency across consecutive generations produced a modality-selective and task-dependent impairment in cognitive and motivated behavior distinct from the deficits observed in adults. Although this dietary deficiency affected expression of dopamine-related proteins in both age groups in adolescents but not adults, there was an increase in tyrosine hydroxylase expression that was selective to the dorsal striatum. These data support a nutritional contribution to optimal cognitive and affective functioning in adolescents. (1) KINETICS OF EICOSAPENTAENOIC ACID IN BRAIN, HEART AND LIVER OF CONSCIOUS RATS FED A HIGH N-3 PUFA CONTAINING DIET. Eicosapentaenoic acid (EPA, 20:5n-3), a precursor of docosahexaenoic acid (DHA), may benefit cardiovascular and brain health. Quantifying EPA's in vivo kinetics might elucidate these effects. 1-14CEPA was infused i.v. for 5min in unanesthetized male rats fed a standard EPA-DHA diet. Plasma and microwaved tissue were analyzed. Kinetic parameters were calculated using our compartmental model. At 5min, 31-48% of labeled EPA in brain and heart was oxidized, 7% in liver. EPA incorporation rates from brain and liver precursor EPA-CoA pools into lipids, mainly phospholipids, were 36 and 2529nmol/s/g10(-4), insignificant for heart. Deacylation-reacylation half-lives were 22h and 38-128min. Conversion rates to DHA equaled 0.65 and 25.1nmol/s/g10(-4), respectively. The low brain concentration and incorporation rate and high oxidation of EPA suggest that, if EPA has a beneficial effect in brain, it might result from its suppression of peripheral inflammation and hepatic conversion to bioactive DHA. (2) NEUROPATHOLOGICAL RESPONSES TO CHRONIC NMDA IN RATS ARE WORSENED BY DIETARY N-3 PUFA DEPRIVATION BUT ARE NOT AMELIORATED BY FISH OIL SUPPLEMENTATION. Dietary long-chain n-3 polyunsaturated fatty acid (PUFA) supplementation may be beneficial for chronic brain illnesses, but the issue is not agreed on. We examined effects of dietary n-3 PUFA deprivation or supplementation, compared with an n-3 PUFA adequate diet (containing alpha-linolenic acid 18:3 n-3 but not docosahexaenoic acid DHA, 22:6n-3), on brain markers of lipid metabolism and excitotoxicity, in rats treated chronically with NMDA or saline. Male rats after weaning were maintained on one of three diets for 15 weeks. After 12 weeks, each diet group was injected i.p. daily with saline (1 ml/kg) or a subconvulsive dose of NMDA (25 mg/kg) for 3 additional weeks. Then, brain fatty acid concentrations and various markers of excitotoxicity and fatty acid metabolism were measured. Compared to the diet-adequate group, brain DHA concentration was reduced, while n-6 docosapentaenoic acid (DPA, 22:5n-6) concentration was increased in the n-3 deficient group; arachidonic acid (AA, 20:4n-6) concentration was unchanged. These concentrations were unaffected by fish oil supplementation. Chronic NMDA increased brain cPLA2 activity in each of the three groups, but n-3 PUFA deprivation or fish oil did not change cPLA2 activity or protein compared with the adequate group. sPLA2 expression was unchanged in the three conditions, whereas iPLA2 expression was reduced by deprivation but not changed by supplementation. BDNF protein was reduced by NMDA in N-3 PUFA deficient rats, but protein levels of IL-1β, NGF, and GFAP did not differ between groups. N-3 PUFA deprivation significantly worsened several pathological NMDA-induced changes produced in diet adequate rats, whereas n-3 PUFA supplementation did not affect NMDA induced changes. Supplementation may not be critical for this measured neuropathology once the diet has an adequate n-3 PUFA content. (3)

青少年的行为和多巴胺的可获得性对饮食中N-3脂肪酸含量很敏感。了解有助于行为健康的环境因素，对于有精神障碍风险的个人采取成功的预防策略至关重要。N-3多不饱和脂肪酸(PUFAs)的饮食不足与精神分裂症和情绪障碍有关，这些疾病通常发生在青春期到成年早期。因此，青春期可能是饮食作为对环境的侮辱产生负面影响的关键年龄段。建立了一种涉及连续几代n-3多不饱和脂肪酸缺乏的大鼠模型，该模型假设饮食中这些多不饱和脂肪酸的摄入量减少的趋势始于4-50年前当前青少年的父母出生时。比较了青少年和成年大鼠在一系列任务中的行为表现以及多巴胺相关神经传递的标记物，其中n-3PUFA充足和不足的饮食。在青少年中，连续几代人的n-3多不饱和脂肪酸缺乏会在认知和动机行为方面产生一种通道选择性和任务依赖性的损害，与成年人观察到的缺陷不同。尽管这种饮食缺乏影响了两个年龄组的青少年但不是成年人的多巴胺相关蛋白的表达，但对背侧纹状体具有选择性的酪氨酸羟基酶的表达增加了。这些数据支持营养对青少年最佳认知和情感功能的贡献。(1) 高N-3多不饱和脂肪酸饲料喂养清醒大鼠脑、心、肝组织中二十碳五烯酸的动力学二十碳五烯酸(EPA，20：5N-3)是二十二碳六烯酸(DHA)的前体，可能有益于心血管和大脑健康。量化EPA在体内的动力学可能会解释这些影响。静脉滴注1-14CEPA。给未麻醉雄性大鼠喂饲标准EPA-DHA饲料5分钟。对血浆和微波组织进行分析。用我们的隔室模型计算了动力学参数。在5分钟时，31-48%的标记EPA在脑和心脏被氧化，7%在肝脏中被氧化。从脑和肝脏前体EPA-CoA池到脂质(主要是磷脂)的EPA掺入率分别为36和2529nmol/S/G10(-4)，对心脏影响不显著。去酰化半衰期为22h，半衰期为38~128min。DHA的转化率分别为0.65和25.1nmol/S/G10(-4)。脑内EPA浓度低、掺入率低、氧化程度高，提示EPA在脑内的有益作用可能与其抑制外周炎症和肝脏向生物活性DHA的转化有关。(2) 大鼠对慢性NMDA的神经病理反应因饮食中N-3多不饱和脂肪酸缺乏而恶化，但不能通过补充鱼油而改善。饮食中补充长链n-3多不饱和脂肪酸(PUFA)可能对慢性脑部疾病有益，但这一问题尚未达成一致。我们观察了饮食中n-3PUFA的缺乏或补充，与n-3PUFA适量饮食(含有18：3n-3但不含二十二碳六烯酸DHA，22：6n-3)相比，对长期服用NMDA或生理盐水治疗的大鼠的脑脂代谢和兴奋性毒性标志物的影响。断乳后的雄性大鼠在三种饲料中的一种上维持15周。12周后，各饮食组均注射生理盐水。每日给予生理盐水(1ml/kg)或亚抽搐剂量的NMDA(25 mg/kg)，持续3周。然后测定脑内脂肪酸浓度及兴奋性毒性和脂肪酸代谢的各项指标。与饮食充足组相比，n-3缺乏组小鼠脑DHA含量降低，n-6-二十二碳五烯酸(DPA，22：5n-6)含量升高，花生四烯酸(AA，20：4n-6)含量无明显变化。这些浓度不受补充鱼油的影响。慢性NMDA使三组大鼠脑内cPLA2活性均升高，但与适量组相比，n-3PUFA剥夺或鱼油对cPLA2活性或蛋白无明显影响。在三种情况下，sPLA2的表达没有变化，而iPLA2的表达因剥夺而减少，但不受补充的影响。N-3多不饱和脂肪酸缺乏大鼠的BDNF蛋白水平被NMDA降低，但IL-1、NGF和GFAP的蛋白水平在不同组间没有差异。N-3PUFA剥夺显著加重了饮食充足大鼠NMDA诱导的几种病理变化，而补充n-3PUFA不影响NMDA诱导的变化。一旦饮食有足够的n-3多不饱和脂肪酸含量，补充可能不是测量到的神经病理的关键。(3)

项目成果

Dietary n-6 polyunsaturated fatty acid deprivation increases docosahexaenoic acid metabolism in rat brain.

• DOI: 10.1111/j.1471-4159.2011.07597.x
• 发表时间: 2012-03
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Igarashi M;Kim HW;Chang L;Ma K;Rapoport SI
• 通讯作者: Rapoport SI

Dietary n-6 PUFA deprivation downregulates arachidonate but upregulates docosahexaenoate metabolizing enzymes in rat brain.

• DOI: 10.1016/j.bbalip.2010.10.005
• 发表时间: 2011-02
• 期刊: Biochimica et biophysica acta
• 作者: Kim HW;Rao JS;Rapoport SI;Igarashi M
• 通讯作者: Igarashi M

Can the rat liver maintain normal brain DHA metabolism in the absence of dietary DHA?

• DOI: 10.1016/j.plefa.2009.05.021
• 发表时间: 2009-08
• 期刊: Prostaglandins, leukotrienes, and essential fatty acids
• 作者: Rapoport SI;Igarashi M
• 通讯作者: Igarashi M

Dietary n-6 PUFA deprivation for 15 weeks reduces arachidonic acid concentrations while increasing n-3 PUFA concentrations in organs of post-weaning male rats.

• DOI: 10.1016/j.bbalip.2008.11.002
• 发表时间: 2009-02
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
• 影响因子: 4.8
• 作者: Igarashi, Miki;Gao, Fei;Kim, Hyung-Wook;Ma, Kaizong;Bell, Jane M.;Rapoport, Stanley I.
• 通讯作者: Rapoport, Stanley I.

Quantitative contributions of diet and liver synthesis to docosahexaenoic acid homeostasis.

• DOI: 10.1016/j.plefa.2010.02.015
• 发表时间: 2010-04
• 期刊: Prostaglandins, leukotrienes, and essential fatty acids
• 作者: Rapoport SI;Igarashi M;Gao F
• 通讯作者: Gao F