中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
中枢神经系统中和外周组织对亮氨酸缺乏时能量稳态调控的机制研究

文献类型:学位论文

作者成瀛
学位类别博士
答辩日期2010-05-27
授予单位中国科学院上海生命科学研究院营养科学研究所
授予地点中国科学院上海生命科学研究院
导师郭非凡
关键词中枢神经系统 外周组织 亮氨酸缺乏 能量稳态
学位专业生物化学与分子生物学
中文摘要肥胖是由于能量摄入和能量消耗的不平衡而产生的疾病。摄入过多的能量会以甘油三脂的形式储存在白色脂肪中,当机体能量需求增加时,这些甘油三酯会通过脂肪动员来产生自由脂肪酸进入循环系统,循环系统中的脂肪酸可以被组织吸收利用从而放出能量供机体组织使用。褐色脂肪组织是机体内另一与能量平衡相关的重要组织。褐色脂肪组织摄取脂肪酸并将其氧化,通过其褐色脂肪细胞线粒体内膜上的解偶联蛋白1(UCP1)的解耦联作用来产生热量,从而增加机体的能量消耗。目前有多种治疗手段提高脂肪动员和增加能量利用来治疗肥胖。通过大分子营养物的干预来治疗肥胖越来越受到重视。研究发现,通过控制饮食中亮氨酸,精氨酸和谷氨酸等必需氨基酸可以调控脂肪代谢和糖代谢。这些研究主要集中在增加饮食中的必需氨基酸。 我们研究主要针对亮氨酸缺乏时能量稳态及脂质代谢展开深入的研究。我们前期的研究发现,亮氨酸缺乏饮食导致腹部脂肪快速丢失,但其分子机制却不清楚。我们目前的研究就是为了阐明亮氨酸缺乏饮食导致的脂肪丢失的分子机理。在我们的研究中,我们发现亮氨酸缺乏饮食导致脂肪快速丢失,主要不是由于微小的摄食量降低的结果。亮氨酸缺乏饮食导致的白色脂肪细胞明显减少,主要是一方面,亮氨酸缺乏饮食增加了白色脂肪组织中脂解作用增加,以及增加了脂肪酸b氧化相关的基因PPARa,CPT1,ACO的表达和降低了脂肪酸合成基因FAS,SCD1,SREBP-1c等表达和活性而造成的;另一方面,我们还发现亮氨酸缺乏饮食增加了褐色脂肪组织的UCP1的表达和产热作用。这些结果共同导致了亮氨酸缺乏饮食诱导的脂肪丢失。 我们进一步研究发现,白色脂肪组织脂解作用的增加和褐色脂肪组织的UCP1表达增加受中枢调控。在亮氨酸缺乏饮食下,通过脑室回补亮氨酸可以显著地阻止亮氨酸缺乏诱导的脂肪丢失和体重降低,而回补其他氨基酸却没有此效果。再通过脑室注射不同的激活剂和拮抗剂,研究发现亮氨酸缺乏饮食是通过抑制下丘脑雷帕霉素靶蛋白(mTOR)的活性,增加下丘脑促肾上腺素皮质激素释放激素(CRH)的表达,激活交感神经系统,从而促进了白色脂肪组织的脂解作用和褐色脂肪组织的UCP1表达,最终导致了脂肪丢失。 综上研究我们发现了亮氨酸缺乏条件下中枢神经系统和外周组织在调节能量稳态中的重要作用。
索取号D2010-050
英文摘要Obesity develops from an imbalance between calorie intake and energy expenditure. Excess calories are stored in the white adipose tissue (WAT) as triglyceride (TG). Increased energy demands stimulate the TG hydrolyzed into free fatty acid, which enter circulation, then uptake and utilized by the tissues. Brown adipose tissue (BAT) is another important tiusse involved in regulation of energy homeostasis. BAT utilizes free fatty acid and produces heat by the uncoupling protein 1 (UCP1) located in the inner membrane of mitochondria. Therefore, BAT plays important role in energy expenditure. Various strategies have been proposed to treat obesity by promoting fat mobilization and/or increasing energy expenditure. Recently, there has been a growing interest in controlling body weight by manipulating macronutrients. Recent studies have shown that dietary manipulation of essential amino acids, including leucine, arginine, and glutamine, have significant effects on lipid metabolism and glucose utilization. Most of these studies, however, have focused on the effects of increased levels of essential amino acids in the diet. By contrast, our research has focused on the effect of eliminating leucine from the diet on lipid metabolism. As we recently reported, mice maintained on a leucine deficient diet for 7 days experienced a dramatic reduction in abdominal fat mass. The cellular mechanisms responsible for this loss, however, are unclear. The goal of our current research is to elucidate the molecular and cellular mechanisms underlying the rapid fat loss induced by leucine deprivation. In our current study, we observed increases in lipolysis and expression of b-oxidation related genes, such as PPARa, CPT1,ACO, and decreases in expression and activity of lipogenic related genes and protein, such as FAS, SCD1, SREBP-1c in WAT. In addition, we observed for the first time that leucine deprivation increases expression of uncoupling protein UCP1 in BAT and increases body temperature, suggesting increased thermogenesis and energy expenditure. Furthermore, we found that leucine deprivation-induced change in WAT and BAT is regulated by central nervous system. Intracerebroventricular (icv) administration of leucine, but not other amino acids, significantly prevents leucine-deficient diet-induced fat loss. Further, by icv administration of different agonists and antagonists, we found that leucine deprivation decreases mTOR activity in hypothalamus, which increases expression of hypothalamic corticotrophin-releasing hormone and activation of SNS. Activated SNS increases lipolysis in WAT and expression of UCP1 in BAT, resulting in fat loss. Taken together, we found the central nervous system and peripheral tissues play important role in energy homeostasis under leucine deprivation.
语种中文
公开日期2016-02-26
源URL[http://202.127.25.144/handle/331004/390]  
专题中国科学院上海生命科学研究院营养科学研究所_代谢的遗传与营养调控研究组
推荐引用方式
GB/T 7714
成瀛. 中枢神经系统中和外周组织对亮氨酸缺乏时能量稳态调控的机制研究[D]. 中国科学院上海生命科学研究院. 中国科学院上海生命科学研究院营养科学研究所. 2010.

入库方式: OAI收割

来源:上海营养与健康研究所

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