中链甘油三酯饮食对大鼠肥胖、胰岛素抵抗的影响及其机制研究
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摘要
研究背景
肥胖是目前全世界范围内的一大公共卫生问题,与胰岛素抵抗等非传染性慢性病的发生发展密切相关。脂肪摄入增加是导致肥胖的一个重要饮食因素,因此,控制能量和脂肪摄入量成为防治肥胖的首要饮食原则,但传统的低脂或无脂饮食又容易导致脂类维生素缺乏,并增加心脏疾病的危险性。所以如何提高脂类摄入的质量就变得非常重要。近年来人们发现,用低能量密度的MCT代替部分传统饮食中的LCT能提高脂类摄入的质量。尽管还存在争议,许多动物和人群研究证实了MCT能减轻体重和体脂,增加胰岛素敏感性,同时MCT还有助于维生素的吸收,抑制炎症因子的产生。
普遍认为MCT减轻体重和减少脂肪沉积,调节体内能量平衡可能有以下几方面原因:低能量密度,快速的肝内转运和氧化,直接作用于脂肪组织调节相关基因表达和酶的活性,增加饱腹感以抑制食欲,增加能量消耗,许多研究也验证了MCT的这些特征。其中,MCT导致饱腹感的机制中涉及的激素包括缩胆囊肽、YY肽、抑胃肽、神经紧张素和胰多肽。但以往的研究都集中在MCT调节代谢的外周机制,如对肝脏、脂肪组织相关基因表达的影响,MCT影响能量代谢和食欲的中枢机制还不清楚。
下丘脑是机体能量平衡的调节中枢。血液中存在的瘦素(leptin),以信号分子的形式随血液循环作用于下丘脑,然后以反馈环的形式调节摄食行为和能量平衡,保持体重的稳定。动物试验已经证明下丘脑神经中枢由于含有瘦素的受体,可以接受和整合这一信号。大量的实验证实NPY是leptin中枢作用的一种中介递质。leptin注射入血中能迅速进入下丘脑的内侧基底部、弓状核及附近的脑区,与这些部位的leptin受体结合,对NPYmRNA进行调控。因此,leptin-NPY轴可能对能量代谢调节起重要作用。在动物实验中,缺乏leptin,使小鼠出现多食、血糖增高、肥胖及弓状核NPYmRNA水平增高,给予外源性leptin,可使弓状核NPYmRNA表达接近正常,而使多食、血糖增高、肥胖等症状逆转,说明leptin参与摄食及体内能量代谢调节时,可通过NPY而发挥作用。Stephen等也发现瘦素与NPY有拮抗作用,瘦素可以通过抑制NPY的表达而降低摄食,增加产热,降低体重。研究显示MCT能影响血清瘦素浓度和脂肪组织表达瘦素mRNA,但对下丘脑瘦素受体及NPY的影响尚无相关研究。
肥胖与胰岛素抵抗的相关性已经得到较多学者的认同,饮食诱导肥胖常伴有胰岛素抵抗的发生。研究显示脂肪组织与胰岛素抵抗密切相关,尤其是内脏脂肪。基于脂肪组织在胰岛素抵抗发生过程中的主导作用,它也被看成是调节胰岛素敏感性的作用靶点之一,通过减少体内脂肪沉积从而调节胰岛素也是可行的方法。Han等研究显示MCT能升高胰岛素敏感性和葡萄糖耐受性,该作用可能与MCT减少体重和体脂沉积有关。有研究报道MCT能增加糖尿病人和非糖尿病人的胰岛素敏感性,发现其能增加糖耐量,但其中机制尚不清楚。脂连素是近来发现的两种脂肪细胞因子,由成熟脂肪细胞分泌,在血液中浓度较高。现已证实脂连素能增加胰岛素敏感性。高脂饮食能增加脂肪组织脂肪细胞的大小,同时降低脂连素mRNA水平,这些研究表明脂肪细胞减小导致血浆脂连素水平升高,对胰岛素抵抗有保护作喟。过氧化物体增殖物激活受体Y(PPARγ)和脂肪细胞分化及脂质代谢有关,激活PPARr可促进小脂肪细胞分化,减小细胞体积,还可上调脂连素mRNA,增加胰岛素敏感性,改善胰岛素抵抗。
本实验试图通过动物实验和分子生物学实验,观察含MCT或LCT的中等水平高脂饮食(29%)对大鼠体脂、体重、血脂、血糖、胰岛素敏感性等代谢指标的影响,并通过检测下丘脑瘦素受体、NPY和脂肪组织内脂肪细胞因子的表达水平了解MCT影响代谢可能的分子机制,为肥胖的防治和MCT的推广应用提供资料。为此,实验从以下3部分进行研究。
第一部分MCT对大鼠代谢指标的影响
目的高脂饮食可诱导肥胖,但饮食中脂肪含量过高可影响大鼠食欲,使致肥率降低。本实验在总结前人实验的基础上,将饮食中的脂肪含量确定在15%(W/W),供能比约占20%,为后续实验打下基础。本实验对大鼠体重、体脂、血糖、血脂、瘦素及胰岛素水平进行比较,观察MCT对大鼠代谢的影响,并帮助理解肥胖的发生机制。
方法体重为85～115g的wistar雄性大鼠,按体重随机分为基础对照组(对照组)、含MCT的高脂组(MCT组)和含LCT的高脂组(LCT组),适宜环境下分别饲以相应饲料,记录进食量,每周称体重1次,共8周。8周术,禁食12小时,麻醉后腹主动脉取血,分离血清,罗氏公司ACCU-CHEK advantage血糖仪测定血清血糖,用全自动生化分析仪测定血脂(TG、TC、LDL、HDL),ELISA法测定空腹血清瘦素,放射免疫法测定血清胰岛素水平,根据空腹血糖和血清胰岛素计算胰岛素敏感指数(ISI),其余血清-85℃保存备用。剥离肾周及睾周脂肪组织挚,用滤纸吸干组织液后,称重。留取各组大鼠的右侧肾周脂肪组织垫,于10%福尔马林溶液中固定,病理检测脂肪细胞的大小。留取部分肝脏,病理下观察肝细胞的形态。留取左侧肾周脂肪组织挚,-80℃保存待测。同时迅速分离出下丘脑置液氮中保存,5只全脑用于下丘脑NPY、leptin含量测定,另5只用于瘦素受体(Ob-Rb)和神经肽Y(NPY)mRNA测定。
结果MCT组大鼠体重、体脂增长均小于LCT组,与对照组相近。MCT组血浆TC浓度、低密度脂蛋白胆固醇(LDL-C)浓度、高密度脂蛋白(HDL-C)浓度均比LCT组低(P＜0.01),MCT组血清TG则比LCT组显著升高(P＜0.01)。MCT血清SOD活性显著高于LCT组,MDA水平明显低于LCT组。MCT组肝脏脂肪病变较轻。MCT组血清胰岛素显著低于LCT组(P＜0.01),胰岛素敏感性显著高于LCT组(P＜0.01),与对照组无显著差异。MCT和LET两组间饲料消耗量、能量消耗量、空腹血糖没有差异。
结论MCT供能占总能量29%的高脂饮食能预防肥胖,减少体重增长和体脂累积。MCT饮食能增加胰岛素敏感性,改善胰岛素抵抗。MCT能减轻体内氧化应激,减轻肝脏内脂肪沉积。MCT抑制体重增长的机制,与抑制食欲,减少进食量无关,可能与通过外周或中枢机制影响能量代谢相关。
第二部分MCT降低体重及对下丘脑瘦素受体、NPY轴的影响
目的人群和动物研究显示中链甘油三脂(MCT)能降低体重,其机制与MCT能够抑制食欲,减少进食量和增加能量消耗有关。研究证实瘦素进入下丘脑后与瘦素受体(leptin receptor)结合通过NPY调节进食和能量消耗。本部分将观察MCT对血清、下丘脑瘦素、NPY浓度,下丘脑长型瘦素受体(Ob-Rb)、神经肽Y(NPY)mRNA和蛋白表达的影响,探讨MCT减肥的中枢机制。
方法wistar大鼠用含29%MCT或LCT的饲料喂养8周,用ELISA法测定血清和下丘脑瘦素的水平,用放射免疫法检测外周血和下丘脑NPY的浓度,用Real-timeRT-PCR技术测定NPY、瘦素受体(Ob-Rb)基因表达水平的差异。
结果MCT组大鼠体重增长量和体脂含量均小于LCT组(P＜0.01);MCT组下丘脑瘦素高于LCT组,但无显著差异,MCT组瘦素脑/血比明显高于LCT组,MCT组大鼠下丘脑Ob-Rb基因表达水平明显高于LCT组(P＜0.01);MCT组下丘脑及血清NPY浓度明显低于LCT组(P＜0.01),两组间下丘脑NPY mRNA水平没有差异。
结论MCT通过促进Ob-Rb基因表达,抑制NPY合成和分泌,这可能是MCT减肥的重要作用机制之一。还需进一步研究观察瘦素对SCOS-3及MSH和大麻素系统的影响。
第三部分MCT对胰岛素抵抗及其相关基因表达的影响
目的动物试验和人群研究表明,与LCT相比,MCT能提高糖耐量。脂连素被证实与胰岛素敏感性相关。过氧化物体增殖物激活受体γ(PPARγ)激活后可促进小脂肪细胞分化,增加胰岛素敏感性,还可调节脂连素和TNF-α的转录水平。TNF-α本身也可影响脂肪细胞中脂连素的表达。本课题研究MCT对血清和脂肪组织中脂连素、PPARγ、TNF-α水平的影响。
方法雄性wistar大鼠,分别饲喂含20%MCT和LCT,8w后病理检测右侧肾周脂肪细胞的大小。ELISA法检测血清中脂连素、TNF-α的水平。Real-time RT-PCT测定脂肪组织中脂连素、PPARγmRNA表达水平,Western-blot测定脂肪组织中脂连素、PPARγ蛋白表达的水平。
结果MCT组体脂(body fat accumulation)、外周脂肪组织的细胞直径小于LCT组。MCT组的血清脂连素含量显著低于LCT组,两组间血清TNF-α无显著差异。MCT组外周脂肪组织中脂连素、PPARγmRNA和蛋白表达水平显著高于LCT。
结论MCT饮食增加脂肪组织中脂连素mRNA和蛋白的表达。脂肪组织中PPARγ的表达和脂连素一致,与胰岛素敏感性相关。MCT饮食可通过增加PPARγ表达,促进脂连素基因和蛋白表达,并诱导小脂肪细胞分化,减少脂肪细胞体积,从而改善机体的胰岛素敏感性。
Obesity is a public health problem.It increase the risk of life threatening diseases such as hypertension,type 2 diabetes and atherosclerosis.Increased fat intake induces overweight and obesity.Switching to low-fat or fat-free diets may not be ideal because of vitamin loss and increased risk for heart disease.One of the alternative strategies is to replace part of the conventional dietary long-chain triglyceride(LCT) with medium-chain TG(MCT) oil.Despite controversy,many studies have documented that MCTs cause significant reduction in body weight or fat pad size in animals and humans, as recently reviewed by St-Onge et al.MCTs also facilitate vitamin delivery and inhibit the production of inflammatory cytokines.
MCT have several unique physiological and biological characteristics,as reported elsewhere over the past half-century.MCT,composed exclusively of MCFA(medium-chain fatty acid),are metabolized differently from LCT,composed exclusively of LCFA(long chain fatty acid).MCFA are absorbed via the portal system and are transported to the liver directly,whereas LCT are absorbed via the intestinal lymphatic ducts and transported as chylomicrons through the thoracic duct to reach systemic circulation.MCFA and hence MCT are easily oxidized because their intramitochondrial transport does not require carnitine palmitoyltransferase(CPT),a rate-limiting enzyme of mitochondrial-oxidation.MCT are absorbed and metabolized as rapidly as glucose.Several studies showed that MCT have more energy expenditure. They are utilized to prevent obesity and several lifestyle-related diseases.Previous studies have concentrated on the pheripheral mechanism,such as adiposity,liver, gastrointestinal hormones.However,the effect of MCT on central neuropeptide,such as neuropeptide Y(NPY),leptin receptor(Ob-R) are still unknow.
NPY,a potent stimulator of feed intake,is mainly synthesized in the arcuate nucleus and injected into the paraventricular nucleus induced hyperphagia and reduced energy expenditure.Leptin is a signal for the regulation of food intake through hypothalamic leptin receptor(Ob-R) to regulate body fat mass.Kalra et al indicated that the over expression of Ob-Rb in the hypothalamus may contribute to the inhibitory effects of leptin on food intake and body weight.It has been well established that leptin receptor (Ob-R) regulating food intake and energy expenditure with NPY.It has been concluded that the type and amount of dietary fat can modulate the NPY mRNA expression.It is possible that the inhibitory effect of MCT on body weight gain is caused by altered downstream of the actions of Ob-Rb.We hypothesized that dietary MCT might alter leptin and leptin signaling to the brain(leptin-related hypothalamic neuropetide mRNA expression) resulting in less body weight gain.
Insulin resistance is characterized by a reduced sensitivity of insulin to target tissues. Although obesity is a common cause of insulin resistance,the molecular link between increased adiposity and insulin sensitivity remain unclear.Animal and human studies have provided evidence that MCT impact not only lipid metabolism but also glucose metablism.Han et al found improved glucose tolerance and insulin sensitivity in MCT-fed rats,compared with LCT.Eckel et al reported that an MCT diet,compared with an LCT diet,increased insulin sensitivity in both diabetic patients and nondiabetic subjects.Adipose tissue synthesizes and secretes biologically active molecular that might be called "adipocytokines".Dysregulation of adipocytokines in obesity might play a role in the development of insulin resistance.More recently,resistin,which is a novel adipose-specific cysteine-rich protein,has been found to impair insulin sensitivity and glucose tolerance.Adiponectin is a product of the apM1 gene,which is specifically and highly expressed in human adipose tissue.Plasma adiponectin concentration and mRNA expression were decreased in obese humans,with increased adiposity,and in patients with type 2 diabetes with insulin resistance.The peroxisome proliferator-activated receptor(PPAR)-γis the master regulator of adipocyte differentiation and controls many adipocytes genes.Its synthetic ligands,thiazolidinediones(TZDs),are a new class of antidiabetic drugs that improve insulin action.Many studies demonstrated TZDs can markedly enhance the expression and secretion of adiponectin in vitro and in vivo through the activation of its promoter.Furthermore,retinoid X receptor(RXR),liver receptor homolog-1(LRH-1),tumor necrosis factor a(TNF-a) are all involved in transactivation machinery of adiponectin gene.
Here,we tried to determine whether dietary MCT woule affect leptin and leptin's signaling pathway.Meanwhile,we also investigated the effect of MCT diet on adipose adiponectin,resistin,PPARγ,TNF-a mRNA
PART 1 METABOLIC EFFECTS OF A MEDIUM-CHAIM TRIGLYCERIDES DIET
Object:It is well know that high fat-diet induce obesity,but the result will be adiverse when there is too much fat in diet,because studies on establishment of obese models have revealed that too much fat down-regulatees the appetite of subjects.Thus,we induced obesity by feeding rats a high fat diet containing about 15%fat in order to provide a solid foundation for the next work.The aim of the present part was to investigated the effects of MCT diet on some physiological factors such as body weight, food intake,adipose depots,size of fat cells,serum lipid profiles,serum glucose,and insulin levels.
Methods:Thirty male wistar rats weighting 85～115g were fed standard laboratory chow for the 1~(st) wk to allow them to adjust to the new environment.Mice were then randomly assigned to a control group(5%of weight as fat),MCT group(14%of weight as MCT) and LCT group(15%of weight as LCT).All rats were maintained in cages under appropriate temperatue,humidity,and light-dark cycle conditions.Weekly body weight and daily food intake were measured for 8 weeks.At the end of feeding period,the rats were killed by anesthetizing with sodium pentobarbital(7ml/100g of body weight i.p.) after 12h of food deprivation.Blood(inferior vena cava) was collected to obtain serum, which was stored at -80℃for analysis.One aliquot of blood was collected directly in a tube containing heparin(10μl/ml of total blood) and aprotinin(500U/ml of total blood) placed on ice and centrifuged;and the obtained blood plasma was stored at -20℃for leptin and NPY determination.The abdominal adipose tissues(perirenal,epididymal) were carefully removed using scissors and weighed.At the same time,the whole brains of five rats in each group was obtained and stored in liquid nitrogen.They were putted on ice plate the next day;the hypothalamuses were sampled and weighed,then putted in glass homogenizer.It was added with 1ml 1NHCL and homogenized,then transferred to plastic tube and stored 100min under room temperature to make the bioactive peptides dissolved completely in acid solution.After adding 1ml 1N NAOH,it was centrifuged for 10min by 4000×g under 4℃.The supernatant was stored at -20℃for determination of NPY and leptin contents.The other hypothalami was also sampled and frozen for extraction of RNA and quantitative real-time RT-PCR experiments.
Results:Significantly decrease of body weight,the weight of adipose pads,serum total cholesterol(TC),low density lipoprotein-cholesterol(LDL) and high density lipoprotein-cholesterol(HDL-C) were noted in the group fed MCT as compared with those fed LCT.In contrast,serum total triaglyceride(TG) were significantly increased in MCT group compared to those in LCT group.There were no significant differences in serum glucose,food intake,energy intake between them.The insulin resistance in MCT group was ameliorated compared with those in LCT group.MCT diet reduced adipocyte diameter enlarged by LCT diet.
conclusions:The results suggested dietary MCT can reduce body weigh gain,the weight of adipose pads,diameter of adipocyte,serum total cholesterol and LDL after a eight-week feeding period,and can reverse insulin resistance.
PART 2 High Expression of Leptin Receptor in Rats Fed with Medium-chain TAG Compared with Long-chain TAG
Object:Previous studies demonstrated that,compared with long-chain TAG(LCT), dietary medium-chain TAG(MCT) could reduce body weight gain.It has been well established that leptin acts as a signal for body fat storage through the hypothalamic leptin receptor(OB-R) regulating food intake and energy expenditure with neuropeptide Y.
Methods:Male Wistar rats were fed with diets containing 30%MCT or LCT for 8 wk. The effects of dietary MCT on serum leptin concentration,leptin receptor and NPY mRNA levels in hypothalamus were studied in rats.NPY and leptin was extracted and measured with a specific radioimmunoassay and ELISA.
Results:Rats fed with the MCT diets had less body weight gain and body fat accumulation in the MCT diet group than those fed with the LCT diets(P＜0.01). Hypothalamus and serum NPY concentrations in rats fed with the MCT diets were lower than those in LCT group.MCT rats had significantly higher ratio of hypothalamus/serum leptin compared with LCT rats.The Ob-Rb mRNA level in the hypothalamus was significantly higher in the rats fed with the MCT diets than in those fed with the LCT diets.There was no significant difference in NPY expression between the LCT and MCT groups.
Conculsions:These findings suggest that dietary MCT,compared with LCT,results in higher Ob-Rb mRNA level in rats.The effects of MCT on other actions of leptin such as its effects on the SCOS-3,melanocortin or endocannabinoid system should be investigated.
PART 3 High Expression of Adiponectin and PPARγin Rats Fed with Medium-chain TAG Compared with Long-chain TAG
Objective:Previous studies demonstrated that,compared with long-chain TAG (LCT),dietary medium-chain TAG(MCT) could improve glucose tolerance in rats and humans.It has been well established that adiponetin acts to increase insulin sensitivity. The peroxisome proliferator-activated receptorγ(PPARγ) is the master regulator of adipocyte differentiation and controls many adipocytes genes,including adiponectin and TNF-a.Furthermore,TNF-a are all involved in transactivation machinery of adiponectin gene.The effects of dietary MCT on adiponection,PPARγ,TNF-a levels in serum and adipose tissue were studied in rats.
Methods:Serum adiponectin and TNF-a were assayed by enzyme linked immunosorbant assay(ELISA).Total RNA was isolated from the retroperitoneal fat by the method of GIT,and real-time reverse transcription polymerase chain reaction was performed to quantify mRNA of PPARγ,adiponectin.Western-blot was perfomed to quantify protein of PPARγ,adiponectin in white adipose tissue.
Results:Rats fed the MCT diet had smaller cell diameter of the perirenal adipose tissue (P＜0.01).The serum adiponectin concentration was high(P＜0.01) in the MCT diet group than in the LCT diets group.Adipose adiponectin,PPARγmRNA expression was much higher in the MCT diet group than in the LCT diet group.In contrast,no differences in serum TNF-a levels expressions were found between the two groups.
Conclusions:Dietary MCT result in a high serum adiponectin level with transcriptional activation of the adiponectin gene in rats compared with LCT diet.We speculate that improved glucose tolerance in rats fed an MCT diet may be ascribe to the high serum adiponetin level.Our results also indicate that PPARγplay significant roles in the transcriptional activation of adiponectin gene.
肥胖是目前全世界范围内的一大公共卫生问题,与胰岛素抵抗等非传染性慢性病的发生发展密切相关。脂肪摄入增加是导致肥胖的一个重要饮食因素,因此,控制能量和脂肪摄入量成为防治肥胖的首要饮食原则,但传统的低脂或无脂饮食又容易导致脂类维生素缺乏,并增加心脏疾病的危险性。所以如何提高脂类摄入的质量就变得非常重要。近年来人们发现,用低能量密度的MCT代替部分传统饮食中的LCT能提高脂类摄入的质量。尽管还存在争议,许多动物和人群研究证实了MCT能减轻体重和体脂,增加胰岛素敏感性,同时MCT还有助于维生素的吸收,抑制炎症因子的产生。
普遍认为MCT减轻体重和减少脂肪沉积,调节体内能量平衡可能有以下几方面原因:低能量密度,快速的肝内转运和氧化,直接作用于脂肪组织调节相关基因表达和酶的活性,增加饱腹感以抑制食欲,增加能量消耗,许多研究也验证了MCT的这些特征。其中,MCT导致饱腹感的机制中涉及的激素包括缩胆囊肽、YY肽、抑胃肽、神经紧张素和胰多肽。但以往的研究都集中在MCT调节代谢的外周机制,如对肝脏、脂肪组织相关基因表达的影响,MCT影响能量代谢和食欲的中枢机制还不清楚。
下丘脑是机体能量平衡的调节中枢。血液中存在的瘦素(leptin),以信号分子的形式随血液循环作用于下丘脑,然后以反馈环的形式调节摄食行为和能量平衡,保持体重的稳定。动物试验已经证明下丘脑神经中枢由于含有瘦素的受体,可以接受和整合这一信号。大量的实验证实NPY是leptin中枢作用的一种中介递质。leptin注射入血中能迅速进入下丘脑的内侧基底部、弓状核及附近的脑区,与这些部位的leptin受体结合,对NPYmRNA进行调控。因此,leptin-NPY轴可能对能量代谢调节起重要作用。在动物实验中,缺乏leptin,使小鼠出现多食、血糖增高、肥胖及弓状核NPYmRNA水平增高,给予外源性leptin,可使弓状核NPYmRNA表达接近正常,而使多食、血糖增高、肥胖等症状逆转,说明leptin参与摄食及体内能量代谢调节时,可通过NPY而发挥作用。Stephen等也发现瘦素与NPY有拮抗作用,瘦素可以通过抑制NPY的表达而降低摄食,增加产热,降低体重。研究显示MCT能影响血清瘦素浓度和脂肪组织表达瘦素mRNA,但对下丘脑瘦素受体及NPY的影响尚无相关研究。
肥胖与胰岛素抵抗的相关性已经得到较多学者的认同,饮食诱导肥胖常伴有胰岛素抵抗的发生。研究显示脂肪组织与胰岛素抵抗密切相关,尤其是内脏脂肪。基于脂肪组织在胰岛素抵抗发生过程中的主导作用,它也被看成是调节胰岛素敏感性的作用靶点之一,通过减少体内脂肪沉积从而调节胰岛素也是可行的方法。Han等研究显示MCT能升高胰岛素敏感性和葡萄糖耐受性,该作用可能与MCT减少体重和体脂沉积有关。有研究报道MCT能增加糖尿病人和非糖尿病人的胰岛素敏感性,发现其能增加糖耐量,但其中机制尚不清楚。脂连素是近来发现的两种脂肪细胞因子,由成熟脂肪细胞分泌,在血液中浓度较高。现已证实脂连素能增加胰岛素敏感性。高脂饮食能增加脂肪组织脂肪细胞的大小,同时降低脂连素mRNA水平,这些研究表明脂肪细胞减小导致血浆脂连素水平升高,对胰岛素抵抗有保护作喟。过氧化物体增殖物激活受体Y(PPARγ)和脂肪细胞分化及脂质代谢有关,激活PPARr可促进小脂肪细胞分化,减小细胞体积,还可上调脂连素mRNA,增加胰岛素敏感性,改善胰岛素抵抗。
本实验试图通过动物实验和分子生物学实验,观察含MCT或LCT的中等水平高脂饮食(29%)对大鼠体脂、体重、血脂、血糖、胰岛素敏感性等代谢指标的影响,并通过检测下丘脑瘦素受体、NPY和脂肪组织内脂肪细胞因子的表达水平了解MCT影响代谢可能的分子机制,为肥胖的防治和MCT的推广应用提供资料。为此,实验从以下3部分进行研究。
第一部分MCT对大鼠代谢指标的影响
目的高脂饮食可诱导肥胖,但饮食中脂肪含量过高可影响大鼠食欲,使致肥率降低。本实验在总结前人实验的基础上,将饮食中的脂肪含量确定在15%(W/W),供能比约占20%,为后续实验打下基础。本实验对大鼠体重、体脂、血糖、血脂、瘦素及胰岛素水平进行比较,观察MCT对大鼠代谢的影响,并帮助理解肥胖的发生机制。
方法体重为85～115g的wistar雄性大鼠,按体重随机分为基础对照组(对照组)、含MCT的高脂组(MCT组)和含LCT的高脂组(LCT组),适宜环境下分别饲以相应饲料,记录进食量,每周称体重1次,共8周。8周术,禁食12小时,麻醉后腹主动脉取血,分离血清,罗氏公司ACCU-CHEK advantage血糖仪测定血清血糖,用全自动生化分析仪测定血脂(TG、TC、LDL、HDL),ELISA法测定空腹血清瘦素,放射免疫法测定血清胰岛素水平,根据空腹血糖和血清胰岛素计算胰岛素敏感指数(ISI),其余血清-85℃保存备用。剥离肾周及睾周脂肪组织挚,用滤纸吸干组织液后,称重。留取各组大鼠的右侧肾周脂肪组织垫,于10%福尔马林溶液中固定,病理检测脂肪细胞的大小。留取部分肝脏,病理下观察肝细胞的形态。留取左侧肾周脂肪组织挚,-80℃保存待测。同时迅速分离出下丘脑置液氮中保存,5只全脑用于下丘脑NPY、leptin含量测定,另5只用于瘦素受体(Ob-Rb)和神经肽Y(NPY)mRNA测定。
结果MCT组大鼠体重、体脂增长均小于LCT组,与对照组相近。MCT组血浆TC浓度、低密度脂蛋白胆固醇(LDL-C)浓度、高密度脂蛋白(HDL-C)浓度均比LCT组低(P＜0.01),MCT组血清TG则比LCT组显著升高(P＜0.01)。MCT血清SOD活性显著高于LCT组,MDA水平明显低于LCT组。MCT组肝脏脂肪病变较轻。MCT组血清胰岛素显著低于LCT组(P＜0.01),胰岛素敏感性显著高于LCT组(P＜0.01),与对照组无显著差异。MCT和LET两组间饲料消耗量、能量消耗量、空腹血糖没有差异。
结论MCT供能占总能量29%的高脂饮食能预防肥胖,减少体重增长和体脂累积。MCT饮食能增加胰岛素敏感性,改善胰岛素抵抗。MCT能减轻体内氧化应激,减轻肝脏内脂肪沉积。MCT抑制体重增长的机制,与抑制食欲,减少进食量无关,可能与通过外周或中枢机制影响能量代谢相关。
第二部分MCT降低体重及对下丘脑瘦素受体、NPY轴的影响
目的人群和动物研究显示中链甘油三脂(MCT)能降低体重,其机制与MCT能够抑制食欲,减少进食量和增加能量消耗有关。研究证实瘦素进入下丘脑后与瘦素受体(leptin receptor)结合通过NPY调节进食和能量消耗。本部分将观察MCT对血清、下丘脑瘦素、NPY浓度,下丘脑长型瘦素受体(Ob-Rb)、神经肽Y(NPY)mRNA和蛋白表达的影响,探讨MCT减肥的中枢机制。
方法wistar大鼠用含29%MCT或LCT的饲料喂养8周,用ELISA法测定血清和下丘脑瘦素的水平,用放射免疫法检测外周血和下丘脑NPY的浓度,用Real-timeRT-PCR技术测定NPY、瘦素受体(Ob-Rb)基因表达水平的差异。
结果MCT组大鼠体重增长量和体脂含量均小于LCT组(P＜0.01);MCT组下丘脑瘦素高于LCT组,但无显著差异,MCT组瘦素脑/血比明显高于LCT组,MCT组大鼠下丘脑Ob-Rb基因表达水平明显高于LCT组(P＜0.01);MCT组下丘脑及血清NPY浓度明显低于LCT组(P＜0.01),两组间下丘脑NPY mRNA水平没有差异。
结论MCT通过促进Ob-Rb基因表达,抑制NPY合成和分泌,这可能是MCT减肥的重要作用机制之一。还需进一步研究观察瘦素对SCOS-3及MSH和大麻素系统的影响。
第三部分MCT对胰岛素抵抗及其相关基因表达的影响
目的动物试验和人群研究表明,与LCT相比,MCT能提高糖耐量。脂连素被证实与胰岛素敏感性相关。过氧化物体增殖物激活受体γ(PPARγ)激活后可促进小脂肪细胞分化,增加胰岛素敏感性,还可调节脂连素和TNF-α的转录水平。TNF-α本身也可影响脂肪细胞中脂连素的表达。本课题研究MCT对血清和脂肪组织中脂连素、PPARγ、TNF-α水平的影响。
方法雄性wistar大鼠,分别饲喂含20%MCT和LCT,8w后病理检测右侧肾周脂肪细胞的大小。ELISA法检测血清中脂连素、TNF-α的水平。Real-time RT-PCT测定脂肪组织中脂连素、PPARγmRNA表达水平,Western-blot测定脂肪组织中脂连素、PPARγ蛋白表达的水平。
结果MCT组体脂(body fat accumulation)、外周脂肪组织的细胞直径小于LCT组。MCT组的血清脂连素含量显著低于LCT组,两组间血清TNF-α无显著差异。MCT组外周脂肪组织中脂连素、PPARγmRNA和蛋白表达水平显著高于LCT。
结论MCT饮食增加脂肪组织中脂连素mRNA和蛋白的表达。脂肪组织中PPARγ的表达和脂连素一致,与胰岛素敏感性相关。MCT饮食可通过增加PPARγ表达,促进脂连素基因和蛋白表达,并诱导小脂肪细胞分化,减少脂肪细胞体积,从而改善机体的胰岛素敏感性。
Obesity is a public health problem.It increase the risk of life threatening diseases such as hypertension,type 2 diabetes and atherosclerosis.Increased fat intake induces overweight and obesity.Switching to low-fat or fat-free diets may not be ideal because of vitamin loss and increased risk for heart disease.One of the alternative strategies is to replace part of the conventional dietary long-chain triglyceride(LCT) with medium-chain TG(MCT) oil.Despite controversy,many studies have documented that MCTs cause significant reduction in body weight or fat pad size in animals and humans, as recently reviewed by St-Onge et al.MCTs also facilitate vitamin delivery and inhibit the production of inflammatory cytokines.
MCT have several unique physiological and biological characteristics,as reported elsewhere over the past half-century.MCT,composed exclusively of MCFA(medium-chain fatty acid),are metabolized differently from LCT,composed exclusively of LCFA(long chain fatty acid).MCFA are absorbed via the portal system and are transported to the liver directly,whereas LCT are absorbed via the intestinal lymphatic ducts and transported as chylomicrons through the thoracic duct to reach systemic circulation.MCFA and hence MCT are easily oxidized because their intramitochondrial transport does not require carnitine palmitoyltransferase(CPT),a rate-limiting enzyme of mitochondrial-oxidation.MCT are absorbed and metabolized as rapidly as glucose.Several studies showed that MCT have more energy expenditure. They are utilized to prevent obesity and several lifestyle-related diseases.Previous studies have concentrated on the pheripheral mechanism,such as adiposity,liver, gastrointestinal hormones.However,the effect of MCT on central neuropeptide,such as neuropeptide Y(NPY),leptin receptor(Ob-R) are still unknow.
NPY,a potent stimulator of feed intake,is mainly synthesized in the arcuate nucleus and injected into the paraventricular nucleus induced hyperphagia and reduced energy expenditure.Leptin is a signal for the regulation of food intake through hypothalamic leptin receptor(Ob-R) to regulate body fat mass.Kalra et al indicated that the over expression of Ob-Rb in the hypothalamus may contribute to the inhibitory effects of leptin on food intake and body weight.It has been well established that leptin receptor (Ob-R) regulating food intake and energy expenditure with NPY.It has been concluded that the type and amount of dietary fat can modulate the NPY mRNA expression.It is possible that the inhibitory effect of MCT on body weight gain is caused by altered downstream of the actions of Ob-Rb.We hypothesized that dietary MCT might alter leptin and leptin signaling to the brain(leptin-related hypothalamic neuropetide mRNA expression) resulting in less body weight gain.
Insulin resistance is characterized by a reduced sensitivity of insulin to target tissues. Although obesity is a common cause of insulin resistance,the molecular link between increased adiposity and insulin sensitivity remain unclear.Animal and human studies have provided evidence that MCT impact not only lipid metabolism but also glucose metablism.Han et al found improved glucose tolerance and insulin sensitivity in MCT-fed rats,compared with LCT.Eckel et al reported that an MCT diet,compared with an LCT diet,increased insulin sensitivity in both diabetic patients and nondiabetic subjects.Adipose tissue synthesizes and secretes biologically active molecular that might be called "adipocytokines".Dysregulation of adipocytokines in obesity might play a role in the development of insulin resistance.More recently,resistin,which is a novel adipose-specific cysteine-rich protein,has been found to impair insulin sensitivity and glucose tolerance.Adiponectin is a product of the apM1 gene,which is specifically and highly expressed in human adipose tissue.Plasma adiponectin concentration and mRNA expression were decreased in obese humans,with increased adiposity,and in patients with type 2 diabetes with insulin resistance.The peroxisome proliferator-activated receptor(PPAR)-γis the master regulator of adipocyte differentiation and controls many adipocytes genes.Its synthetic ligands,thiazolidinediones(TZDs),are a new class of antidiabetic drugs that improve insulin action.Many studies demonstrated TZDs can markedly enhance the expression and secretion of adiponectin in vitro and in vivo through the activation of its promoter.Furthermore,retinoid X receptor(RXR),liver receptor homolog-1(LRH-1),tumor necrosis factor a(TNF-a) are all involved in transactivation machinery of adiponectin gene.
Here,we tried to determine whether dietary MCT woule affect leptin and leptin's signaling pathway.Meanwhile,we also investigated the effect of MCT diet on adipose adiponectin,resistin,PPARγ,TNF-a mRNA
PART 1 METABOLIC EFFECTS OF A MEDIUM-CHAIM TRIGLYCERIDES DIET
Object:It is well know that high fat-diet induce obesity,but the result will be adiverse when there is too much fat in diet,because studies on establishment of obese models have revealed that too much fat down-regulatees the appetite of subjects.Thus,we induced obesity by feeding rats a high fat diet containing about 15%fat in order to provide a solid foundation for the next work.The aim of the present part was to investigated the effects of MCT diet on some physiological factors such as body weight, food intake,adipose depots,size of fat cells,serum lipid profiles,serum glucose,and insulin levels.
Methods:Thirty male wistar rats weighting 85～115g were fed standard laboratory chow for the 1~(st) wk to allow them to adjust to the new environment.Mice were then randomly assigned to a control group(5%of weight as fat),MCT group(14%of weight as MCT) and LCT group(15%of weight as LCT).All rats were maintained in cages under appropriate temperatue,humidity,and light-dark cycle conditions.Weekly body weight and daily food intake were measured for 8 weeks.At the end of feeding period,the rats were killed by anesthetizing with sodium pentobarbital(7ml/100g of body weight i.p.) after 12h of food deprivation.Blood(inferior vena cava) was collected to obtain serum, which was stored at -80℃for analysis.One aliquot of blood was collected directly in a tube containing heparin(10μl/ml of total blood) and aprotinin(500U/ml of total blood) placed on ice and centrifuged;and the obtained blood plasma was stored at -20℃for leptin and NPY determination.The abdominal adipose tissues(perirenal,epididymal) were carefully removed using scissors and weighed.At the same time,the whole brains of five rats in each group was obtained and stored in liquid nitrogen.They were putted on ice plate the next day;the hypothalamuses were sampled and weighed,then putted in glass homogenizer.It was added with 1ml 1NHCL and homogenized,then transferred to plastic tube and stored 100min under room temperature to make the bioactive peptides dissolved completely in acid solution.After adding 1ml 1N NAOH,it was centrifuged for 10min by 4000×g under 4℃.The supernatant was stored at -20℃for determination of NPY and leptin contents.The other hypothalami was also sampled and frozen for extraction of RNA and quantitative real-time RT-PCR experiments.
Results:Significantly decrease of body weight,the weight of adipose pads,serum total cholesterol(TC),low density lipoprotein-cholesterol(LDL) and high density lipoprotein-cholesterol(HDL-C) were noted in the group fed MCT as compared with those fed LCT.In contrast,serum total triaglyceride(TG) were significantly increased in MCT group compared to those in LCT group.There were no significant differences in serum glucose,food intake,energy intake between them.The insulin resistance in MCT group was ameliorated compared with those in LCT group.MCT diet reduced adipocyte diameter enlarged by LCT diet.
conclusions:The results suggested dietary MCT can reduce body weigh gain,the weight of adipose pads,diameter of adipocyte,serum total cholesterol and LDL after a eight-week feeding period,and can reverse insulin resistance.
PART 2 High Expression of Leptin Receptor in Rats Fed with Medium-chain TAG Compared with Long-chain TAG
Object:Previous studies demonstrated that,compared with long-chain TAG(LCT), dietary medium-chain TAG(MCT) could reduce body weight gain.It has been well established that leptin acts as a signal for body fat storage through the hypothalamic leptin receptor(OB-R) regulating food intake and energy expenditure with neuropeptide Y.
Methods:Male Wistar rats were fed with diets containing 30%MCT or LCT for 8 wk. The effects of dietary MCT on serum leptin concentration,leptin receptor and NPY mRNA levels in hypothalamus were studied in rats.NPY and leptin was extracted and measured with a specific radioimmunoassay and ELISA.
Results:Rats fed with the MCT diets had less body weight gain and body fat accumulation in the MCT diet group than those fed with the LCT diets(P＜0.01). Hypothalamus and serum NPY concentrations in rats fed with the MCT diets were lower than those in LCT group.MCT rats had significantly higher ratio of hypothalamus/serum leptin compared with LCT rats.The Ob-Rb mRNA level in the hypothalamus was significantly higher in the rats fed with the MCT diets than in those fed with the LCT diets.There was no significant difference in NPY expression between the LCT and MCT groups.
Conculsions:These findings suggest that dietary MCT,compared with LCT,results in higher Ob-Rb mRNA level in rats.The effects of MCT on other actions of leptin such as its effects on the SCOS-3,melanocortin or endocannabinoid system should be investigated.
PART 3 High Expression of Adiponectin and PPARγin Rats Fed with Medium-chain TAG Compared with Long-chain TAG
Objective:Previous studies demonstrated that,compared with long-chain TAG (LCT),dietary medium-chain TAG(MCT) could improve glucose tolerance in rats and humans.It has been well established that adiponetin acts to increase insulin sensitivity. The peroxisome proliferator-activated receptorγ(PPARγ) is the master regulator of adipocyte differentiation and controls many adipocytes genes,including adiponectin and TNF-a.Furthermore,TNF-a are all involved in transactivation machinery of adiponectin gene.The effects of dietary MCT on adiponection,PPARγ,TNF-a levels in serum and adipose tissue were studied in rats.
Methods:Serum adiponectin and TNF-a were assayed by enzyme linked immunosorbant assay(ELISA).Total RNA was isolated from the retroperitoneal fat by the method of GIT,and real-time reverse transcription polymerase chain reaction was performed to quantify mRNA of PPARγ,adiponectin.Western-blot was perfomed to quantify protein of PPARγ,adiponectin in white adipose tissue.
Results:Rats fed the MCT diet had smaller cell diameter of the perirenal adipose tissue (P＜0.01).The serum adiponectin concentration was high(P＜0.01) in the MCT diet group than in the LCT diets group.Adipose adiponectin,PPARγmRNA expression was much higher in the MCT diet group than in the LCT diet group.In contrast,no differences in serum TNF-a levels expressions were found between the two groups.
Conclusions:Dietary MCT result in a high serum adiponectin level with transcriptional activation of the adiponectin gene in rats compared with LCT diet.We speculate that improved glucose tolerance in rats fed an MCT diet may be ascribe to the high serum adiponetin level.Our results also indicate that PPARγplay significant roles in the transcriptional activation of adiponectin gene.
引文
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