摘要
高血压、糖尿病、脂质代谢紊乱和肥胖常常簇集出现而形成代谢综合征,严重影响到公众的健康水平。脂肪细胞可以产生和分泌促炎因子如TNFα、IL-1β和IL-6,很多肥胖相关的疾病状态与这些促炎因子等的不适当分泌有关。
高血压和肥胖患者患2型糖尿病的风险增加。近期临床试验表明,阻断肾素一血管紧张素系统(RAS)可能对这一高风险人群具有一定的保护作用。RAS系统组分存在于脂肪组织和脂肪细胞,因此脂肪组织和细胞可能成为血管紧张素受体拮抗剂(ARBs)的作用靶点。
基于以上背景,本研究通过动物实验和细胞实验研究ARBs对于脂肪组织和细胞本身糖脂代谢以及分泌炎症因子的影响,并对作用机制进行了初步探讨。
目的观察血管紧张素Ⅱ受体拮抗剂(AngiotensinⅡtype 1 receptorblockers,ARBs)对于脂肪组织和细胞糖脂代谢以及分泌炎症因子的影响以探讨ARBs改善胰岛素抵抗的机制。
方法1.动物实验:以Wistar雄性大鼠为研究对象,应用坎地沙坦酯(Candesartan,8mg/kg·d)对高脂饲养的Wistar大鼠进行为期4周的干预,用正葡萄糖钳夹试验比较干预组(高脂+坎地沙坦组,HF+C组)和非干预组(单纯高脂,HF组)的胰岛素敏感性,同时留取血清检测各组动物血糖、血脂、胰岛素以及促炎因子IL-1β、IL-6和TNFα的水平,并对干预后各组体重、肾周和附睾脂肪组织含量进行检测;
2.细胞实验:以3T3-L1细胞株为研究对象,1)MTT法检测不同浓度Telmi sartan对3T3-L1前脂肪细胞增殖的影响。2)应用替米沙坦(Telmisartan)以及联合PPARγ拮抗剂GW9662对3T3-L1细胞分化的早期(分化开始12h,24h)进行干预,倒置显微镜下以及油红0染色定量分析Telmisartan对于前脂肪细胞分化和分化过程中成脂作用的可能影响以及应用Q-PCR(Realtime QuantitativePCR)检测Telmisartan干预下3T3-L1分化过程中的PPARγmRNA表达情况;3)应用不同浓度Telmisartan(0.01-10 ug/ml)处理诱导成熟的3T3-L1脂肪细胞,通过检测脂肪细胞~(18)F-FDG摄取、培养液中游离脂肪酸(FFA)、IL-1β、IL-6和TNFα,观察Telmisartan对于成熟脂肪细胞糖脂代谢以及炎症因子分泌的影响;4)为进一步明确机制,利用高通量的基因表达谱芯片对替米沙坦引起的3T3-L1脂肪细胞差异基因表达进行筛选和分析,筛选的部分基因由Q-PCR进行验证。
结果1.动物实验结果:1)Candesartan干预的高脂喂养大鼠(HF+C)组体重、肾周和附睾脂肪量均较HF组显著降低(体重478±35g vs 51 8±28g,P<0.01;肾周脂肪20±4g vs 26±4g,P<0.01;附睾脂肪9.6±1.8g vs 11.5±2.0g,P<0.05),空腹血糖差异无统计学意义(P>0.05);2)HF+C组血浆炎症因子IL-6、TNFα水平较HF组也显著降低(IL-6分别为54.03±13.32pg/ml和85.35±16.93pg/ml,P<0.05;TNFα分别为33.18±5.51pg/ml和48.2 0±7.87g/ml,P＜0.05),IL-1β在HF组和HF+C组差异无显著意义(41.04±10.12pg/ml vs 29.72±7.66 pg/ml,P＞0.05);3)正葡萄糖钳夹试验表明,两组的葡萄糖输注率(GIR)存在显著差异,HF+C组GIR显著高于HF组(22.4±5.12mg/kg·min vs 13.54±3.92 mg/kg·min,P＜0.05);
2.细胞实验结果表明:1)MTT法检测表明,浓度为0.01-1.0 ug/ml的Telmisartan对于3T3-L1前脂肪细胞的增殖无显著影响; 2)3T3-L1细胞的分化的早期(诱导起始12h和24h)应用Telmisartan(0.1ug/ml)干预可以促进细胞的分化以及分化过程中的脂质聚集,同时Realtime PCR显示Telmisartan可增加诱导过程中PPARγ基因的表达增高(在诱导的第3天和第6天分别增加2.51倍和1.46倍);3)对诱导成熟3T3-L1脂肪细胞进行干预,Telmisartan可以呈剂量依赖的降低细胞脂质含量,增加~(18)F-FDG摄取。同时,Telmisartan可以降低培养液中IL-6和TNFα的分泌,增加培养液中FFA的含量。基因芯片结果筛选157个差异表达基因或基因片段。这些基因涉及细胞内脂质代谢和转运、细胞的分化以及氧化应激和炎性途径,这些途径介导了Telmisartan发挥调节细胞脂质代谢和炎症因子分泌的作用。另外,Nos 3(内皮型-氧化氮合酶基因)和CPT1A(肉碱脂酰转移酶-1α基因)基因表达的改变可能介导了Telmisartan发挥调节细胞糖脂代谢的作用。
结论1)Candesartan可以减少高脂喂养大鼠的体重和脂肪组织,降低血清炎症因子水平,改善大鼠糖、脂代谢;2)Telmisartan可以促进前脂肪细胞向脂肪细胞的转化,促进成熟脂肪细胞糖摄取,减少成熟脂肪细胞脂质含量,这种对于脂肪细胞的直接作用可能是由细胞炎性途径以及脂肪酸代谢途径所介导的。提示某些ARBs对动物机体以及脂肪组织和脂肪细胞本身的糖脂代谢有重要影响。
The cluster of hypertension, diabetes mellitus, dyslipidemia and body obesity, collectively referred to as the metabolic syndrome, is a common cause of atherosclerotic cardiovascular diseases and one of the most serious threats to public health. Adipose tissue produces and secretes some proinflammatory factors. Dysregulated production of proinflammatory factors, such as tumor necrosis factor-α(TNFα), interleukin-1β(IL-1β) and iterleukin-6 (IL-6), is associated with the pathophysiology of obesity-related disorders.
Patients with essential hypertension and obesity are at the increased risk of type 2 diabetes. Several recent clinical trials have suggested that blockade of the rennin-angiotensin system (RAS) may protect against the development of de-novo diabetes in 'at risk' patients. Evidences show that the RAS may have a direct role in the pathogenesis of diabetes. RAS components exist in the adipocyte, which makes the adipose tissue is the potential target of angiotensinⅡreceptor blockers.
In this context, the present study was designed to elucidate the effect of angiotensinⅡreceptor blockers on the adipocytes in vivo and in vitro.
Objective: To investigate the effect of angiotensinⅡtype 1 receptor blockers on the proinflammatory factors' secretion and metabolisms of glucose and lipid of the the adipose tissue and adipocytes, and possible molecular mechanisms.
Method: 1. in vivo study: 45 male Wistar rats were randomly divided into 3 groups: normal chow group (NC, n=15) fed with normal diet, high fat diet group (HF, n=15) fed with high fat diet, and high-fat diet with daily candesartan treatment group (HF+C, n=15) fed with high fat diet and given orally with candesartan 8 mg/kg per day. Body weight was measured weekly. Four weeks later, euglycemic-hyperinsulinemic clamp technique was performed to estimate the insulin sensitivity. After 12h fasting blood samples were collected from the abdominal aorta for measurement of the contents of blood glucose, and serum triglyceride (TG), total cholesterol (TC), LDL, HDL, and free fatty acid (FFA). Radioimmunoassay was used to detect the serum insulin. ELISA was used to mesure the level of the serum IL-1β, IL-6 and TNFα.
2. in vitro study : 1) MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was processed to determine the effects of various concentrations of Telmisartan (0.01ug/ml, 0.1ug/ml and 1ug/ml) on the proliferation of 3T3-L1 preadipocytes. 2) Various concentrations of Telmisartan and GW9662 (PPARγantagonist) were applied to interfere the early phase (12h and 24h) in the process of the induction of 3T3-L1 preadipocytes and oil red O staining were processed to determine the effect of telmisartan on the differentiation of 3T3-L1 preadipocytes. The expression of PPARγmRNA were obtained with quantitative real-time PCR (Q-PCR). 3) Various concentrations (0.01, 0.1, 1 and 10 ug/ml) of telmisartan were applied to interfere with the mature 3T3-L1 adipocytes. Free fatty acids、IL-6 and TNFαof cultured medium were evaluated. Oil red O staining was processed to determine the effects of telmisartan on the adipogenesis of 3T3-L1 adipocytes. ~(18)F-FDG uptake levels were determined by cellular radioactivity measured after 25-min incubation. 4) The total RNA was isolated from the control group and the telmisartan group (0.1ug/mL) for hybridization experiment of the microarray. And the part of results was verified by Q-PCR.
Results: 1. in vivo study: HF group was significantly higher than that of the HF+C goup (P<0.01). The epididymal and perirenal fat weights of the HF group were all significantly higher than those of the HF+C group and NC group (both P<0.01). The difference of the fasting blood glucose among the 3 groups was no significance (P>0.05). Serum levels of IL-6 and TNFαwere significantly decreased in the HF+C treated group, compared with the HF group [IL-6 54.03±13.32 pg/ml vs 85.35±16.93pg/ml (P <0.05); TNFα33.18±5.51 pg/ml vs 48.20±7.87 pg/ml (P<0.05)]. IL-1βlevel was no significantely different between the HF and HFD+C [41.04±10.12 pg/ml vs 29.72±7.66 pg/ml (P>0.05)]. The glucose infusion rate (GIR) of HF+C group was significantly higher than that of the HF group [22±5 mmol/L vs 14±4 mmol/L, (P＜0.01)].
2. in vitro study: 1) MMT showed that Telmisartan (0.01-1.0ug/ml) had no effect on the proliferations of 3T3-L1 preadipocytes; 2) In the process of induction of 3T3-L1 preadipocytes, Telmisartan (0.1ug/ml) promoted the differention of the cells, and increased adiposity during the process of differentiation. At the same time, the expression of PPARγdetected by Q-PCR was increased by telmisartan. 3) Various concentrations of telmisartan were applied to interfere with the mature 3T3-L1 adipocytes. Telmisartan reduced the lipid storage and increased the ~(18)F-FDG uptake of mature 3T3-L1 adipocytes in a dose-dependent manner. At the same time, Telmisartan reduced the levels of IL-6 and TNFαand increased that of FFAs in the cultural medium. One hundred and fifty seven genes differentially expressed between the groups were found by microarray. These were involved in lipid synthesis, eatabolism and transport in the adipocyte. Preliminary analyses of these gene functions and their relationship were performed. MAP kinas signaling pathway involving the secretion of proinflammatory factor and lipid metabolisms were affected by telmisartan. Up-regulation of Nos3 and CPT1A expression by telmisartan may also underlied the improvement in the lipid metabolisms.
Conclusions: Candesartan might reduce the proinflammmatory factors, improve the lipid metabolisms and insulin resistance .And Telmisartan has important direct effects on the lipid metabolisms and the proinflammatory factors secretion of the adipocyte.These showed that some of the ARBs affected lipometabolisms and the proinflammatory factors secreted from adipocytes, and improve the insulin resistance.
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