非诺贝特、吡格列酮对SD大鼠Visfatin蛋白表达的影响
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摘要
目的研究非诺贝特、吡格列酮对SD大鼠Visfatin蛋白表达的影响。方法120只6周龄雄性SD大鼠随机分为普食组和高脂组,每组60只。普食组给予普通饲料喂养,高脂组予高脂饲料。定期称重大鼠,12周肥胖大鼠形成模型后,药物干预组(普食+非诺贝特组、高脂+非诺贝特组、普食+吡格列酮组、高脂+吡格列酮组,每组20只)分别予非诺贝特30mg/kg.d、吡格列酮10mg/kg.d灌胃4周,余对照组(普食组、高脂组,每组20只)予相应溶剂灌胃,容积分别为2ml/kg.d。16周时抽血备测血清Visfatin、游离脂肪酸(FFA)、甘油三酯(TG)、胆固醇(TCH)、空腹血糖(FBG)、空腹胰岛素(FINS)等指标,分离附睾周围脂肪、肾周脂肪、网膜脂肪(三者合称为内脏脂肪组织)和腹部皮下脂肪,称重并提取蛋白质,用Western blot法检测Visfatin蛋白表达;分离腓肠肌组织,用Western blot法检测Visfatin蛋白量和免疫组化方法检测肌肉组织中Visfatin蛋白的定位。结果(1)与普食组相比:高脂组大鼠体重(BW)、内脏脂肪重量、皮下脂肪重量、血清Visfatin、FBG、FINS、TG、FFA、HOMA-index均明显增高(P<0.05); TCH差异无统计学意义;普食组、普食+非诺贝特组和普食+吡格列酮组大鼠BW、内脏脂肪重量、皮下脂肪重量、血清Visfatin、FBG、FINS、TG、FFA、TCH、HOMA-index差异无统计学意义。与高脂组相比:高脂+非诺贝特组BW、内脏脂肪重量、血清Visfatin、FBG、FINS、TG、FFA、HOMA-index均显著下降(P<0.05),皮下脂肪重量、TCH也下降,但差异无统计学意义;高脂+吡格列酮组较高脂组血清Visfatin、FBG、FINS、TG、FFA、HOMA-index均显著下降(P<0.05),BW和皮下脂肪重量升高(P<0.05),内脏脂肪重量下降,但差异无统计学意义;(2)用Western blot法在内脏脂肪、皮下脂肪和肌肉组织中都检测到Visfatin蛋白的表达,各组动物内脏脂肪组织中Visfatin表达均高于皮下脂肪组织(P<0.05),皮下脂肪组织中Visfatin表达高于肌肉组织(P<0.05);与普食组相比,普食+非诺贝特组、普食+吡咯列酮组的内脏脂肪、皮下脂肪、肌肉组织中Visfatin表达差异无统计学意义。与高脂组相比,高脂+非诺贝特组、高脂+吡咯列酮组内脏脂肪Visfatin表达下降(P<0.05),但皮下脂肪组织、肌肉脂肪组织中Visfatin表达差异无统计学意义。(3)免疫组化显示:肌肉组织中Visfatin主要表达于肌肉细胞而非肌肉间质的脂肪细胞或其他成纤维细胞等。(4)相关分析显示:血清Visfatin与内脏脂肪重量、内脏脂肪中Visfatin表达、FBG、HOMA-index、TG呈正相关。结论(1)高脂饮食可诱导大鼠产生营养性肥胖,出现糖脂代谢紊乱;非诺贝特和吡格列酮可以调节高脂饮食诱导的大鼠血脂代谢紊乱、改善胰岛素抵抗,同时非诺贝特可以降低肥胖大鼠体重;该两种药物对正常饮食状态下大鼠血糖、血脂无调节作用。(2)Visfatin广泛表达于内脏脂肪、皮下脂肪和肌肉组织,其是主要表达于内脏脂肪的脂肪因子;(3)在高脂饮食诱导SD大鼠出现肥胖、胰岛素抵抗状态时,血清和内脏脂肪Visfatin出现代偿性高表达,非诺贝特和吡格列酮在改善糖脂代谢紊乱同时伴随有血清和内脏脂肪Visfatin表达下降。非诺贝特和吡格列酮对普通饮食状态下Visfatin表达无明显调节作用。
Objective: To investigate the effects of fenofibrate、pioglitazone onVisfatin protein expression in SD rats.
Methods: 120 6-wk-old male SD rats were divided into 2 groups randomly : NC group and HF group (n=60). NC group were fed with normal chow and the others with high-fat diets. After 12 weeks, models of obese rats were established, then the drug treated groups (NC + fenofibrate group, NC + pioglitazone group , HF + fenofibrate group and HF + pioglitazone group, n=20) were treated with 30mg/kg fenofibrate, 10mg/kg pioglitazone intragastric daily for 4 weeks, and the control groups with homologous solvent. The volume of drug or solvent was 2ml/kg daily. Body weight was measured regularly. Serum Visfatin、free fatty acids (FFA)、triglyceride (TG)、total cholesterol (TCH)、fasting blood glucose (FBG) and fasting insulin (FINS) were detected after 16 weeks. Epididymis fat、kidney fat、omenta fat ( the three as visceral fat) and abdominal subcutaneous fat were weighed and harvested for protein extraction and western blot analysis. Gastrocnemius was also harvested for western blot and immunohistochemistry.
Results (1) Compared with NC group , body weight (BW)、visceral fat、subcutaneous fat、serum Visfatin、FBG、FINS、TG、FFA and HOMA-index of HF group were elevated significantly (P<0.05);but not TCH (P>0.05); BW、visceral fat、subcutaneous fat、serum Visfatin、FBG、FINS、TG、FFA、TCH and HOMA-index were not affected by fenofibrate or pioglitazone in the rats fed normal chow (P>0.05);Compared with HF group, BW、visceral fat、serum Visfatin、FBG、FINS、TG、FFA and HOMA-index were all downregulated in HF+fenofibrate group(P<0.05),but not subcutaneous fat or TCH (P >0.05);Serum Visfatin、FBG、FINS、TG、FFA and HOMA-index were decreased by pioglitazone in HF +pioglitazone group (P<0.05),and pioglitazone increased BW and subcutaneous fat (P<0.05) in high-fat diet fed SD rats but not visceral fat; (2) Visfatin was expressed widely in visceral fat、subcutaneous fat and muscle. Visfatin expression was much higher in visceral fat than subcutaneous fat than muscle in all of the rats. Additionally, there was no difference of Visfatin in subtaneous fat and muscle of different group animals (P>0.05). Fenofibrate and pioglitazone could downregulate visceral fat Visfatin in high-fat diets fed rats (P<0.05) but not subcutaneous fat or muscle (P>0.05). Both of the two drugs had no effect on Visfatin expression in the tissues of the animals fed normal chow. (3) Immunohistochemistry: in the muscle, Visfatin was expression in the muscle cells but not the interstitial tissue. (4) Correlation analysis: serum Visfatin was positively correlated with the weight of visceral fat、Visfatin expression in visceral fat、FBG、HOMA-index and TG.
Conclusion: (1) High-fat diets could induced obesity in rats and metabolic disturbance of glucose and lipid; fenofibrate and pioglitazone could reduce lipid profiles and increase insulin sensitivity. Meanwhile, fenofibrate could reduce adiposity; both of the two drugs had no effects on metabolic disturbance of glucose and lipid in the animals of NC group. (2) Visfatin is an adipocytokine predominantly expressed in visceral fat and it could be detected in visceral fat、subcutaneous fat and muscle. (3) High-fat diets induced the rats to be obese with insulin resistance and the compensatory increase of Visfatin expressionl; fenofibrate and pioglitazone ameliorated the development of insulin resistance in HF-fed rats with a major decrease in Visfatin expression, the effects of pioglitazone and fenofibrate on Visfatin in HF-fed rats are secondary to changes in metabolic parameters; both of the two drugs had no effect on Visfatin expression in the rats of NC group; the mechanisms of the effects of fenofibrate and pioglitazone on Visfatin expression in the rats of different status await further investigation.
Objective: To investigate the effects of fenofibrate、pioglitazone onVisfatin protein expression in SD rats.
Methods: 120 6-wk-old male SD rats were divided into 2 groups randomly : NC group and HF group (n=60). NC group were fed with normal chow and the others with high-fat diets. After 12 weeks, models of obese rats were established, then the drug treated groups (NC + fenofibrate group, NC + pioglitazone group , HF + fenofibrate group and HF + pioglitazone group, n=20) were treated with 30mg/kg fenofibrate, 10mg/kg pioglitazone intragastric daily for 4 weeks, and the control groups with homologous solvent. The volume of drug or solvent was 2ml/kg daily. Body weight was measured regularly. Serum Visfatin、free fatty acids (FFA)、triglyceride (TG)、total cholesterol (TCH)、fasting blood glucose (FBG) and fasting insulin (FINS) were detected after 16 weeks. Epididymis fat、kidney fat、omenta fat ( the three as visceral fat) and abdominal subcutaneous fat were weighed and harvested for protein extraction and western blot analysis. Gastrocnemius was also harvested for western blot and immunohistochemistry.
Results (1) Compared with NC group , body weight (BW)、visceral fat、subcutaneous fat、serum Visfatin、FBG、FINS、TG、FFA and HOMA-index of HF group were elevated significantly (P<0.05);but not TCH (P>0.05); BW、visceral fat、subcutaneous fat、serum Visfatin、FBG、FINS、TG、FFA、TCH and HOMA-index were not affected by fenofibrate or pioglitazone in the rats fed normal chow (P>0.05);Compared with HF group, BW、visceral fat、serum Visfatin、FBG、FINS、TG、FFA and HOMA-index were all downregulated in HF+fenofibrate group(P<0.05),but not subcutaneous fat or TCH (P >0.05);Serum Visfatin、FBG、FINS、TG、FFA and HOMA-index were decreased by pioglitazone in HF +pioglitazone group (P<0.05),and pioglitazone increased BW and subcutaneous fat (P<0.05) in high-fat diet fed SD rats but not visceral fat; (2) Visfatin was expressed widely in visceral fat、subcutaneous fat and muscle. Visfatin expression was much higher in visceral fat than subcutaneous fat than muscle in all of the rats. Additionally, there was no difference of Visfatin in subtaneous fat and muscle of different group animals (P>0.05). Fenofibrate and pioglitazone could downregulate visceral fat Visfatin in high-fat diets fed rats (P<0.05) but not subcutaneous fat or muscle (P>0.05). Both of the two drugs had no effect on Visfatin expression in the tissues of the animals fed normal chow. (3) Immunohistochemistry: in the muscle, Visfatin was expression in the muscle cells but not the interstitial tissue. (4) Correlation analysis: serum Visfatin was positively correlated with the weight of visceral fat、Visfatin expression in visceral fat、FBG、HOMA-index and TG.
Conclusion: (1) High-fat diets could induced obesity in rats and metabolic disturbance of glucose and lipid; fenofibrate and pioglitazone could reduce lipid profiles and increase insulin sensitivity. Meanwhile, fenofibrate could reduce adiposity; both of the two drugs had no effects on metabolic disturbance of glucose and lipid in the animals of NC group. (2) Visfatin is an adipocytokine predominantly expressed in visceral fat and it could be detected in visceral fat、subcutaneous fat and muscle. (3) High-fat diets induced the rats to be obese with insulin resistance and the compensatory increase of Visfatin expressionl; fenofibrate and pioglitazone ameliorated the development of insulin resistance in HF-fed rats with a major decrease in Visfatin expression, the effects of pioglitazone and fenofibrate on Visfatin in HF-fed rats are secondary to changes in metabolic parameters; both of the two drugs had no effect on Visfatin expression in the rats of NC group; the mechanisms of the effects of fenofibrate and pioglitazone on Visfatin expression in the rats of different status await further investigation.
引文
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10.周笑漪,徐焱成.高脂饮食诱导的胰岛素抵抗大鼠内脂素的表达水平[J].武汉大学学报,2007;28(3):325-9.
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2. Fukuhara A,MatsudaM,NishizawaM, et al. Visfatin: a p rotein secreted by visceral fat that mimics the effects of insulin [J]. Science, 2005, 307 (5708) : 426-30.
3. Brendt J,Kl~Ring N,Kralisch s,et a1.Plasma visfatin conccntrations and fat depot-specific mRNA expresion in humans[J].Diabetes,2005,54(1O):2911—6.
4. Choi KC, Ryu OH, Lee KW, et al. Effect of PPAR-alpha and–gamma agonist on the expression of visfatin,adiponectin, and TNF-alpha in visceral fat of OLETF rats. Biochem Biophys Res Commun. 2005; 336:747-53.
5. Jian WX, Luo TH, Gu YY, et al. The visfatin gene is associated with glucose and lipid metabolism in a Chinese population. Diabet Med 2006; 23 : 967-73.
6. Krzysik-Walker SM, Ocón-Grove OM, Maddineni SR, et al. Is visfatin an adipokine or myokine? Evidence for greater visfatin expression in skeletal muscle than visceral fat in chickens. Endocrinology 2008; 149 : 1543-50.
7. López-Bermejo A, Chico-JuliàB, Fernàndez-Balsells M, et al. Serum visfatin increases with progressive beta-cell deterioration. Diabetes 2006; 55 : 2871-5.
8. Chen CC, Li TC, Li CI, et al. The relationship between visfatin levels and anthropometric and metabolic parameters: association with cholesterol levels in women. Metabolism 2007; 56 : 1216-20.
9. Dogru T, Sonmez A, Tasci I, et al. Plasma visfatin levels in patients with newly diagnosed and untreated type 2 diabetes. Diabetes Res Clin Pract.2007 ;76(1):24-9.
10.周笑漪,徐焱成.高脂饮食诱导的胰岛素抵抗大鼠内脂素的表达水平[J].武汉大学学报,2007;28(3):325-9.
11. Chen MP, Chung FM, Chang DM, et al. Elevated p lasma level of visfatin /p re2Bcell colony 2 enhancing factor in patients with type 2 diabetesmellitus [ J ]. J Clin endoerinol Metab, 2006, 91 ( 1 ) :295-9.
12. Hug C,Lodish HF. Medicine. Visfatin: a new adipokine [ J ]. Science, 2005, 307 (5708) : 366-7.
13.Teruel T, Smith SA, Prterson J, et al. Synergistic activation of UCP-3 expression in culture fetal brown adipocytes by PPARalpha and PPAR gamma ligands. Biochem Biophys Res Commum.2000;273(2):560-4.
14. Larsen PJ, Jensen PB, Sorensen RV, et al. Differential influences of peroxisome proliferator-activated receptors-gamma and alpha and food intake and energy homeostasis. Diabetes.2003;52(90)249-59.
15.Marcus S L, Miyata K S, Zhang B W, et al. Diverse peroxisome proliiferator activated receptors bind to the peroxisome proliferators- responsive elements of the rat hydratase/de-hydroganase and fatty acyl-CoA oxidase genes but differentially induce expression. Proc Natl Acad Sci USA.1993;90:5723-7.
16. Zhang BW, Marcus SL, Sajjadi FG, et al. Identification of peroxisome proliferators responsive element upstream of the gene encoding rat peroxisome-alanoyl- CoA hydratase/3-hydroxyacyl-CoA dehydrogenase. Proc Natl Acad Sci USA.1992;89;7541-5.
17.Rosen ED, Sarraf AE, Troy G, et al. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro . Molecular Cell. 1999;4:611-7.
18.EI Jack A K. Hamm J K. Pilch P F,et al. SR farmer reconstitution of insulin sensitive glucose transport in fibroblasts requires expression of both PPAR gamma and C/EBP alpha. J Biol Chem. 1999;274:7946-57.
19.WANG Q, DRYDEN S, FRANKISH HM, et al. Increased feeding in fatty Zucker rats by the thiazolidinedione BRL49653(rosiglitazone) and the possible involvement of leptin and hypothalamic neuropeptide Y. Br J Pharmacol. 1997;122(7):1405-10.
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