大豆提取物PC对食源性肥胖大鼠的作用及肥胖儿童的血浆蛋白组学研究
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摘要
第一部分PC对食源性肥胖大鼠作用的研究
目的：观察大豆提取物PC对食源性肥胖大鼠体重和胰岛素抵抗的影响并探讨其机制。
方法：用高脂高蛋白饮食致大鼠肥胖（肥胖大鼠模型），体重大于对照组平均体重加1.96倍标准差定为食源性肥胖大鼠（DIO）。研究大鼠分为五组：（1）肥胖对照组（DIO）；（2）肥胖组+灌服150mg/kg PC(DIO+PC150)；（3）肥胖组+灌服75mg/kgPC(DIO+PC75)；（4）肥胖组+灌服37.5mg/kg PC(DIO+PC37.5)；（5）10只普通饲料组大鼠作为正常对照组（Control, CN）。每日一次，连续灌服PC8周。处死大鼠，检测/记录体重、摄食量、肾周脂肪、睾周脂肪以及肝、肾脏器官指数变化；按照试剂盒的要求检测血糖、血清胰岛素、血脂、肝功能等指标，用ELISA法检测血清脂联素、血清瘦素、血清抵抗素水平，并观察各指标变化；肝组织用不同方法切片、染色后，分别用光镜和电镜观察其病理改变。
结果：（1）灌服PC后，肥胖大鼠的摄食量、体重、肾周脂肪、睾周脂肪以及肝脏器官指数均较模型组明显减少（P<0.05，P<0.01）。（2）灌服PC后，血清胰岛素、HOMA-HR、血清抵抗素、瘦素、胆固醇、甘油三酯、AST、ALT水平均显著降低而高密度脂蛋白水平升高，与模型组比较（P<0.05，P<0.01）。LDL和脂联素水平无明显变化（P<0.05）。（3）光学显微镜显示：食源性肥胖大鼠肝组织有大量脂肪变性，胞质内充满大小不一的脂滴空泡，血管周围炎症细胞浸润严重。电镜检查显示：食源性肥胖大鼠肝脏肝脂滴明显增多，线粒体肿胀，部分有纤维化。而灌服PC大鼠可明显减轻肥胖大鼠肝脏组织结构的病理改变轻微。
结论：灌服PC具有明显的减轻体重和改善胰岛素抵抗的作用，该作用与抑制摄食量，降低肾周脂肪、睾周脂肪重量及体脂比、减轻血清胰岛素、HOMA-HR、血清抵抗素、瘦素水平有关。PC对肥胖的脂肪肝也有一定的防治作用，使AST、ALT水平降低。其机制可能与其降低瘦素水平和减轻肝脏的脂肪变性有关。
第二部分PC对3T3-L1脂肪细胞增殖、分化及GLUT4蛋白表达的影响
目的：观察PC对前脂肪细胞增殖、生长周期、分化及细胞膜上GLUT4蛋白表达的影响，探讨PC对减轻体重及改善胰岛素抵抗可能的作用机制。
方法：采用MTT和流式细胞仪法观察PC对3T3-L1细胞增殖和生长周期的影响；用诱导剂诱导3T3-L1细胞分化，并观察PC对细胞分化的作用；采用流式细胞仪和免疫组化两种方法观察PC对脂肪细胞膜上GLUT4蛋白表达的影响。
结果：（1）PC能显著抑制3T3-L1细胞的增殖和分化；
（2）PC影响脂肪细胞生长的周期，使其停止于S期；
（3）PC使脂肪细胞膜上GLUT4蛋白表达水平显著升高（P<0.05，P<0.01）。
结论：PC减轻体重的作用可能与其抑制3T3-L1脂肪细胞的增殖和分化，干扰其正常的生长周期有关；其改善胰岛素抵抗作用可能与增加脂肪细胞细胞膜上的GLUT4蛋白表达，促进葡萄糖的转运有关。
第三部分肥胖儿童血浆蛋白质组学研究和差异蛋白质的亚细胞定位
目的：筛选肥胖儿童血浆中的差异蛋白质，为肥胖研究及PC药物作用机制的研究提供新的靶点。
方法：收集肥胖儿童及健康儿童血浆，用免疫亲和柱去除高丰度蛋白，用胰蛋白酶酶解蛋白，运用基于液相色谱串联质谱无标记物（Label-free）的新技术进行蛋白定量；通过Maxquant软件检索人的数据库Uniport，获得候选蛋白信息，找出差异蛋白；并用CELLO v.2.5软件将筛选出的差异蛋白进行亚细胞定位。
结果：（1）经过对儿童肥胖蛋白质组学检测，成功发现了14个差异蛋白质，主要是与凝血和免疫功能相关的蛋白。其中肥胖儿童血浆中上调的免疫球蛋白有2种，下调的免疫球蛋白有3种；补体C5、C6和不同因子B、I均上调，共有4种。血红蛋白α和β亚单位、纤维蛋白原α和β亚单位均上调，而富含组氨酸糖蛋白下调。（2）筛选出的差异蛋白中位于细胞外的蛋白质最多，高达57%，其次是细胞核29%，位于细胞质膜以及细胞外膜的蛋白质均为7%。
结论：（1）筛选出了肥胖的差异蛋白共14种，为肥胖发病机制及药物治疗研究提供新的思路和途径。（2）推测PC可能通过调节补体C5、C6、补体B、I因子改善炎性反应和肝脏的脂肪变性，使富含组氨酸糖蛋白、补体因子B等指标恢复正常，从而延缓肥胖及其相关并发症的发生。（3）亚细胞定位于胞质外的蛋白质最多，其次是细胞核，位于细胞质膜及外膜的蛋白质极少，提示肥胖的发生是多条途径相互影响的结果。该信息为推断该蛋白质的生物学功能以及差异蛋白间的相互作用提供了必要的信息。
1Investigating the Effects of PC on Diet-induced Obesity
Objective: To investigate the effects of PC on Diet-induced Obesity (DIO) and itsmechanisms.
Methods: The obesity model was induced by high-fat and high-protein diet. Rats withbody weight>ME+1.96SD were identified obesity.Obesity rats were randomly divided intofour groups:(1) Obesity rats (DIO),(2)Obesity rats treated with150mg/kgPC(DIO+PC150),(3)Obesity rats treated with75mg/kg PC(DIO+PC75),(4)Obesity ratstreated with37.5mg/kg PC(DIO+PC37.5). Normal rats act as the control group(NC). PCwas administered by the intragastric route once a day for eight weeks. Body weight,quantity of food intake and caloric intake were measured after four and eight weeks. Thequantity of epididymal fat, perirenal fat, liver weight and kidney weight were measuredafter eight weeks, and the lipid ratio, as well as the liver weight/body weight, kidneyweight/body weight were counted as formula.The blood glucose(BG), insulin,cholesterol(TC), triglycerides (TG), high-density lipoprotein(HDL) and low-densitylipoprotein(LDL), alamine aminotransferase (AST) and aspartate aminotransferase(ALT),leptine, adiponectin(ADP) and resistant in serum were determined after eight weeks byusing commercially available kits following the manufacturer’s instructions.Thehomeostasis model assessment-IR (HOMA-IR) was obtained according to insulin and BG.The pathological changes of liver were evaluated under light and electron microscope afterstaining.
Results:(1) Supplement with PC, the food intake, energy intake, perirenal fat,epididymal fat, the liver weight, liver weight/body weight, serum insulin, HOMA-HR,serum resistant, leptin, TC, TG, AST, ALT, were decreased significantly (compared to DIOrats, P<0.05and P<0.01);(2) Supplement with PC, the serum HDL was increased significantly (P<0.05); There was no difference in serum LDL and leptin level betweengroups (P<0.05);(3) Its observed that the pathological change in liver was smaller in PCsupplement rats.
Conclusions: The present study suggested that PC supplement had some beneficialeffect on obesity rats and improve insulin resistance, which partly through decreasing thefood (caloric) intake, perirenal fat, epididymal fat and body fat ratio, serum insulin,HOMA-HR, serum resistin, leptin. PC also had a therapeutic effect for obesity fatty liver,with decreasing the level of AST and ALT, its mechanism may be associated withdecreasing resistin and leptin levels,against the fatty degeneration in liver.
2Effects of PC on Proliferation, Cell cycle andDifferentiation in Preadipocyte
Objective: To study the effects of PC on proliferation, cell cycle and differentiationon preadipocyte.
Methods: The effects of PC on proliferation on3T3-L1lines were determined byMTT assay, and cell cycle was determined by flow cytometry; The effect of PC onadipocyte differentiation was observed under light microscope after treated with3-Isobutyl-1-methylxanthine, insuline and dexamethasone. Immunohistochemicalstaining and flow cytometry analysis were used to investigate the influence of PC onexpression of GLTU4protein in membrane.
Results:(1) The proliferation and differentiation of3T3-L1cell were inhibited afterincubated with PC.(2) The cell cycle was blocked in S phase after treated with PC;(3) The expression of GLUT4in preadipocyte was increased significantly after treatedwith PC（P<0.05，P<0.01）。
Conclusions: The results indicated that PC had some protective effect against obesityand improved insulin resistance, wihic partly through inhibiting the proliferation anddifferentiation and up-regulating GLUT4expression of membrane lipocyte.
3Study on Plasma Proteomics in obese children and subcellularlocalization for the different proteins
Objective: To study the plasma proteomics of obese children and search fordifferent protein and their subcellular localization.
Methods: Blood samples for plasma proteomic analysis were obtained from obeseand healthy children. Low-abundance proteins were separated with Seppro IgY14Spincolumns according to the instructions of manufacturer.Then the low-abundance proteinwas digested with trypsin. The protein quantification was using liquid chromatographytandem mass spectrometry with label-free. To analylsis the different expressed proteins byMaxquant software and Uniport database. The subcellular localization information ofdifferent proteins was analysis by using CELLO v.2.5software.
Results:(1) Fourteen different proteins were founed in obesity children,10up-regulated and4down-regulated. The coagulation-associated potein and immuneassociated protein were involved in these different protein.
(2) Using CELLO v.2.5software, entered the amino acid sequence of14differentproteins and obtained subcelluar localtion information for each protein. Most proteinslocated in the extracelluar, up to57%,29%proteins in nuclear, while just14%incytoplasmic and out membrane respectively. But there was no protein in mitochondria.
Conclusion: Fourteen different protein were found in obese children which willprovide new ideas about the pathogenesis of obesity and drug target. We could concludethat PC may improve the insulin resistance and inflammatory by adjusting complement C5,C6and complement factor B, I, and increase the secretion of histidine-rich glycoprotein,then ameliorate the obesity and related-disease.The subcelluar location indicated that theremay be multi-channel interaction in extra-celluar, nuclear, cytoplasmic and out membranein the mechanisms of obesity. The present study provided new information about thesedifferent proteins.
目的：观察大豆提取物PC对食源性肥胖大鼠体重和胰岛素抵抗的影响并探讨其机制。
方法：用高脂高蛋白饮食致大鼠肥胖（肥胖大鼠模型），体重大于对照组平均体重加1.96倍标准差定为食源性肥胖大鼠（DIO）。研究大鼠分为五组：（1）肥胖对照组（DIO）；（2）肥胖组+灌服150mg/kg PC(DIO+PC150)；（3）肥胖组+灌服75mg/kgPC(DIO+PC75)；（4）肥胖组+灌服37.5mg/kg PC(DIO+PC37.5)；（5）10只普通饲料组大鼠作为正常对照组（Control, CN）。每日一次，连续灌服PC8周。处死大鼠，检测/记录体重、摄食量、肾周脂肪、睾周脂肪以及肝、肾脏器官指数变化；按照试剂盒的要求检测血糖、血清胰岛素、血脂、肝功能等指标，用ELISA法检测血清脂联素、血清瘦素、血清抵抗素水平，并观察各指标变化；肝组织用不同方法切片、染色后，分别用光镜和电镜观察其病理改变。
结果：（1）灌服PC后，肥胖大鼠的摄食量、体重、肾周脂肪、睾周脂肪以及肝脏器官指数均较模型组明显减少（P<0.05，P<0.01）。（2）灌服PC后，血清胰岛素、HOMA-HR、血清抵抗素、瘦素、胆固醇、甘油三酯、AST、ALT水平均显著降低而高密度脂蛋白水平升高，与模型组比较（P<0.05，P<0.01）。LDL和脂联素水平无明显变化（P<0.05）。（3）光学显微镜显示：食源性肥胖大鼠肝组织有大量脂肪变性，胞质内充满大小不一的脂滴空泡，血管周围炎症细胞浸润严重。电镜检查显示：食源性肥胖大鼠肝脏肝脂滴明显增多，线粒体肿胀，部分有纤维化。而灌服PC大鼠可明显减轻肥胖大鼠肝脏组织结构的病理改变轻微。
结论：灌服PC具有明显的减轻体重和改善胰岛素抵抗的作用，该作用与抑制摄食量，降低肾周脂肪、睾周脂肪重量及体脂比、减轻血清胰岛素、HOMA-HR、血清抵抗素、瘦素水平有关。PC对肥胖的脂肪肝也有一定的防治作用，使AST、ALT水平降低。其机制可能与其降低瘦素水平和减轻肝脏的脂肪变性有关。
第二部分PC对3T3-L1脂肪细胞增殖、分化及GLUT4蛋白表达的影响
目的：观察PC对前脂肪细胞增殖、生长周期、分化及细胞膜上GLUT4蛋白表达的影响，探讨PC对减轻体重及改善胰岛素抵抗可能的作用机制。
方法：采用MTT和流式细胞仪法观察PC对3T3-L1细胞增殖和生长周期的影响；用诱导剂诱导3T3-L1细胞分化，并观察PC对细胞分化的作用；采用流式细胞仪和免疫组化两种方法观察PC对脂肪细胞膜上GLUT4蛋白表达的影响。
结果：（1）PC能显著抑制3T3-L1细胞的增殖和分化；
（2）PC影响脂肪细胞生长的周期，使其停止于S期；
（3）PC使脂肪细胞膜上GLUT4蛋白表达水平显著升高（P<0.05，P<0.01）。
结论：PC减轻体重的作用可能与其抑制3T3-L1脂肪细胞的增殖和分化，干扰其正常的生长周期有关；其改善胰岛素抵抗作用可能与增加脂肪细胞细胞膜上的GLUT4蛋白表达，促进葡萄糖的转运有关。
第三部分肥胖儿童血浆蛋白质组学研究和差异蛋白质的亚细胞定位
目的：筛选肥胖儿童血浆中的差异蛋白质，为肥胖研究及PC药物作用机制的研究提供新的靶点。
方法：收集肥胖儿童及健康儿童血浆，用免疫亲和柱去除高丰度蛋白，用胰蛋白酶酶解蛋白，运用基于液相色谱串联质谱无标记物（Label-free）的新技术进行蛋白定量；通过Maxquant软件检索人的数据库Uniport，获得候选蛋白信息，找出差异蛋白；并用CELLO v.2.5软件将筛选出的差异蛋白进行亚细胞定位。
结果：（1）经过对儿童肥胖蛋白质组学检测，成功发现了14个差异蛋白质，主要是与凝血和免疫功能相关的蛋白。其中肥胖儿童血浆中上调的免疫球蛋白有2种，下调的免疫球蛋白有3种；补体C5、C6和不同因子B、I均上调，共有4种。血红蛋白α和β亚单位、纤维蛋白原α和β亚单位均上调，而富含组氨酸糖蛋白下调。（2）筛选出的差异蛋白中位于细胞外的蛋白质最多，高达57%，其次是细胞核29%，位于细胞质膜以及细胞外膜的蛋白质均为7%。
结论：（1）筛选出了肥胖的差异蛋白共14种，为肥胖发病机制及药物治疗研究提供新的思路和途径。（2）推测PC可能通过调节补体C5、C6、补体B、I因子改善炎性反应和肝脏的脂肪变性，使富含组氨酸糖蛋白、补体因子B等指标恢复正常，从而延缓肥胖及其相关并发症的发生。（3）亚细胞定位于胞质外的蛋白质最多，其次是细胞核，位于细胞质膜及外膜的蛋白质极少，提示肥胖的发生是多条途径相互影响的结果。该信息为推断该蛋白质的生物学功能以及差异蛋白间的相互作用提供了必要的信息。
1Investigating the Effects of PC on Diet-induced Obesity
Objective: To investigate the effects of PC on Diet-induced Obesity (DIO) and itsmechanisms.
Methods: The obesity model was induced by high-fat and high-protein diet. Rats withbody weight>ME+1.96SD were identified obesity.Obesity rats were randomly divided intofour groups:(1) Obesity rats (DIO),(2)Obesity rats treated with150mg/kgPC(DIO+PC150),(3)Obesity rats treated with75mg/kg PC(DIO+PC75),(4)Obesity ratstreated with37.5mg/kg PC(DIO+PC37.5). Normal rats act as the control group(NC). PCwas administered by the intragastric route once a day for eight weeks. Body weight,quantity of food intake and caloric intake were measured after four and eight weeks. Thequantity of epididymal fat, perirenal fat, liver weight and kidney weight were measuredafter eight weeks, and the lipid ratio, as well as the liver weight/body weight, kidneyweight/body weight were counted as formula.The blood glucose(BG), insulin,cholesterol(TC), triglycerides (TG), high-density lipoprotein(HDL) and low-densitylipoprotein(LDL), alamine aminotransferase (AST) and aspartate aminotransferase(ALT),leptine, adiponectin(ADP) and resistant in serum were determined after eight weeks byusing commercially available kits following the manufacturer’s instructions.Thehomeostasis model assessment-IR (HOMA-IR) was obtained according to insulin and BG.The pathological changes of liver were evaluated under light and electron microscope afterstaining.
Results:(1) Supplement with PC, the food intake, energy intake, perirenal fat,epididymal fat, the liver weight, liver weight/body weight, serum insulin, HOMA-HR,serum resistant, leptin, TC, TG, AST, ALT, were decreased significantly (compared to DIOrats, P<0.05and P<0.01);(2) Supplement with PC, the serum HDL was increased significantly (P<0.05); There was no difference in serum LDL and leptin level betweengroups (P<0.05);(3) Its observed that the pathological change in liver was smaller in PCsupplement rats.
Conclusions: The present study suggested that PC supplement had some beneficialeffect on obesity rats and improve insulin resistance, which partly through decreasing thefood (caloric) intake, perirenal fat, epididymal fat and body fat ratio, serum insulin,HOMA-HR, serum resistin, leptin. PC also had a therapeutic effect for obesity fatty liver,with decreasing the level of AST and ALT, its mechanism may be associated withdecreasing resistin and leptin levels,against the fatty degeneration in liver.
2Effects of PC on Proliferation, Cell cycle andDifferentiation in Preadipocyte
Objective: To study the effects of PC on proliferation, cell cycle and differentiationon preadipocyte.
Methods: The effects of PC on proliferation on3T3-L1lines were determined byMTT assay, and cell cycle was determined by flow cytometry; The effect of PC onadipocyte differentiation was observed under light microscope after treated with3-Isobutyl-1-methylxanthine, insuline and dexamethasone. Immunohistochemicalstaining and flow cytometry analysis were used to investigate the influence of PC onexpression of GLTU4protein in membrane.
Results:(1) The proliferation and differentiation of3T3-L1cell were inhibited afterincubated with PC.(2) The cell cycle was blocked in S phase after treated with PC;(3) The expression of GLUT4in preadipocyte was increased significantly after treatedwith PC（P<0.05，P<0.01）。
Conclusions: The results indicated that PC had some protective effect against obesityand improved insulin resistance, wihic partly through inhibiting the proliferation anddifferentiation and up-regulating GLUT4expression of membrane lipocyte.
3Study on Plasma Proteomics in obese children and subcellularlocalization for the different proteins
Objective: To study the plasma proteomics of obese children and search fordifferent protein and their subcellular localization.
Methods: Blood samples for plasma proteomic analysis were obtained from obeseand healthy children. Low-abundance proteins were separated with Seppro IgY14Spincolumns according to the instructions of manufacturer.Then the low-abundance proteinwas digested with trypsin. The protein quantification was using liquid chromatographytandem mass spectrometry with label-free. To analylsis the different expressed proteins byMaxquant software and Uniport database. The subcellular localization information ofdifferent proteins was analysis by using CELLO v.2.5software.
Results:(1) Fourteen different proteins were founed in obesity children,10up-regulated and4down-regulated. The coagulation-associated potein and immuneassociated protein were involved in these different protein.
(2) Using CELLO v.2.5software, entered the amino acid sequence of14differentproteins and obtained subcelluar localtion information for each protein. Most proteinslocated in the extracelluar, up to57%,29%proteins in nuclear, while just14%incytoplasmic and out membrane respectively. But there was no protein in mitochondria.
Conclusion: Fourteen different protein were found in obese children which willprovide new ideas about the pathogenesis of obesity and drug target. We could concludethat PC may improve the insulin resistance and inflammatory by adjusting complement C5,C6and complement factor B, I, and increase the secretion of histidine-rich glycoprotein,then ameliorate the obesity and related-disease.The subcelluar location indicated that theremay be multi-channel interaction in extra-celluar, nuclear, cytoplasmic and out membranein the mechanisms of obesity. The present study provided new information about thesedifferent proteins.
引文
1. Holemans K,Caluwaerts S,Poston L,et al. Diet-induced obesity in the rat: a model forgestational diabetes mellitus.Am J Obstet Gynecol,2004;190(3):858-865.
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