胃壁注射A型肉毒毒素对大鼠胃动力、胃Caja1间质细胞以及脑肠肽Ghrelin、NPY、PYY表达的影响
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摘要
[背景与目的]
肥胖症是一个世界范围内的健康难题。饮食、药物和行为疗法对部分患者有效但疗效难以维持。外科手术治疗(如胃囊带术或分流术),尽管对有些肥胖患者有效,但创伤大、副反应多。寻求创伤小、便捷有效的减肥方法是目前医学科学的努力方向。近年有学者提出将A型肉毒毒素(BTX-A)应用于肥胖治疗领域具有诸多优势,受到人们的热切关注。少许报道认为,BTX-A胃壁注射可以导致摄食减少,体重下降,这一结果可能通过抑制胃排空和食欲的途径而实现。国内刘庆森教授率先将BTX-A应用于肥胖治疗领域,初期研究取得了肯定疗效。但具体机制仍不清楚。本课题通过胃壁肌层不同点位注射BTX-A,并在不同时间段内系统观察BTX-A胃壁注射对大鼠胃动力、胃Cajal间质细胞以及脑肠肽ghrelin、NPY、PYY表达的影响,旨在深入探索BTX-A胃壁注射法治疗肥胖症的分子机制。
[方法]
将72只雄性Wistar大鼠随机分为三批(2周,6周,12周),每批24只。每批再分为4组(对照组、胃窦BTX-A组、胃底体BTX-A组、全胃多点BTX-A组),每组6只。每只大鼠剖腹后暴露胃,在胃壁肌层分别注射BTX-A或生理盐水,术后单笼饲养,跟踪记录大鼠的摄食量和体重至12周,分别于术后2周、6周、12周时进行胃动力检测并留取标本。实验参数包括两部分：一为胃动力相关部分：核素扫描胃固体半排空时间的测定；胃肌电图描记；Cajal间质细胞(ICC)免疫组化测定及半定量分析；ICC透射电镜观察。二为脑肠肽相关部分：酶联免疫吸附法(ELISA)检测血浆ghrelin、PYY浓度；免疫组化法检测胃ghrelin、下丘脑NPY的表达；Western blotting法检测胃ghrelin的半定量表达；实时荧光定量PCR (RT-qPCR)法检测ghrelin-mRNA、下丘脑NPY-mRNA的相对定量表达。
[结果]
1.BTX-A注射组与对照组比较,大鼠摄食量减少,体重减低。
2.BTX-A胃壁注射对胃动力的影响BTX-A注射组胃固体半排空时间(T1/2)较对照组明显延长。BTX-A组胃电图可见胃动过缓、节律紊乱。并且胃ICC表达数目减少,ICC网络结构紊乱。
3. BTX-A胃壁注射对脑肠肽的影响：在BTX-A注射组,血浆ghrel in浓度降低,血浆PYY浓度升高；通过免疫组化、Western blotting、RT-qPCR等方法发现,在蛋白质和mRNA水平,BTX-A组ghrelin和NPY的表达均较对照组明显降低。
4.在BTX-A注射的3个组中观察,均发现胃排空延缓、胃电节律失常,以及ICC、ghrelin、NPY的表达下降,上述参数的改变,以多点组最为明显,其次为胃底组,再次为胃窦组。在BTX-A注射后不同时间段观察,BTX-A组与对照组的差异性,以注射后2周最为明显,其次为6周,再次为12周。
[结论]
1.胃壁注射BTX-A,使ICC的发育成熟障碍,从而影响胃肌电正常慢波的形成和扩布,造成胃电节律减缓和紊乱,延缓胃排空。这可能是造成大鼠摄食减少、体重下降的重要机制之一
2.胃壁注射BTX-A,下调了促食因子(ghrelin和NPY)的表达,上调了抑食因子(PYY)的表达。这也是导致大鼠摄食和体重减少的机制之一
3.在胃的不同部位注射BTX-A产生的效果不同,以全胃多点注射BTX-A对大鼠摄食和体重减低的作用表现得最为显著。在3个不同时间段分别与对照组比较,在2周时BTX-A组效果最为显著,持续至12周时仍有一定效果,故认为,BTX-A的抑食、减重作用在短期内(12周)效果明显。
在本课题中,我们探讨了应用BTX-A治疗肥胖症的可能分子机制,为该法更合理地应用于临床提供了更全面可靠的理论依据。
[Background and aims]
Obesity is a worldwide health problem. Dietary, pharmacological and behavioral treatments are effective in some of the patients, but the efficacy is temporal if the intervention is interrupted. Surgical treatments (gastric banding and bypass) are effective in some patients, but they are invasive and may induce severe complications. It is important to seek a kind of method with potent efficacy and minimal invasion for obese patients. Recently, as a novel method, intragastric injection of Botulinum Toxin A (BTX-A) is proposed and tried with enthusiasm. Till now, a few reports have showed that intramuscular injections of BTX-A into the gastric wall could induce a reduction in food intake and body weight. These effects might be mediated by delaying gastric emptying or reducing appetite. In China, LIU Qing-sen et al. initially employed BTX-A on the treatment of obesity and confirmed its efficacy in the pilot studies. However the mechanisms are still unclear. In order to explore the possible molecular mechanisms of BTX-A for the treatment of obesity, we investigated the effects of BTX-A injection into different gastric regions for different treatment period, and observed the effects on gastric motility, interstitial cells of Cajal (ICC), and expression of some of the braingut peptides (ghrelin, NPY, PYY) in this study.
[Methods]
Seventy-two male Wistar rats were randomly assigned to three batches (2-week batch,6-week batch,12-week batch) (24 rats/batch). Then the rats in each batch were assigned to four groups (n=6 rats/group). Control group:saline injection in the gastric wall; antrum group:BTX-A injection in the antrum; fundus group:BTX-A injection in the fundus; multi-site group:BTX-A injection at multiple sites. EACh rat was laparotomized and the stomach was exposed. The BTX-A or saline was injected into the gastric wall individually. After operation, every rat was fed in a separated cage with water and food ad libitum. The food intake and body weight were measured and followed up for 12 weeks. For each batch, gastric motility of rats were tested then samples were harvested at week 2, week 6 or week 12, respectively. The parameters included two parts:part one consisted of gastric motility-related parameters including scintigraphic test of gastric emptying, gastroelectromyogram, expression of ICCs in stomach measured by immunohistochemical analysis, the ultrastructure of ICCs observed by transmission electron microscopy (TEM). Part two consisted of braingut peptides-related parameters such as plasma concentrations of ghrelin and PYY determined by an ELISA analysis, expression of ghrelin and NPY measured by immunohistochemical analysis, Western blotting, and mRNA fluorescent quantitation PCR.
[Results]
1. The BTX-A treated groups showed a significant reduction of food intake and body weight as compared to the control group.
2. The effects of BTX-A on gastric emptying were characterized by a significant increase in half emptying time. Gastroelectromyograms showed bradygastria and rhythm disturbance after expoxure to BTX-A. Expression of ICC and destruction of the ICC net-work structure were noticed in the BTX-A treated groups in comparison to the control group.
3. Significant reduction of plasma ghrelin and elevation of plasma PYY was noted in the BTX-A treated groups. Levels of protein and mRNA expression of grelin and NPY were decreased significantly in the BTX-A treated groups as compared to the control group, measured by immunohistochemistry, western blotting and RT-qPCR analysis.
4. Significant delaying of gastric emptying, disturbance of gastric electrical rhythm and reduced expression of ICC, ghrelin, and NPY were observed in all the three BTX-A treated groups (Antrum, Fundus, and Multi-site). Among them, the greatest effect was noted in the Multi-site group, followed by Fundus group and Antrum group (P<0.05). The greatest effects were observed in the 2-week batch, and the effects attenuated in the 6-week and 12-week batches (P<0.05)
[Conclusions]
1. Intragastric injection of BTX-A is proposed to cause the dysmaturity of ICCs and destruction of ICC net-work, to affect the formation and propagation of normal slow-wave, and to disorder the gastric electro-rhythm. This may be one of the important mechanisms of decreasing food intake and body weight in rats.
2. In the BTX-A treated groups, down-regulation of appetide-promoting factors (e.g., ghrelin and NPY) and up-regulation of appetide-inhibiting factor (e.g., PYY) were proved. This mechanism may also play a role in reduction of food intake and body weight.
3. Among the 4 groups of different injection sites, food intake and body weight reduction were most significantly in the Multi-site group, and the effects were greatest at week 2 among the 3 batches. It was confirmed that the treatment of obesity using BTX-A was effective as long as 12 weeks.
In this study, the possible molecular mechanisms of BTX-A in the treatment of obesity was investigated. This may provides more extensive and reliable evidences on the utilization of BTX-A for the treatment of obesity in the future.
肥胖症是一个世界范围内的健康难题。饮食、药物和行为疗法对部分患者有效但疗效难以维持。外科手术治疗(如胃囊带术或分流术),尽管对有些肥胖患者有效,但创伤大、副反应多。寻求创伤小、便捷有效的减肥方法是目前医学科学的努力方向。近年有学者提出将A型肉毒毒素(BTX-A)应用于肥胖治疗领域具有诸多优势,受到人们的热切关注。少许报道认为,BTX-A胃壁注射可以导致摄食减少,体重下降,这一结果可能通过抑制胃排空和食欲的途径而实现。国内刘庆森教授率先将BTX-A应用于肥胖治疗领域,初期研究取得了肯定疗效。但具体机制仍不清楚。本课题通过胃壁肌层不同点位注射BTX-A,并在不同时间段内系统观察BTX-A胃壁注射对大鼠胃动力、胃Cajal间质细胞以及脑肠肽ghrelin、NPY、PYY表达的影响,旨在深入探索BTX-A胃壁注射法治疗肥胖症的分子机制。
[方法]
将72只雄性Wistar大鼠随机分为三批(2周,6周,12周),每批24只。每批再分为4组(对照组、胃窦BTX-A组、胃底体BTX-A组、全胃多点BTX-A组),每组6只。每只大鼠剖腹后暴露胃,在胃壁肌层分别注射BTX-A或生理盐水,术后单笼饲养,跟踪记录大鼠的摄食量和体重至12周,分别于术后2周、6周、12周时进行胃动力检测并留取标本。实验参数包括两部分：一为胃动力相关部分：核素扫描胃固体半排空时间的测定；胃肌电图描记；Cajal间质细胞(ICC)免疫组化测定及半定量分析；ICC透射电镜观察。二为脑肠肽相关部分：酶联免疫吸附法(ELISA)检测血浆ghrelin、PYY浓度；免疫组化法检测胃ghrelin、下丘脑NPY的表达；Western blotting法检测胃ghrelin的半定量表达；实时荧光定量PCR (RT-qPCR)法检测ghrelin-mRNA、下丘脑NPY-mRNA的相对定量表达。
[结果]
1.BTX-A注射组与对照组比较,大鼠摄食量减少,体重减低。
2.BTX-A胃壁注射对胃动力的影响BTX-A注射组胃固体半排空时间(T1/2)较对照组明显延长。BTX-A组胃电图可见胃动过缓、节律紊乱。并且胃ICC表达数目减少,ICC网络结构紊乱。
3. BTX-A胃壁注射对脑肠肽的影响：在BTX-A注射组,血浆ghrel in浓度降低,血浆PYY浓度升高；通过免疫组化、Western blotting、RT-qPCR等方法发现,在蛋白质和mRNA水平,BTX-A组ghrelin和NPY的表达均较对照组明显降低。
4.在BTX-A注射的3个组中观察,均发现胃排空延缓、胃电节律失常,以及ICC、ghrelin、NPY的表达下降,上述参数的改变,以多点组最为明显,其次为胃底组,再次为胃窦组。在BTX-A注射后不同时间段观察,BTX-A组与对照组的差异性,以注射后2周最为明显,其次为6周,再次为12周。
[结论]
1.胃壁注射BTX-A,使ICC的发育成熟障碍,从而影响胃肌电正常慢波的形成和扩布,造成胃电节律减缓和紊乱,延缓胃排空。这可能是造成大鼠摄食减少、体重下降的重要机制之一
2.胃壁注射BTX-A,下调了促食因子(ghrelin和NPY)的表达,上调了抑食因子(PYY)的表达。这也是导致大鼠摄食和体重减少的机制之一
3.在胃的不同部位注射BTX-A产生的效果不同,以全胃多点注射BTX-A对大鼠摄食和体重减低的作用表现得最为显著。在3个不同时间段分别与对照组比较,在2周时BTX-A组效果最为显著,持续至12周时仍有一定效果,故认为,BTX-A的抑食、减重作用在短期内(12周)效果明显。
在本课题中,我们探讨了应用BTX-A治疗肥胖症的可能分子机制,为该法更合理地应用于临床提供了更全面可靠的理论依据。
[Background and aims]
Obesity is a worldwide health problem. Dietary, pharmacological and behavioral treatments are effective in some of the patients, but the efficacy is temporal if the intervention is interrupted. Surgical treatments (gastric banding and bypass) are effective in some patients, but they are invasive and may induce severe complications. It is important to seek a kind of method with potent efficacy and minimal invasion for obese patients. Recently, as a novel method, intragastric injection of Botulinum Toxin A (BTX-A) is proposed and tried with enthusiasm. Till now, a few reports have showed that intramuscular injections of BTX-A into the gastric wall could induce a reduction in food intake and body weight. These effects might be mediated by delaying gastric emptying or reducing appetite. In China, LIU Qing-sen et al. initially employed BTX-A on the treatment of obesity and confirmed its efficacy in the pilot studies. However the mechanisms are still unclear. In order to explore the possible molecular mechanisms of BTX-A for the treatment of obesity, we investigated the effects of BTX-A injection into different gastric regions for different treatment period, and observed the effects on gastric motility, interstitial cells of Cajal (ICC), and expression of some of the braingut peptides (ghrelin, NPY, PYY) in this study.
[Methods]
Seventy-two male Wistar rats were randomly assigned to three batches (2-week batch,6-week batch,12-week batch) (24 rats/batch). Then the rats in each batch were assigned to four groups (n=6 rats/group). Control group:saline injection in the gastric wall; antrum group:BTX-A injection in the antrum; fundus group:BTX-A injection in the fundus; multi-site group:BTX-A injection at multiple sites. EACh rat was laparotomized and the stomach was exposed. The BTX-A or saline was injected into the gastric wall individually. After operation, every rat was fed in a separated cage with water and food ad libitum. The food intake and body weight were measured and followed up for 12 weeks. For each batch, gastric motility of rats were tested then samples were harvested at week 2, week 6 or week 12, respectively. The parameters included two parts:part one consisted of gastric motility-related parameters including scintigraphic test of gastric emptying, gastroelectromyogram, expression of ICCs in stomach measured by immunohistochemical analysis, the ultrastructure of ICCs observed by transmission electron microscopy (TEM). Part two consisted of braingut peptides-related parameters such as plasma concentrations of ghrelin and PYY determined by an ELISA analysis, expression of ghrelin and NPY measured by immunohistochemical analysis, Western blotting, and mRNA fluorescent quantitation PCR.
[Results]
1. The BTX-A treated groups showed a significant reduction of food intake and body weight as compared to the control group.
2. The effects of BTX-A on gastric emptying were characterized by a significant increase in half emptying time. Gastroelectromyograms showed bradygastria and rhythm disturbance after expoxure to BTX-A. Expression of ICC and destruction of the ICC net-work structure were noticed in the BTX-A treated groups in comparison to the control group.
3. Significant reduction of plasma ghrelin and elevation of plasma PYY was noted in the BTX-A treated groups. Levels of protein and mRNA expression of grelin and NPY were decreased significantly in the BTX-A treated groups as compared to the control group, measured by immunohistochemistry, western blotting and RT-qPCR analysis.
4. Significant delaying of gastric emptying, disturbance of gastric electrical rhythm and reduced expression of ICC, ghrelin, and NPY were observed in all the three BTX-A treated groups (Antrum, Fundus, and Multi-site). Among them, the greatest effect was noted in the Multi-site group, followed by Fundus group and Antrum group (P<0.05). The greatest effects were observed in the 2-week batch, and the effects attenuated in the 6-week and 12-week batches (P<0.05)
[Conclusions]
1. Intragastric injection of BTX-A is proposed to cause the dysmaturity of ICCs and destruction of ICC net-work, to affect the formation and propagation of normal slow-wave, and to disorder the gastric electro-rhythm. This may be one of the important mechanisms of decreasing food intake and body weight in rats.
2. In the BTX-A treated groups, down-regulation of appetide-promoting factors (e.g., ghrelin and NPY) and up-regulation of appetide-inhibiting factor (e.g., PYY) were proved. This mechanism may also play a role in reduction of food intake and body weight.
3. Among the 4 groups of different injection sites, food intake and body weight reduction were most significantly in the Multi-site group, and the effects were greatest at week 2 among the 3 batches. It was confirmed that the treatment of obesity using BTX-A was effective as long as 12 weeks.
In this study, the possible molecular mechanisms of BTX-A in the treatment of obesity was investigated. This may provides more extensive and reliable evidences on the utilization of BTX-A for the treatment of obesity in the future.
引文
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