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Journal of Southern Medical University logoLink to Journal of Southern Medical University
. 2018 Apr 20;38(4):460–465. [Article in Chinese] doi: 10.3969/j.issn.1673-4254.2018.04.15

长期高脂饮食对大鼠海马胰岛素受体底物的基因表达及其学习和记忆能力的影响

Long-term high-fat diet inhibits hippocampal expression of insulin receptor substrates and accelerates cognitive deterioration in obese rats

胡 冬华 1, 李 雅兰 1,*, 梁 赵佳 1, 钟 瞾 1, 唐 杰柯 1, 廖 婧 1, 田 和 1, 佘 高明 1, 刘 誉 2, 邢 会杰 3
PMCID: PMC6765670  PMID: 29735448

Abstract

目的

探讨长期高脂饮食对大鼠海马胰岛素受体底物的基因表达及大鼠空间学习和记忆能力的影响。

方法

100只4周龄雄性SD大鼠，随机分为普通饮食组（CD，n=40）、高脂饮食组（HFD，n=60），CD组给予普通饮食、HFD组给予高脂饮食，分别在4、8、12、16周，20周末于两组中随机选择8只大鼠进行Morrise水迷宫测试，连续5 d测试结束后处死大鼠，取血清检测代谢参数，取海马CA1区检测胰岛素受体底物-1（IRS-1）和胰岛素受体底物-2（IRS-2）的基因表达量。

结果

与CD组相比，HFD组大鼠的逃避潜伏期和游泳距离长，平均游泳速度快，停留在平台所在象限时间短；血清胰岛素含量升高，海马CA1区IRS-1和IRS-2的基因表达量下调（P＜0.05）。

结论

长期高脂饮食导致肥胖大鼠胰岛素抵抗，干扰了海马的胰岛素受体底物的基因表达，影响脑内胰岛素代谢，损害其空间学习和记忆等认知功能，加速认知退化。

Keywords: 高脂饮食, 海马, 胰岛素底物-1, 胰岛素底物-2, 认知功能

人类营养结构和生活方式的改变导致肥胖和代谢综合征的发病率不断升高以至于流行的状态[1-3]，特别是青少年的肥胖比例[4-5]。肥胖已成为当今全球性卫生健康课题，它不仅影响内分泌和心血管[6-9]，也危及中枢神经系统的功能，有研究显示：肥胖与认知功能障碍密切相关[10]，中年肥胖会加速老年期认知功能退化[11]。而产生这些临床现象的原因依然不清楚。有研究代谢的学者发现[12]IRS-1和[13]IRS-2介导胰岛素在外周组织物质代谢、细胞增殖分化中发挥重要的信号级联效应作用。然而，IRS在认知功能退化及肥胖者脑内胰岛素信号转导过程中的变化尚未见报道。本实验通过高脂饮食诱导肥胖胰岛素抵抗大鼠模型，测试其不同时期的学习和记忆功能，随后检测血清胰岛素，血脂，血糖，海马组织内IRS-1和IRS-2 mRNA表达量。探讨外周胰岛素抵抗（IR）时脑内胰岛素信号通路中IRS的变化及其与认知功能的关系，为肥胖的研究提供指引。

1. 材料和方法

1.1. 实验动物

4周龄SPF级健康雄性SD大鼠100只，体质量100~110 g。采购于广东省医学实验动物中心，动物许可证号为SCXK（粤）2011-0015，饲养和无菌手术都在暨南大学SPF级实验动物中心进行，并按实验动物使用的3R原则给予人道关怀。

普通饲料：脂肪5%，糖55%，蛋白质22%，灰分9%，纤维9%；高脂饲料：脂肪38%，糖40%，蛋白质15%，灰分4%，纤维3%。

1.2. 方法

1.2.1. 动物分组与肥胖SD大鼠模型的建立

SD大鼠在SPF级饲养环境中适应1周，按随机数字表法分为普通饮食组（CD，n=40）、高脂饮食组（HFD，n=60），CD组给予普通饲料，HFD组给予高脂饲料。所有动物12 h/12 h昼/夜，自由饮水、摄食。以体质量比CD组平均体质量增加20%且Lee's指数比CD组平均水平增加1.5%作为肥胖大鼠的标准，选出成模的肥胖大鼠进行实验。

1.2.2. 行为学测试

Morris水迷宫由荷兰Noldus公司提供的Ethovision XT 8.0小动物行为分析系统进行测试分析。测试由定位航行实验和空间探索实验两部分组成，历时6 d，每天固定时间段进行，连续训练4次。定位航行实验：将平台置于某一象限内水面下0.5~1.0 cm，将大鼠头朝池壁分别从东南西北4个象限入水点放入水中进行游泳，记录逃避潜伏期（从入水至找到平台的时间），当大鼠在60 s内没有找到平台，则引导大鼠找到平台，找到平台后使大鼠在平台上停留10 s。同时记录60 s内的总游泳行程（即游泳距离）和平均游泳速度，取上述3个指标4次成绩的平均值反映其当日的学习能力。空间探索实验：第6天时将平台撤除，分别在4个象限中任一个作为入水点，采用图像采集系统及分析系统记录大鼠60 s内在原平台所在象限探索时间、探索距离和准确穿越平台次数，反映其记忆能力。整个测试期间，保持环境安静以及实验室内灯光、物品摆放等空间位置一致，以排除环境干扰。

1.2.3. 标本采集与标本制备

两组大鼠经Morris水迷宫测试完成后禁食12 h，用戊巴比妥腹腔注射麻醉，翻正反射消失后开腹经下腔静脉采血5 mL，血液在室温下静置2 h后，用-4 ℃低温离心机以4000 r/min的速度离心后分装保存于-80 ℃冰箱备用，快速断头处死大鼠，取新鲜脑组织，在冰上分离皮层和海马，用预冷去离子水冲洗去血渍，用滤纸吸去多余的液体，海马液氮速冻，转移至-80 ℃冰箱内保存备测。

1.2.4. 血清胰岛素、血脂和血糖测定

行为学实验结束后，大鼠经12 h禁食，麻醉后，开腹经下腔静脉采血，离心并分离出血清，采用ELISA试剂盒检测胰岛素的量。按试剂盒说明操作，管中顺序加入样品各100 μL，37 ℃孵育90 min；弃孔内液加入抗体100 μL，37 ℃孵育60 min；洗涤3次，加入酶结合物100 μL，37 ℃孵育30 min；洗涤5次，加入90 μL底物溶液，37 ℃孵育15 min；加入50 μL终止液，立即在A450 nm波长处测量各孔光密度，分析计算，血脂和血糖按相应试剂盒说明操作。

1.2.5. IRS-1和IRS-2测定

采用实时荧光定量PCR法，以GADPH为内参照，检测脑海马组织中IRS-1和IRS-2的mRNA表达。Trizol法提取大鼠脑海马组织总RNA，逆转录为cDNA，取2 μL进行PCR反应，体系为20 μL，IRS-2正义链5'-GCCACCGTGGTGAAAGAGTA，IRS-2，反义链5'-AGCGTTGGTTGGAAACATGC；IRS-1正义链5'-CCTCACCAACCCTTAGGCAG，IRS-1反义链5'-GTCTTTCATTCTGCCTGTGACG；GAPDH正义链5'-AGACAGCCGCATCTTCTTGT，反义链5'-TGATGGCAACAATGTCCACT。反应条件为95 ℃预变性30 s，95 ℃ 3 s，60 ℃ 34 s，共40个循环。以GAPDH为内参照，利用2-△△CT方法分析不同组间IRS-1和IRS-2的表达水平。

1.3. 统计学处理

所有资料采用SPSS13.0统计软件处理，计量资料的数据以均数±标准差表示，重复测量设计方差分析比较组内和组间的差异，以P＜0.05为差异有统计学意义。

2. 结果

经Morris水迷宫测试，两组大鼠在5个不同的时间点，连续5 d平均的逃逸潜伏期比较显示：从第12周末到20周时，HFD组的平均逃逸潜伏期比CD组长（P＜0.05），平均游泳距离从第8周末到20周时，HFD组的游泳距离比CD组长（P＜0.05）。两组大鼠在不同的时间点，平均游泳速度从第12周末到20周时，HFD组的平均游泳速度比CD组快（P＜0.05，表 1）。

1.

比较两组大鼠在不同时间点的体质量、脂肪质量、Lee's指数和生化指标

Body weight, fat weight, Lee's index and blood biochemical parameters of the rats in the two groups at different time points (Mean±SD)

Group 4 th week 8th week 12th week 16th week 20th week
Body quality vs CD group, *P＜0.01; Lee's index vs CD group, #P＜0.01; Wet weight of fat vs CD group, αP＜0.01; The serum total cholesterol concentrations vs CD group, βP＜0.01; The serum triglyceride concentrations vs CD group, θP＜0.05; The serum low density lipoprotein cholesterol concentrations vs CD group, ◇P＜0.01; The serum high density lipoprotein cholesterol concentrations vs CD group, *P＜0.01; The serum glucose concentrations vs CD group, ￥P＞0.05.
HFD weight 158.9±9.15 340.80±12.21* 506.30±19.31* 571.90±28.07* 644.10±31.12*
  Lee's index 277.83±13.29 299.90±11.25# 324.91±6.58# 311.12±13.16# 309.81±5.87#
  Fat 0.845±0.476 3.617±1.38α 9.353±1.658α 15.522±3.731α 29.29±4.383α
  TC 2.383±0.419 3.187±0.715β 3.480±0.939β 3.892±0.899β 5.750±0.622β
  TG 0.892±0.267 1.104±0.195θ 1.065±0.162θ 1.342±0.447θ 1.810±0.208θ
  LDL-C 0.875±0.228 1.248±0.294◇ 2.063±0.086◇ 2.625±0.324◇ 3.445±0.495◇
  HDL-C 2.083±0.442※ 1.833±0.331※ 2.133±0.428※ 2.135±0.128※ 3.558±0.361※
  Sugar 8.367±0.659￥ 7.833±1.088￥ 8.217±0.741￥ 7.85±1.00￥ 8.15±0.84￥
CD weight 158.4±6.43 283.70±15.55 373.70±22.39 410.40±25.11 496.00±23.69
  Lee's index 277.78±10.10 277.59±10.94 304.66±13.69 298.92±9.55 295.14±13.77
  Fat 0.873±0.306 1.149±0.404 1.635±0.520 4.826±1.99 8.456±1.409
  TC 2.438±0.559 2.717±0.502 2.650±0.704 2.830±0.541 4.302±0.530
  TG 0.910±0.220 0.940±0.190 0.958±0.193 1.080±0.333 1.262±0.198
  LDL-C 0.898±0.168 1.108±0.278 2.107±0.277 2.735±0.603 4.315±0.434
  HDL-C 2.152±0.470 2.500±0.400 2.545±0.501 2.560±0.189 4.320±0.689
  Sugar 7.867±1.148 8.117±0.755 8.50±0.716 8.367±0.824 7.683±0.349
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经续连5 d的Morris水迷宫定位航行测试后，撤除隐藏平台，测试两组大鼠在1 min内准确穿越平台的平均次数，从第8周末到20周时，HFD组准确穿越平台的平均次数比CD组少（P＜0.05），在平台所在象限停留的平均时间，从第8周末到20周时，HFD组大鼠在平台所在象限停留的平均时间比CD组短（P＜0.05，表 2）。

2.

比较两组大鼠在不同时间点的游泳平均潜伏期、速度、距离、穿越平台的次数和平台区的停留时间

Average escape latency, swimming speed, swimming distance, frequency of crossing the platform and duration of stay in the target quadrant in the two groups at different time points (Mean±SD)

Group 4th week 8th week 12th week 16th week 20th week
Latency vs CD group, *P＜0.05; Speed vs CD group, #P＜0.05; Distance vs CD group, αP＜0.05; Frequency vs CD group, βP＜0.05; Duration vs CD group, θP＜0.05.
HFD latency (s) 9.35±11.3* 14.3±15.3* 23.5±19.2* 27.0±20.3* 28.5±21.2*
Speed (cm/s) 7.85±2.88# 10.05±2.11# 11.57±4.68# 16.09±5.98# 18.17±4.18#
Distance (cm) 158.3±245.1α 325.11±388.1α 1001.1±330.4α 1122.7±686.6α 1120.2±596.1α
Frequency (sec/m) 8.75±2.54β 3.75±2.77β 2.83±2.08β 2.71±1.81β 2.46±1.91β
Duration (s) 18.35±4.70θ 11.77±6.11θ 9.04±4.62θ 5.76±5.57θ 3.95±4.45θ
CD latency (s) 9.78±6.22 10.35±11.44 11.08±6.99 15.02±17.10 17.23±18.76
Speed (cm/s) 7.22±1.91 7.25±3.07 8.27±2.47 8.38±2.41 12.60±7.56
Distance (cm) 188.2±275.3 184.16±326.3 223.51±203.2 524.3±528.2 523.2±626.8
Frequency (sec/m) 8.92±2.72 5.33±2.79 4.17±2.67 4.08±1.69 3.58±2.39
Duration (s) 19.53±3.99 14.30±4.83 13.42±4.35 13.03±4.10 10.93±8.07
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两组大鼠在不同时间点血清胰岛素含量的比较，从第8周末开始到20周，HFD组大鼠血清胰岛素升高明显比CD组快（P＜0.05）。两组大鼠在不同时间点大脑海马中IRS-1 mRNA表达量的比较，从第8周末开始到20周，HFD组大鼠大脑海马中IRS-1 mRNA表达量的下降明显比CD组快（P＜0.05）。两组大鼠在不同时间点大脑海马中IRS-2 m-RNA表达量的比较，从第8周末开始到20周，HFD组大鼠大脑海马中IRS-2 m-RNA表达量的下降明显比CD组快（P＜0.05，表 3）。

3.

比较两组大鼠在不同时间点血清胰岛素的量和海马IRS1、IRS2的m-RNA表达量

Serum insulin level and expression levels IRS1 and IRS2 mRNAs in the hippocampus of rats in the two groups at different time points (Mean±SD)

Group 4th week 8th week 12th week 16th week 20th week
The serum insulin concentrations vs CD group, μP＜0.01; m-RNA expression levels IRS1 in the hippocampus vs CD group, *P＜0.05; m-RNA expression levels IRS2 in the hippocampus vs CD group, #P＜0.05.
HFD insulin 9.00±1.45μ 15.37±2.81μ 14.33±1.89μ 18.79±0.93μ 28.49±2.73μ
  IRS1 1.013±0.185* 0.850±0.076* 0.545±0.091* 0.308±0.120*
  IRS2 0.245±0.112# 0.308±0.130# 0.425±0.117# 0.458±0.161#
CD insulin 9.52±1.77 11.43±1.72 11.68±1.948 12.66±1.77 20.07±1.62
  IRS1 1.085±0.112 1.10±0.088 0.943±0.071 0.860±0.123
  IRS2 0.945±0.081 0.972±0.193 1.205±0.241 1.282±0.236
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3. 讨论

大鼠经过4周高脂饲料喂养后，即8周龄HFD组大鼠的平均体质量比对照组重20%以上，Lee's比对照组增加1.5%以上，随着喂养时间的延长，血清中血脂和胰岛素的量都比对照组高，肥胖程度更突出，高脂肥胖模型建模成功。

Morris水迷宫[14]是行为神经科学常用的研究方法，所检测大鼠在多次训练中学会寻找固定位置隐蔽平台，形成固定空间位置认知，这种空间认知是通过获取、加工和储存空间信息逐渐形成的。本实验Morris水迷宫测试结果是：HFD组大鼠的平均游泳速度，游泳距离及逃避潜伏期都大于CD组的大鼠；而撤除平台后，HFD组大鼠在平台所在的象限停留的平均时间和准确穿越平台的次数明显少于CD组大鼠。这显示了长期高脂饮食影响了大鼠对空间信息的获取、加工和储存，使得HFD组大鼠定位导航实验成绩不如CD组大鼠，平均潜伏期长；空间探索实验的成绩比CD组差，撤除平台后，在原来平台所在象限停留的平均时间比CD组短，准确穿越平台的平均次数少于CD组。这一结果说明：长期喂食高脂饮食影响了大鼠的空间学习和记忆能力，损害了大鼠的认知功能。

葡萄糖是大脑能量的重要来源，也是胰岛素从神经元囊泡释放的重要条件，胰岛素是具有多种生物学功能的活性物质，调节血糖和其他物质代谢，还能调节中枢及外周神经系统的活动。自从脑内胰岛素受体被发现后，相继研究显示脑内胰岛素除调节新陈代谢、影响摄食、促进神经组织细胞生长发育、参与调节神经递质的释放外，还在学习和记忆等高级智能活动中发挥重要作用[15]。胰岛素受体是一种受体酪氨酸激酶，与胰岛素受体底物（IRS）结合发挥作用，IRS蛋白有多个亚型，其中IRS1与IRS2同胰岛素受体密切相关。外周胰岛素经转运到脑，调节脑部的葡萄糖代谢和大脑结构的可塑性，保护神经细胞，改善记忆[16]。胰岛素抵抗一般是指胰岛素靶细胞对胰岛素的敏感性和反应性降低，是一个特征性的代谢缺陷，它与高胰岛素血症并存，而长期的高胰岛素血症破坏血脑屏障的功能，影响胰岛素的活性。有研究发现阿尔兹海默病（AD）患者脑内胰岛素水平和脑脊液中胰岛素水平降低，血浆胰岛素水平升高[17-19]。在本实验观察到大鼠从4周喂养到20周后，空腹血清胰岛素量的平均值由10 mU/L上升到了22 mU/L，而经过16周高脂饮食喂养的SD大鼠的血清中胰岛素量的平均值更是达到30 mU/L，随着时间的推移两组大鼠血清中胰岛素含量逐渐升高，20周龄组大鼠血清中胰岛素量远高于4周龄和8周龄组大鼠血清中胰岛素的量，显示高脂饮食加速了胰岛素抵抗的发展。这与其他研究在高脂饮食对胰岛素影响的结果基本一致[20-22]。但是，两组大鼠在不同时间点的血糖没有明显波动。

胰岛素对物质代谢的调节主要通过与相应组织细胞上的胰岛素受体结合后，沿着胰岛素受体（IR）-胰岛素受体底物（IRS）-磷酸肌醇-3激酶（PI3K）-蛋白激酶B（PKB/Akt）的激活顺序激活下游信号通路而发挥作用。胰岛素受体后的信号转导通路机制复杂，而转导胰岛素生物作用的共同信号蛋白是胰岛素受体底物IRS（如IRS-1和IRS-2），IRS的磷酸化成为多种蛋白激酶、蛋白磷酸酶的锚定部位和激活位点，以及连接蛋白、磷脂酶和离子通道的易化因子，介导下游反应[23-24]。脑内胰岛素受体底物的分布与胰岛素受体相对应，脑内胰岛素底物的量和活性直接反应胰岛素代谢的状态，脑内胰岛素的功能发挥与胰岛素受体的分布密切相关。胰岛素和胰岛素受体在整个大脑神经元和神经胶质细胞广泛分布表达，尤其在大脑皮质、海马、下丘脑、嗅球中更为多见，对胰岛素敏感的葡萄糖载体存在于以上区域，增强胰岛素信号，并且增加脑内葡萄糖的利用，调节学习和记忆[25]。还有报道显示IRS在大脑皮层和海马神经元突触含量丰富，推测胰岛素信号通路在一定程度上影响神经元突触的可塑性，影响脑的学习记忆功能[26-28]。Feng等[29]用中药对比处理转基因鼠时发现增加海马中IRS-1的表达量，促进了大鼠的学习记忆功能发展。Martin[30]在IRS-2基因敲除鼠的电生理学对比试验中发现IRS-2基因敲除鼠的海马突触传递基础是存在的，但是，NMDA受体的突触活性不足，NMDA受体亚单位酪氨酸磷酸化下降，抑制了NMDA受体对兴奋性突触后电位的影响，长时程增强（LTP）在突触后水平受阻。由于海马结构中的LTP现象与多种形式的学习记忆活动密切相关，是学习和记忆的神经基楚。自从1994年首次提出胰岛素信号通路功能障碍作为AD的发病机制起，AD中胰岛素信号通路的变化及作用受到广泛关注。有报道在AD转基因动物模型中IRS蛋白水平降低，这可能与IRS的降解和合成减少有关[31-32]。随后的研究证实了胰岛素信号通路障碍参与了包括AD在内的多种疾病的发生和发展。IRS在外周以及中枢胰岛素信号通路功能障碍中扮演了重要角色[33-34]。作为胰岛素信号通路中的关键分子，IRS的量及其磷酸化代谢对胰岛素信号通路的功能状态具有重要意义。本实验中采用实时荧光定量RT-PCR检测不同时点两组大鼠海马中胰岛素受体底物（IRS-1和IRS-2）的含量，HFD组IRS-1和IRS-2的mRNA表达量在高脂饮食喂养12周龄开始明显低于CD组，显示长期高脂饮食导致肥胖和胰岛素抵抗的发生，影响了中枢海马内IRS-1和IRS-2的表达，IRS是胰岛素信号通路上关键分子，它的量和质的变化必将影响脑内胰岛素信号通路的功能，改变神经元和突触糖代谢状态，影响神经元的功能活动，损害了学习和记忆等认知功能。水迷宫的测试进步验证了推测结论。

综上所述，个体成熟后机体对胰岛素的敏感性逐渐降低，长期高脂饮食加速大鼠胰岛素抵抗的进程，干扰海马的胰岛素受体底物的蛋白表达，影响海马胰岛素信号通路，损害空间学习和记忆等认知功能。

Biography

胡冬华，医学博士，E-mail: hu.dong.hua.1002@163.com

Funding Statement

广东省科技计划项目（2009030801032）

Contributor Information

胡 冬华 (Donghua HU), Email: hu.dong.hua.1002@163.com.

李 雅兰 (Yalan LI), Email: tyalan@139.com.

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