妊娠期缺氧对子代大鼠胰岛素抵抗的影响及其机制研究
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摘要
目的：本项目旨在研究妊娠期缺氧对出生后子代大鼠胰岛素抵抗的影响，并初步探索脂肪因子分泌型卷曲相关蛋白5（secreted frizzled-related protein5，Sfrp5）与子代胰岛素抵抗可能机制。
方法：Sprague-Dawley (SD)孕鼠16只，于妊娠第7天随机均分为常氧对照组[control]和妊娠期缺氧组[maternal hypoxia, MH]以建立妊娠期SD孕鼠缺氧模型。孕鼠分娩后，选取子代雄性大鼠作为研究对象，予母乳喂养至3周龄断奶给予高脂饮食[high-fat diet,HFD]，将子代雄性大鼠分为4个实验组：常氧对照+正常饮食组[control]；妊娠期缺氧+正常饮食组[MH]；常氧对照+高脂饮食组[HFD]；妊娠期缺氧+高脂饮食组[MH+HFD]，各组继续喂养12周。子代大鼠于3周龄及15周龄分批处死，留取标本进行实验指标检测。留取血液指标进行总胆固醇（total cholesterol, TC），甘油三酯（triglyceride, TG），游离脂肪酸（free fatty acid, FFA），低密度脂蛋白胆固醇（low-density lipoprotein cholesterin, LDL-C），高密度脂蛋白胆固醇（high-densitylipoprotein cholesterin, HDL-C），空腹血糖（fasting blood glucose, FBG）及空腹血清胰岛素（fasting insulin, FINS）测定，并以稳态模型评估其胰岛素抵抗指数（homeostasismodel assessment insulin resistance index，HOMA-IR）；观察15周龄子代雄性大鼠肝脏组织病理形态学表现；免疫组织化学检测脂肪组织中巨噬细胞标志物F4/80蛋白表达情况；采用蛋白印迹法（Western Blot, WB）及实时荧光定量聚合酶链反应（quantitativereal-time polymerase chain reaction, QRT-PCR）方法检测3周龄及15周龄子代雄性SD大鼠脂肪组织中脂肪因子Sfrp5及Wnt5a（Wingless-type MMTV integration site familymembers5a, Wnt5a）mRNA及蛋白表达情况；再采用WB方法对Wnt5a/JNK信号传导通路中主要效应分子c-Jun氨基末端激酶1（c-Jun N-terminal kinase1，JNK-1）、c-Jun及胰岛素受体底物1(insulin receptor substrate1, IRS-1)蛋白表达情况进行检测。
结果：妊娠期缺氧可引起子代雄性SD大鼠血清TC, TG, FFA, LDL-C, FINS及HOMA-IR增高，同时其HDL-C降低，差异具有统计学意义(均P＜0.05)。病理标本提示妊娠期缺氧组子代大鼠中脂肪含量增加，高脂饮食组肝脏组织中脂肪含量增加，差异有统计学意义(均P＜0.05)。免疫组化结果提示妊娠期缺氧组大鼠脂肪组织巨噬细胞标志物F4/80蛋白表达上调(P＜0.05)。WB及QRT-PCR检测结果显示3周龄及15周龄妊娠期缺氧组子代雄性SD大鼠脂肪组织Sfrp5的mRNA及蛋白表达水平显著降低，而Wnt5a的mRNA及蛋白表达呈增加现象，Wnt5a与Sfrp5表达比例失衡（均P＜0.05）。妊娠期缺氧组子代雄性SD大鼠脂肪组织中P-JNK-1(Thr183/Tyr185), P-c-Jun(Ser63)和P-IRS-1(Ser307)蛋白磷酸化表达显著上调（均P＜0.05）。高脂饮食所致高脂血症可协同促进上述各个观察指标的变化(均P＜0.05)。
结论：妊娠期缺氧子代雄性SD大鼠呈现胰岛素抵抗现象，妊娠期缺氧子代大鼠存在胎儿程序控制。妊娠期缺氧对子代大鼠脂肪组织Sfrp5及其配体Wnt5a表达存在影响，进而通过Wnt5a/JNK信号通路影响胰岛素信号转导通路，可能是其致子代发生胰岛素抵抗的分子机制之一。妊娠期缺氧与高脂血症具有协同促进子代雄性SD大鼠胰岛素抵抗作用。
Objective: To explore the effects of maternal hypoxia (MH) during pregnancy on insulinresistance in rat offspring and adipocytokine secreted frizzled-related protein5(Sfrp5) itspossible molecular mechanism contribute to insulin signaling pathway.
Mehtods: According to factorial normal oxygen and maternal under hypoxia environment,Sprague-Dawley (SD) rats were randomly divided into two groups as normal oxygen group(control group,21%O2) and maternal hypoxia during pregnancy group (MH group,10%O2).After delivery, two male offspring of each mother rat were taken out and breast-fed for threeweeks. After weaning, according to a2×2factorial design, consisting of two factors[maternal hypoxia (MH) and postnatal high-fat diet (HFD)], each with two levels, maleoffspring were randomly assigned into four groups (each containing12animals) as follows:maternal hypoxia offspring with postnatal high-fat diet [MH+HFD]; maternal hypoxiaoffspring with postnatal normal diet [MH]; maternal normoxia offspring with postnatalhigh-fat diet [HFD]; maternal normoxia offspring with normal diet [Control]. At Week3andWeek15, blood fat, fasting plasma glucose (FPG), serum total cholesterol (TC), triglyceride(TG), free fatty acid (FFA), low-density lipoprotein cholesterin (LDL-C), high-densitylipoprotein cholesterin (HDL-C) were measured by biochemical methods, and insulin wasmeasured by radioimmunoassay, and then the homeostasis model assessment-insulinresistance index (HOMA-IR) was calculated. HOMA-IR was used for insulin resistancemeasurement, the formula for HOMA-IR was: FPG (mmol/L)×FINS (mIU/L)/22.5.Observed The structural changes of rat adipose tissue and liver tissue; determined theprotein expression of a specific marker of activated macrophage (F4/80) in all the treated rats;meanwhile, the expression of Sfrp5, as well as Wnt5a and the molecular mechanismsinvolved in Wnt5a/JNK(P-JNK-1(Thr183/Tyr185), P-c-Jun(Ser63), P-IRS-1(Ser307) andinsulin signaling pathway were measured by Western Blot (WB）and quantitative real-time polymerase chain reaction（QRT-PCR）in Sprague-Dawley rat offspring adipose tissue.
Results: Maternal hypoxia caused a relative increased insulin levels and P-IRS-1proteinexpression in offspring compared to the normoxic counterparts(all P<0.05). In addition, asignificantly decreased Sfrp5mRNA and protein concentrations in adipose tissue couple withincreased Wnt5a protein was found in the same maternal hypoxia offspring (all P<0.05); andthose changes were accompanied by increased P-JNK-1(Thr183/Tyr185), P-c-Jun(Ser63) andP-IRS-1(Ser307) in hypoxia offspring (all P<0.05). Moreover, a positive interaction effectbetween prenatal hypoxia and hyperlipidemia was found (P<0.05).
Conclusions：Our study results suggested that a maternal hypoxic environment could modifythe expression of adipocytokine Sfrp5and modulate the insulin sensitivity through Wnt/JNKsignaling pathway. Thus, prenatal hypoxia may provide an underlying mechanism for thedevelopment of insulin resistance, therefore serve as a novel risk factor for metabolicsyndrome. Furthermore, the effects of prenatal hypoxia were augmented by hyperlipidemiainduced by a high-fat diet. Therefore, it is necessary to pay more attention to the fetalnutrition and oxygen supply in utero, so as to prevent chronic disease during adulthood, forexample, the early onset of insulin resistance.
方法：Sprague-Dawley (SD)孕鼠16只，于妊娠第7天随机均分为常氧对照组[control]和妊娠期缺氧组[maternal hypoxia, MH]以建立妊娠期SD孕鼠缺氧模型。孕鼠分娩后，选取子代雄性大鼠作为研究对象，予母乳喂养至3周龄断奶给予高脂饮食[high-fat diet,HFD]，将子代雄性大鼠分为4个实验组：常氧对照+正常饮食组[control]；妊娠期缺氧+正常饮食组[MH]；常氧对照+高脂饮食组[HFD]；妊娠期缺氧+高脂饮食组[MH+HFD]，各组继续喂养12周。子代大鼠于3周龄及15周龄分批处死，留取标本进行实验指标检测。留取血液指标进行总胆固醇（total cholesterol, TC），甘油三酯（triglyceride, TG），游离脂肪酸（free fatty acid, FFA），低密度脂蛋白胆固醇（low-density lipoprotein cholesterin, LDL-C），高密度脂蛋白胆固醇（high-densitylipoprotein cholesterin, HDL-C），空腹血糖（fasting blood glucose, FBG）及空腹血清胰岛素（fasting insulin, FINS）测定，并以稳态模型评估其胰岛素抵抗指数（homeostasismodel assessment insulin resistance index，HOMA-IR）；观察15周龄子代雄性大鼠肝脏组织病理形态学表现；免疫组织化学检测脂肪组织中巨噬细胞标志物F4/80蛋白表达情况；采用蛋白印迹法（Western Blot, WB）及实时荧光定量聚合酶链反应（quantitativereal-time polymerase chain reaction, QRT-PCR）方法检测3周龄及15周龄子代雄性SD大鼠脂肪组织中脂肪因子Sfrp5及Wnt5a（Wingless-type MMTV integration site familymembers5a, Wnt5a）mRNA及蛋白表达情况；再采用WB方法对Wnt5a/JNK信号传导通路中主要效应分子c-Jun氨基末端激酶1（c-Jun N-terminal kinase1，JNK-1）、c-Jun及胰岛素受体底物1(insulin receptor substrate1, IRS-1)蛋白表达情况进行检测。
结果：妊娠期缺氧可引起子代雄性SD大鼠血清TC, TG, FFA, LDL-C, FINS及HOMA-IR增高，同时其HDL-C降低，差异具有统计学意义(均P＜0.05)。病理标本提示妊娠期缺氧组子代大鼠中脂肪含量增加，高脂饮食组肝脏组织中脂肪含量增加，差异有统计学意义(均P＜0.05)。免疫组化结果提示妊娠期缺氧组大鼠脂肪组织巨噬细胞标志物F4/80蛋白表达上调(P＜0.05)。WB及QRT-PCR检测结果显示3周龄及15周龄妊娠期缺氧组子代雄性SD大鼠脂肪组织Sfrp5的mRNA及蛋白表达水平显著降低，而Wnt5a的mRNA及蛋白表达呈增加现象，Wnt5a与Sfrp5表达比例失衡（均P＜0.05）。妊娠期缺氧组子代雄性SD大鼠脂肪组织中P-JNK-1(Thr183/Tyr185), P-c-Jun(Ser63)和P-IRS-1(Ser307)蛋白磷酸化表达显著上调（均P＜0.05）。高脂饮食所致高脂血症可协同促进上述各个观察指标的变化(均P＜0.05)。
结论：妊娠期缺氧子代雄性SD大鼠呈现胰岛素抵抗现象，妊娠期缺氧子代大鼠存在胎儿程序控制。妊娠期缺氧对子代大鼠脂肪组织Sfrp5及其配体Wnt5a表达存在影响，进而通过Wnt5a/JNK信号通路影响胰岛素信号转导通路，可能是其致子代发生胰岛素抵抗的分子机制之一。妊娠期缺氧与高脂血症具有协同促进子代雄性SD大鼠胰岛素抵抗作用。
Objective: To explore the effects of maternal hypoxia (MH) during pregnancy on insulinresistance in rat offspring and adipocytokine secreted frizzled-related protein5(Sfrp5) itspossible molecular mechanism contribute to insulin signaling pathway.
Mehtods: According to factorial normal oxygen and maternal under hypoxia environment,Sprague-Dawley (SD) rats were randomly divided into two groups as normal oxygen group(control group,21%O2) and maternal hypoxia during pregnancy group (MH group,10%O2).After delivery, two male offspring of each mother rat were taken out and breast-fed for threeweeks. After weaning, according to a2×2factorial design, consisting of two factors[maternal hypoxia (MH) and postnatal high-fat diet (HFD)], each with two levels, maleoffspring were randomly assigned into four groups (each containing12animals) as follows:maternal hypoxia offspring with postnatal high-fat diet [MH+HFD]; maternal hypoxiaoffspring with postnatal normal diet [MH]; maternal normoxia offspring with postnatalhigh-fat diet [HFD]; maternal normoxia offspring with normal diet [Control]. At Week3andWeek15, blood fat, fasting plasma glucose (FPG), serum total cholesterol (TC), triglyceride(TG), free fatty acid (FFA), low-density lipoprotein cholesterin (LDL-C), high-densitylipoprotein cholesterin (HDL-C) were measured by biochemical methods, and insulin wasmeasured by radioimmunoassay, and then the homeostasis model assessment-insulinresistance index (HOMA-IR) was calculated. HOMA-IR was used for insulin resistancemeasurement, the formula for HOMA-IR was: FPG (mmol/L)×FINS (mIU/L)/22.5.Observed The structural changes of rat adipose tissue and liver tissue; determined theprotein expression of a specific marker of activated macrophage (F4/80) in all the treated rats;meanwhile, the expression of Sfrp5, as well as Wnt5a and the molecular mechanismsinvolved in Wnt5a/JNK(P-JNK-1(Thr183/Tyr185), P-c-Jun(Ser63), P-IRS-1(Ser307) andinsulin signaling pathway were measured by Western Blot (WB）and quantitative real-time polymerase chain reaction（QRT-PCR）in Sprague-Dawley rat offspring adipose tissue.
Results: Maternal hypoxia caused a relative increased insulin levels and P-IRS-1proteinexpression in offspring compared to the normoxic counterparts(all P<0.05). In addition, asignificantly decreased Sfrp5mRNA and protein concentrations in adipose tissue couple withincreased Wnt5a protein was found in the same maternal hypoxia offspring (all P<0.05); andthose changes were accompanied by increased P-JNK-1(Thr183/Tyr185), P-c-Jun(Ser63) andP-IRS-1(Ser307) in hypoxia offspring (all P<0.05). Moreover, a positive interaction effectbetween prenatal hypoxia and hyperlipidemia was found (P<0.05).
Conclusions：Our study results suggested that a maternal hypoxic environment could modifythe expression of adipocytokine Sfrp5and modulate the insulin sensitivity through Wnt/JNKsignaling pathway. Thus, prenatal hypoxia may provide an underlying mechanism for thedevelopment of insulin resistance, therefore serve as a novel risk factor for metabolicsyndrome. Furthermore, the effects of prenatal hypoxia were augmented by hyperlipidemiainduced by a high-fat diet. Therefore, it is necessary to pay more attention to the fetalnutrition and oxygen supply in utero, so as to prevent chronic disease during adulthood, forexample, the early onset of insulin resistance.
引文
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