高脂、高糖对HPA轴功能影响及分子机制研究
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摘要
目的:海马负责HPA轴的负反馈调节。本研究探讨血浆高游离脂肪酸(FFA)是否通过改变海马糖皮质激素受体(GR)、盐皮质激素受体(MR)、11β-羟类固醇脱氢酶1(11β-HSD1)或诱导型一氧化氮合酶(iNOS)的表达,从而“损伤”海马、激活HPA轴。
方法:20只成年雌性Sprague-Dawley大鼠分成两组,一组输注20%脂肪乳(FFA组,n=10),另一组输注0.9%生理盐水作为对照组(NS组,n=10)。留取0分钟血浆后以2ml/小时速度开始输液共持续180分钟,输液结束后将老鼠迅速断头取血备用,摘取脑组织、速冻,供海马原位杂交和免疫组化使用。
结果:(1)输注NS不能升高血浆FFA浓度,而FFA组180分钟的血浆FFA浓度明显升高,是其输液前5.1倍。(2)两组的基础ACTH和皮质酮浓度无差异。比较输液前后的净改变量,FFA组的ΔACTH(15.6±10.2 pg/ml)明显高于NS组的ΔACTH(2.6±3.9 pg/ml)。与基础值相比,两组180分钟的皮质酮水平均下降,但FFA组下降幅度(104.6±193.1 ng/ml)明显低于NS组的Δ皮质酮(187.2±167.3 ng/ml)。相对NS组而言,输注脂肪乳轻度激活HPA轴。(3)与NS组相比,FFA组海马CA4亚区锥体细胞的11β-HSD1蛋白表达水平以及mRNA水平均明显减少。但是FFA组海马CA4亚区锥体细胞的iNOS蛋白表达水平以及mRNA水平却明显增加。(4)两组海马结构的GR与MR蛋白表达水平以及mRNA水平无明显差异。
结论:本研究的结果支持FFA可能“损伤”海马激活HPA轴的假说。这种激活机制可能是由于FFA下调海马局部11β-HSD1的表达、上调iNOS的表达,减弱了海马对HPA轴的抑制调控。
目的:了解多囊卵巢综合症(PCOS)患者空腹血浆皮质醇浓度的变化及其影响因素,以及短期高糖或高胰岛素刺激对其皮质醇水平的影响,同时了解PCOS患者胰岛β细胞功能状况。
方法:84例PCOS患者分为肥胖组(肥胖或超重, n=34)和非肥胖组(正常体重,n=50人);20名正常体重的健康妇女作为对照组。所有受试者先行口服75g无水葡萄糖耐量试验(OGTT),隔天空腹进行60分钟高糖刺激(静脉葡萄糖耐量试验,IVGTT)和120分钟高胰岛素-正糖钳夹术(简称正糖钳夹术)。测定空腹葡萄糖、胰岛素浓度,以及IVGTT、正糖钳夹术期间的皮质醇浓度(0,60,180分钟三个点),皮质醇的相对变化即下降幅度:Δ皮质醇x=空腹皮质醇—皮质醇x (x指时间)。胰岛素敏感性(IS)采用正糖钳夹术阶段胰岛素介导的葡萄糖代谢率(M值,mg.kg-1.min-1)表示。胰岛β细胞功能(βF)采用IVGTT第一时相胰岛素分泌量(AIR)评估。葡萄糖处置指数(DI)= IS×AIR
结果:(1)肥胖PCOS组空腹皮质醇浓度(158.85±78.76 ng/ml)明显低于非肥胖PCOS组(210.70±108.65 ng/ml)和对照组(231.23±89.21ng/ml),而非肥胖组与对照组间无明显差异。(2)高糖刺激结束后,即60分钟时肥胖组血浆皮质醇浓度(87.66±33.74 ng/ml)仍然最低,与正常对照组(141.46±45.84 ng/ml)相比较仍有显著差异,但与非肥胖组(123.76±86.98 ng/ml)的差别已经不明显,而非肥胖组与对照组之间无差异。比较各组60分钟时血浆皮质醇的相对变化Δ皮质醇60,三组间并无差别(肥胖组:65.03±59.28 ng/ml;非肥胖组:86.62±66.71 ng/ml;对照组:89.77±74.26 ng/ml)。(3)高胰岛素刺激结束后,即180分钟时三组的皮质醇浓度已无差异(肥胖组:116.07±48.53 ng/ml;非肥胖组:120.53±83.65 ng/ml;对照组:123.20±53.61 ng/ml)。但是肥胖组血浆皮质醇的相对变化Δ皮质醇180最小(39.28±72.94 ng/ml),与非肥胖组(89.89±102.49 ng/ml)和对照组(108.03±108.17 ng/ml)相比较,存在明显差异。非肥胖组与对照组之间无差异。(4)对84例PCOS患者进行两两相关分析结果显示空腹皮质醇与M值、BMI、空腹血糖存在负相关,相关系数r分别为-0.241、-0.230、-0.253,p值均<0.05。空腹皮质醇和空腹胰岛素的相关系数为-0.200, p=0.071,其相关性可疑。以空腹皮质醇为应变量,多元回归分析的结果提示M值、BMI、空腹胰岛素3个自变量被纳入回归模型中,反而空腹血糖没被引入回归模型中。(5)三组间AIR差别无统计学意义,但PCOS患者有增高趋势,尤以肥胖者明显(P=0.074)。非肥胖和肥胖PCOS组DI比对照组降低,但前两组间差别无统计学意义。
结论:本研究显示PCOS患者基础皮质醇水平不仅与体重有关,还与胰岛素敏感性和空腹胰岛素水平有关;短期高糖刺激并不影响PCOS患者HPA轴的功能;肥胖PCOS患者基础皮质醇水平降低,但是经过大剂量胰岛素刺激后皮质醇水平和其它两组并无差异,提示短期高剂量胰岛素可能会激活肥胖PCOS患者的HPA轴;此外,PCOS患者糖刺激后第一时相胰岛素分泌无降低,但其葡萄糖处置指数降低,提示胰岛β细胞对胰岛素抵抗代偿能力下降。
Objective Hippocampus controls HPA axis negative feedback. The current study aimed to test the hypothesis whether the activation of the HPA axis response to high FFA was due to the lesions of hippocampus, which was associated with the altered expression of GR, MR, 11β-HSD1 or iNOS in hippocampus.
Methods After baseline (0 minute) sample was obtained, 20% Intralipid (FFA group, n=10) or 0.9% saline (as control, NS group, n=10) was infused IV (2ml/h) into Sprague-Dawley rats for 180 minutes. Rats were killed by decapitation after injection, and trunk blood were stored for future measures. For in situ hybridization and immunohistochemistry, whole brains from animals were dissected and immediately frozen.
Results (1)Infusion of Intralipid into rats elevated plasma FFA up to 5.1-fold above basal values (preinfusion) at 180 min. There was no influence on FFA levels after saline infusion(.2)There was no significantly difference in basal ACTH and corticosterone levels between FFA and NS groups. The net change in ACTH (ΔACTH: FFA,15.6±10.2 pg/ml; NS, 2.6±3.9 pg/ml, respectively)during infusion was higher in FFA group than that in NS group. In comparison with basal corticosterone levels, plasma corticosterone levels at 180 min were lower in the two groups. However, the magnitude of decrease in corticosterone levels was significantly less in FFA group compared with NS group (Δcorticosterone: FFA, 104.6±193.1 ng/ml; NS, 187.2±167.3 ng/ml, respectively). The current study showed that administering Intralipid mildly activated the axis compared with NS group.(3)In FFA group, 11β-HSD1 mRNA and protein levels were significantly decreased in the pyramidal cells in hippocampal CA4 subregion compared with NS group. However, Intralipid infusion significantly increased iNOS mRNA and protein levels in the pyramidal cells in the CA4 field of hippocampus.(4)Neither GR mRNA nor protein levels in the hippocampal formation differed between FFA and NS group. Moreover, there was no significant effect on MR mRNA and protein levels in the hippocampal formation after Intralipid infusion.
Conclusion Our findings support the hypothesis that FFA would impair hippocampus and then stimulate the HPA axis. The mechanism of the action of FFA might be attributable to down-regulation of 11β-HSD1 and up-regulation of iNOS expression in hippocampus.
Objective To measure the basal levels of cortisol in patients with Polycystic Ovarian Syndrome (PCOS), analyze its associations with correlative factors, investigate the effects of short-term hyperglycemia or hyperinsulinemia per se on their plasma cortisol concentrations, and evaluate isletβ-cell function in women with PCOS.
Methods 84 PCOS patients divided into two groups (obese group, n=34; non-obese group, n=50) and 21 age-matched healthy women were recruited. All subjects received oral glucose tolerance test (OGTT). After an overnight fasting, an acute 60-minute glucose stimulation was performed by intravenous glucose tolerance test followed by a 120-minute euglycemic hyperinsulinemic clamp. Basal glucose, insulin, and cortisol during IVGTT and euglycemic clamp at 0, 60 and 180 minute (cortisol0, cortisol60 and cortisol180) were measured. The net change in cortisol during IVGTT and euglycemic clamp was calculated asΔcortisolx= cortisol0-cortisolx (x meaned time). Insulin sensitivity (IS) calculated as the glucose infusion rate during the euglycemic clamp phase (M value, mg﹒kg-1﹒min-1). Isletβ-cell function was reflected through acute insulin response (AIR) of IVGTT. Glucose disposition index (DI) = IS×AIR.
Results 1)Basal cortisol levels were similar between the non-obese PCOS group and control groups, and significantly higher than that in the obese PCOS group. 2)The cortisol-60 levels after short-term hyperglycemic challenges were lower in the obese PCOS group than that in the control group, Whereas the net change in cortisol during IVGTT did not significantly differ among the groups. 3)Although the cortisol-180 levels after euglycemic clamp were similar among the groups, the magnitude of the net change in cortisol was significantly less in the obese PCOS group than that in the other groups. 4)In the group of 84 PCOS subjects, simple Pearson correlations showed a negative relationship between basal cortisol with either M value, BMI, or fasting glucose (r=-0.241, -0.230, -0.253 , respectively; all p value <0.05). A shady correlation was found between basal cortisol and fasting insulin (r=0.200; p=0.071). However, with basal cortisol as the independent variable, M value, BMI, fasting glucose and fasting insulin as dependent variables, multiple regression analysis showed that the significance of fasting glucose on basal cortisol was removed when fasting insulin was added as a covariate. 5)AIR was similar in three groups, but there was a trend of increase in women with PCOS patients, especially for the obese(P=0.08). DI was lower in non-obese and obese PCOS patients than that in healthy women, and no significant difference was found between the non-obese and obese PCOS group.
Conclusion Our data suggest that basal level of cortisol correlates not only with body weight, but also with insulin sensitivity and fasting insulin level in patients with PCOS. In present study we did not observe changes in cortisol concentrations after short-term hyperglycemic challenges. Although basal cortisol levels decreased in the obese or overweight patients with PCOS, the cortisol180 levels after short-term hyperinsulinemic challenges were similar among the groups. It suggested that a rise in plasma insulin might moderately activate the HPA axis of obese PCOS patients. Acute insulin response to glucose in women with PCOS doesn’t decrease, but compensatory ability of isletβ-cell for insulin resistance is deficient.
方法:20只成年雌性Sprague-Dawley大鼠分成两组,一组输注20%脂肪乳(FFA组,n=10),另一组输注0.9%生理盐水作为对照组(NS组,n=10)。留取0分钟血浆后以2ml/小时速度开始输液共持续180分钟,输液结束后将老鼠迅速断头取血备用,摘取脑组织、速冻,供海马原位杂交和免疫组化使用。
结果:(1)输注NS不能升高血浆FFA浓度,而FFA组180分钟的血浆FFA浓度明显升高,是其输液前5.1倍。(2)两组的基础ACTH和皮质酮浓度无差异。比较输液前后的净改变量,FFA组的ΔACTH(15.6±10.2 pg/ml)明显高于NS组的ΔACTH(2.6±3.9 pg/ml)。与基础值相比,两组180分钟的皮质酮水平均下降,但FFA组下降幅度(104.6±193.1 ng/ml)明显低于NS组的Δ皮质酮(187.2±167.3 ng/ml)。相对NS组而言,输注脂肪乳轻度激活HPA轴。(3)与NS组相比,FFA组海马CA4亚区锥体细胞的11β-HSD1蛋白表达水平以及mRNA水平均明显减少。但是FFA组海马CA4亚区锥体细胞的iNOS蛋白表达水平以及mRNA水平却明显增加。(4)两组海马结构的GR与MR蛋白表达水平以及mRNA水平无明显差异。
结论:本研究的结果支持FFA可能“损伤”海马激活HPA轴的假说。这种激活机制可能是由于FFA下调海马局部11β-HSD1的表达、上调iNOS的表达,减弱了海马对HPA轴的抑制调控。
目的:了解多囊卵巢综合症(PCOS)患者空腹血浆皮质醇浓度的变化及其影响因素,以及短期高糖或高胰岛素刺激对其皮质醇水平的影响,同时了解PCOS患者胰岛β细胞功能状况。
方法:84例PCOS患者分为肥胖组(肥胖或超重, n=34)和非肥胖组(正常体重,n=50人);20名正常体重的健康妇女作为对照组。所有受试者先行口服75g无水葡萄糖耐量试验(OGTT),隔天空腹进行60分钟高糖刺激(静脉葡萄糖耐量试验,IVGTT)和120分钟高胰岛素-正糖钳夹术(简称正糖钳夹术)。测定空腹葡萄糖、胰岛素浓度,以及IVGTT、正糖钳夹术期间的皮质醇浓度(0,60,180分钟三个点),皮质醇的相对变化即下降幅度:Δ皮质醇x=空腹皮质醇—皮质醇x (x指时间)。胰岛素敏感性(IS)采用正糖钳夹术阶段胰岛素介导的葡萄糖代谢率(M值,mg.kg-1.min-1)表示。胰岛β细胞功能(βF)采用IVGTT第一时相胰岛素分泌量(AIR)评估。葡萄糖处置指数(DI)= IS×AIR
结果:(1)肥胖PCOS组空腹皮质醇浓度(158.85±78.76 ng/ml)明显低于非肥胖PCOS组(210.70±108.65 ng/ml)和对照组(231.23±89.21ng/ml),而非肥胖组与对照组间无明显差异。(2)高糖刺激结束后,即60分钟时肥胖组血浆皮质醇浓度(87.66±33.74 ng/ml)仍然最低,与正常对照组(141.46±45.84 ng/ml)相比较仍有显著差异,但与非肥胖组(123.76±86.98 ng/ml)的差别已经不明显,而非肥胖组与对照组之间无差异。比较各组60分钟时血浆皮质醇的相对变化Δ皮质醇60,三组间并无差别(肥胖组:65.03±59.28 ng/ml;非肥胖组:86.62±66.71 ng/ml;对照组:89.77±74.26 ng/ml)。(3)高胰岛素刺激结束后,即180分钟时三组的皮质醇浓度已无差异(肥胖组:116.07±48.53 ng/ml;非肥胖组:120.53±83.65 ng/ml;对照组:123.20±53.61 ng/ml)。但是肥胖组血浆皮质醇的相对变化Δ皮质醇180最小(39.28±72.94 ng/ml),与非肥胖组(89.89±102.49 ng/ml)和对照组(108.03±108.17 ng/ml)相比较,存在明显差异。非肥胖组与对照组之间无差异。(4)对84例PCOS患者进行两两相关分析结果显示空腹皮质醇与M值、BMI、空腹血糖存在负相关,相关系数r分别为-0.241、-0.230、-0.253,p值均<0.05。空腹皮质醇和空腹胰岛素的相关系数为-0.200, p=0.071,其相关性可疑。以空腹皮质醇为应变量,多元回归分析的结果提示M值、BMI、空腹胰岛素3个自变量被纳入回归模型中,反而空腹血糖没被引入回归模型中。(5)三组间AIR差别无统计学意义,但PCOS患者有增高趋势,尤以肥胖者明显(P=0.074)。非肥胖和肥胖PCOS组DI比对照组降低,但前两组间差别无统计学意义。
结论:本研究显示PCOS患者基础皮质醇水平不仅与体重有关,还与胰岛素敏感性和空腹胰岛素水平有关;短期高糖刺激并不影响PCOS患者HPA轴的功能;肥胖PCOS患者基础皮质醇水平降低,但是经过大剂量胰岛素刺激后皮质醇水平和其它两组并无差异,提示短期高剂量胰岛素可能会激活肥胖PCOS患者的HPA轴;此外,PCOS患者糖刺激后第一时相胰岛素分泌无降低,但其葡萄糖处置指数降低,提示胰岛β细胞对胰岛素抵抗代偿能力下降。
Objective Hippocampus controls HPA axis negative feedback. The current study aimed to test the hypothesis whether the activation of the HPA axis response to high FFA was due to the lesions of hippocampus, which was associated with the altered expression of GR, MR, 11β-HSD1 or iNOS in hippocampus.
Methods After baseline (0 minute) sample was obtained, 20% Intralipid (FFA group, n=10) or 0.9% saline (as control, NS group, n=10) was infused IV (2ml/h) into Sprague-Dawley rats for 180 minutes. Rats were killed by decapitation after injection, and trunk blood were stored for future measures. For in situ hybridization and immunohistochemistry, whole brains from animals were dissected and immediately frozen.
Results (1)Infusion of Intralipid into rats elevated plasma FFA up to 5.1-fold above basal values (preinfusion) at 180 min. There was no influence on FFA levels after saline infusion(.2)There was no significantly difference in basal ACTH and corticosterone levels between FFA and NS groups. The net change in ACTH (ΔACTH: FFA,15.6±10.2 pg/ml; NS, 2.6±3.9 pg/ml, respectively)during infusion was higher in FFA group than that in NS group. In comparison with basal corticosterone levels, plasma corticosterone levels at 180 min were lower in the two groups. However, the magnitude of decrease in corticosterone levels was significantly less in FFA group compared with NS group (Δcorticosterone: FFA, 104.6±193.1 ng/ml; NS, 187.2±167.3 ng/ml, respectively). The current study showed that administering Intralipid mildly activated the axis compared with NS group.(3)In FFA group, 11β-HSD1 mRNA and protein levels were significantly decreased in the pyramidal cells in hippocampal CA4 subregion compared with NS group. However, Intralipid infusion significantly increased iNOS mRNA and protein levels in the pyramidal cells in the CA4 field of hippocampus.(4)Neither GR mRNA nor protein levels in the hippocampal formation differed between FFA and NS group. Moreover, there was no significant effect on MR mRNA and protein levels in the hippocampal formation after Intralipid infusion.
Conclusion Our findings support the hypothesis that FFA would impair hippocampus and then stimulate the HPA axis. The mechanism of the action of FFA might be attributable to down-regulation of 11β-HSD1 and up-regulation of iNOS expression in hippocampus.
Objective To measure the basal levels of cortisol in patients with Polycystic Ovarian Syndrome (PCOS), analyze its associations with correlative factors, investigate the effects of short-term hyperglycemia or hyperinsulinemia per se on their plasma cortisol concentrations, and evaluate isletβ-cell function in women with PCOS.
Methods 84 PCOS patients divided into two groups (obese group, n=34; non-obese group, n=50) and 21 age-matched healthy women were recruited. All subjects received oral glucose tolerance test (OGTT). After an overnight fasting, an acute 60-minute glucose stimulation was performed by intravenous glucose tolerance test followed by a 120-minute euglycemic hyperinsulinemic clamp. Basal glucose, insulin, and cortisol during IVGTT and euglycemic clamp at 0, 60 and 180 minute (cortisol0, cortisol60 and cortisol180) were measured. The net change in cortisol during IVGTT and euglycemic clamp was calculated asΔcortisolx= cortisol0-cortisolx (x meaned time). Insulin sensitivity (IS) calculated as the glucose infusion rate during the euglycemic clamp phase (M value, mg﹒kg-1﹒min-1). Isletβ-cell function was reflected through acute insulin response (AIR) of IVGTT. Glucose disposition index (DI) = IS×AIR.
Results 1)Basal cortisol levels were similar between the non-obese PCOS group and control groups, and significantly higher than that in the obese PCOS group. 2)The cortisol-60 levels after short-term hyperglycemic challenges were lower in the obese PCOS group than that in the control group, Whereas the net change in cortisol during IVGTT did not significantly differ among the groups. 3)Although the cortisol-180 levels after euglycemic clamp were similar among the groups, the magnitude of the net change in cortisol was significantly less in the obese PCOS group than that in the other groups. 4)In the group of 84 PCOS subjects, simple Pearson correlations showed a negative relationship between basal cortisol with either M value, BMI, or fasting glucose (r=-0.241, -0.230, -0.253 , respectively; all p value <0.05). A shady correlation was found between basal cortisol and fasting insulin (r=0.200; p=0.071). However, with basal cortisol as the independent variable, M value, BMI, fasting glucose and fasting insulin as dependent variables, multiple regression analysis showed that the significance of fasting glucose on basal cortisol was removed when fasting insulin was added as a covariate. 5)AIR was similar in three groups, but there was a trend of increase in women with PCOS patients, especially for the obese(P=0.08). DI was lower in non-obese and obese PCOS patients than that in healthy women, and no significant difference was found between the non-obese and obese PCOS group.
Conclusion Our data suggest that basal level of cortisol correlates not only with body weight, but also with insulin sensitivity and fasting insulin level in patients with PCOS. In present study we did not observe changes in cortisol concentrations after short-term hyperglycemic challenges. Although basal cortisol levels decreased in the obese or overweight patients with PCOS, the cortisol180 levels after short-term hyperinsulinemic challenges were similar among the groups. It suggested that a rise in plasma insulin might moderately activate the HPA axis of obese PCOS patients. Acute insulin response to glucose in women with PCOS doesn’t decrease, but compensatory ability of isletβ-cell for insulin resistance is deficient.
引文
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