脂联素球状结构域（gAd）改善3T3-L1脂肪细胞胰岛素抵抗的效果与机制研究
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摘要
目的
探讨脂联素球状结构域(globular domain of adiponectin, gAd)改善3T3-L1脂肪细胞胰岛素抵抗的效果及其可能的机制。
方法
复苏冻存的3T3-L1前脂肪细胞株,置37℃细胞孵育箱中,5%CO2条件下培养并诱导分化为成熟的3T3-L1脂肪细胞,用细胞形态学及油红O染色法鉴定细胞。用梯度透析法复性原核基因重组的gAd蛋白,用考马斯亮蓝法测定gAd蛋白含量。用软脂酸(Plamotic acid, PA)制备3T3-L1脂肪细胞胰岛素抵抗(insulin resisitent, IR)模型。用不同浓度gAd (250ng/mL,500ng/mL, 1000ng/mL)干预己产生IR的脂肪细胞5h,设空白对照组,用葡萄糖氧化酶法测定细胞培养液葡萄糖含量,用实时定量PCR法检测各组3T3-L1脂肪细胞IRS-1 PI-3K、PKB、GLUT-4、AMP、CPT-Ⅰ的mRNA表达水平。用Western blot检测AMPK Thr-172及IRS-1磷酸化水平。用SPSS 17.0统计分析软件建立数据库分析数据,数据以均数±标准差(x-±s)表示,检验水准取α=0.05。
结果
1.3T3-L1脂肪细胞IR模型的制备
不同浓度的PA (0.25mmol/L 0.5 mmol/L、1.0mmol/L)作用于分化成熟的3T3-L1脂肪细胞24h可抑制葡萄糖的摄取,与对照组相比各实验组葡萄糖摄取率分别下降5.25%、10.29%、14.54%。说明PA具有引起3T3-L1脂肪细胞产生IR的作用,且1.0 mmol/L PA作用于3T3-L1细胞24h抑制细胞葡萄糖摄取的效果最显著。
2.gAd对3T3-L1脂肪细胞IR模型葡萄糖摄取能力的影响
不同浓度的gAd (250ng/mL、500ng/mL、1000ng/mL)作用于产生IR的3T3-L1脂肪细胞,可促进脂肪细胞葡萄糖摄取(F=35.499,r=-0.883,P=0.005)。与对照组相比,gAd250 ng/mL时就可显著促进脂肪细胞葡萄糖摄取(p=0.000)。
3.gAd对3T3-L1脂肪细胞IR模型AMPK通路的影响
gAd可增加3T3-L1脂肪细胞IR模型AMPK (F=359.374, r=0.986, P=0.000)、CPT-I (F=180.234, r=0.973, P=0.000)基因的表达,呈剂量依赖关系。各实验组与对照组比较均有显著差异(P<0.01),各实验组组间比较也有显著差异(P<0.01)。Western blot结果显示, gAd可增加3T3-L1脂肪细胞IR模型AMPK Thr-172磷酸化水平,且随着gAd浓度的增加,AMPK Thr-172磷酸化水平逐渐增强(F=269.407,r=0.982,P=0.000)。
4.gAd对3T3-L1脂肪细胞IR模型胰岛素PI-3K途径的影响
与对照组相比,250 ng/mL gAd组可增加3T3-L1脂肪细胞IR模型GLUT-4mRNA的表达(P=0.024),但IRS-1 (P=0.324) PI-3K (P=0.125)、PKB (P=0.748) mRNA表达较对照组无显著差异；500 ng/mL gAd组IRS-1(P=0.031)、PI-3K(P=0.002)、PKB(P=0.01).GLUT-4(P=0.000)的表达均比对照组显著增加,且PI-3K (t=-3.66 P=0.022)、PKB (t=-4.161 P=0.014)、GLUT-4(t=-15.039,P=0.000)的表达均较250 ng/mL gAd组显著增加；1000 ng/mLgAd组IRS-1 (P=0.031). PI-3K (P=0.000)、PKB (P=0.000)、GLUT-4 (P=0.000)的表达均比对照组显著增加,且GLUT-4 (t=10.483, P=0.000) mRNA的表达较500 ng/mL gAd组显著增加。Western blot结果显示,gAd可增加3T3-L1脂肪细胞IR模型IRS-1磷酸化水平,且随着gAd浓度的增加,IRS-1磷酸化水平逐渐增加(F=360.345,r=0.968,P=0.000)。
结论
1.gAd可促进3T3-L1脂肪细胞IR模型葡萄糖的摄取。
2.gAd可能是通过促进AMPK Thr-172磷酸化,激活AMPK,增加CPT-I的活性,促进脂肪酸的氧化,改善3T3-L1脂肪细胞的IR。
3.gAd可增加胰岛素P13K通路IRS-1、PI3K、PKB、GLUT-4基因的表达,并使IRS-1磷酸化水平增加,改善3T3-L1脂肪细胞的IR。
Objective:
The study was to the role and mechanism of Globular domain of adiponectin (gAd) in improving Insulin resistance of the 3T3-L1 adipocytes.
Methods:
Culturing and differentiating 3T3-L1 cells, use oil red O for lipids when the cells were matured. After dialysis of gAd, determine protein concentration by Coomassie brilliant blue. Insulin resistance model of 3T3-L1 adipocytes was prepared with PA. Intervention the adipocytes which have been generated IR with different concentrations of gAd (250 ng/mL、500 ng/mL、1000 ng/mL) for 5h. Blank control group, the cell culture medium glucose content was detected with the glucose oxidize method, the mRNA expression of IRS-1, P13K, PKB, GLUT-4, AMPK, CPT-Ⅰwere detected with real-time quantitative PCR method. Phosphorylation AMPK Thr-172 and IRS-1 was detected by Western blot. SPSS 17.0 statistical analysis software was used to establish a database and analysis of the data, which data were expressed as mean±standard deviation (x±s), and the test level was a= 0.05.
Results:
1. Different concentrations of PA (0.25mmol/L,0.5mmol/L, 1.Ommol/L) effect on 3T3-L1 adipocytes for 24h can inhibited glucose uptake. Compared with the control group, the rate of glucose uptake in all experimental groups decreased 5.25%,10.29%,14.54%. So 3T3-L1 adipocytes can generate IR by PA.1.0 mmol/L of PA can inhibit glucose uptake significantly.
2. Different concentrations of gAd (250 ng/mL,500 ng/mL,1000 ng/mL) acting in 3T3-L1 cells which have generated IR, can stimulate glucose uptake significantly (F=35.499, r=-0.883, P=0.005), Compared with the control group,250ng/mL of gAd can besignificantly enhanced glucose uptake (p=0.000).
3. Different concentrations of gAd gradually increased the mRNA expression levels of AMPK (F=359.374, r=0.986, P=0.000), CPT-I (F=180.234, r=0.973, P=0.000) and in a dose-dependent manner. The experimental group and control group were significantly different (P<0.01), between groups in all experimental groups had significant differences (P <0.01). The results of Western blot illustrate that AMPK Thr-172 phosphorylation levels increased gradually followed by the concentration of gAd (F=269.407, r=0.982, P=0.000).
4. Affect of gAd on IR 3T3-L1 adipocyte models of insulin P13K pathway
Compared with the control group,250 ng/mL gAd group mRNA expression levels of GLUT-4 (P=0.02)increased than the control group, but the IRS-1, PI3K, PKB have no significant difference compared with the control group; 500 ng/mL gAd Group mRNA expression levels of IRS-1 (P=0.031), P13K (P=0.002), PKB (P=0.01), GLUT-4 (P=0.000) significantly increased compared with controls, and the mRNA expression levels of P13K (t=-3.66 P=0.022), PKB (t= 4.161 P=0.014), GLUT-4 (t=-15.039, P=0.000) significantly increased compared with 250 ng/ mL gAd; 1000 ng/mL gAd group mRNA expression levels of IRS-1 (P=0.031), P13K (P= 0.000), PKB (P=0.000), GLUT-4 (P=0.000), was significantly increased compared with controls (P＜0.01), and mRNA expression levels of GLUT-4 (t=10.483, P=0.000), significantly increased compared with 500 ng/mL gAd group. The results of Western blot illustrate that IRS-1 phosphorylation levels increased gradually followed by the concentration of gAd (F=360.345, r=0.968, P=0.000).
Conclusions:
1. GAd can promote glucose uptake of 3T3-L1 adipocyte model which have generated IR.
2. The mechanism of gAd improve insulin resistance may be increase AMPK Thr-172 phosphorylation, activation of AMPK, thus lift the inhibition on CPT-Ⅰ, increase free fatty acid oxidation.
3. GAd can improve insulin resistance by gradually increased the mRNA expression levels of IRS-1、PI3K、PKB、GLUT-4,and increase IRS-1 phosphorylation levels.
探讨脂联素球状结构域(globular domain of adiponectin, gAd)改善3T3-L1脂肪细胞胰岛素抵抗的效果及其可能的机制。
方法
复苏冻存的3T3-L1前脂肪细胞株,置37℃细胞孵育箱中,5%CO2条件下培养并诱导分化为成熟的3T3-L1脂肪细胞,用细胞形态学及油红O染色法鉴定细胞。用梯度透析法复性原核基因重组的gAd蛋白,用考马斯亮蓝法测定gAd蛋白含量。用软脂酸(Plamotic acid, PA)制备3T3-L1脂肪细胞胰岛素抵抗(insulin resisitent, IR)模型。用不同浓度gAd (250ng/mL,500ng/mL, 1000ng/mL)干预己产生IR的脂肪细胞5h,设空白对照组,用葡萄糖氧化酶法测定细胞培养液葡萄糖含量,用实时定量PCR法检测各组3T3-L1脂肪细胞IRS-1 PI-3K、PKB、GLUT-4、AMP、CPT-Ⅰ的mRNA表达水平。用Western blot检测AMPK Thr-172及IRS-1磷酸化水平。用SPSS 17.0统计分析软件建立数据库分析数据,数据以均数±标准差(x-±s)表示,检验水准取α=0.05。
结果
1.3T3-L1脂肪细胞IR模型的制备
不同浓度的PA (0.25mmol/L 0.5 mmol/L、1.0mmol/L)作用于分化成熟的3T3-L1脂肪细胞24h可抑制葡萄糖的摄取,与对照组相比各实验组葡萄糖摄取率分别下降5.25%、10.29%、14.54%。说明PA具有引起3T3-L1脂肪细胞产生IR的作用,且1.0 mmol/L PA作用于3T3-L1细胞24h抑制细胞葡萄糖摄取的效果最显著。
2.gAd对3T3-L1脂肪细胞IR模型葡萄糖摄取能力的影响
不同浓度的gAd (250ng/mL、500ng/mL、1000ng/mL)作用于产生IR的3T3-L1脂肪细胞,可促进脂肪细胞葡萄糖摄取(F=35.499,r=-0.883,P=0.005)。与对照组相比,gAd250 ng/mL时就可显著促进脂肪细胞葡萄糖摄取(p=0.000)。
3.gAd对3T3-L1脂肪细胞IR模型AMPK通路的影响
gAd可增加3T3-L1脂肪细胞IR模型AMPK (F=359.374, r=0.986, P=0.000)、CPT-I (F=180.234, r=0.973, P=0.000)基因的表达,呈剂量依赖关系。各实验组与对照组比较均有显著差异(P<0.01),各实验组组间比较也有显著差异(P<0.01)。Western blot结果显示, gAd可增加3T3-L1脂肪细胞IR模型AMPK Thr-172磷酸化水平,且随着gAd浓度的增加,AMPK Thr-172磷酸化水平逐渐增强(F=269.407,r=0.982,P=0.000)。
4.gAd对3T3-L1脂肪细胞IR模型胰岛素PI-3K途径的影响
与对照组相比,250 ng/mL gAd组可增加3T3-L1脂肪细胞IR模型GLUT-4mRNA的表达(P=0.024),但IRS-1 (P=0.324) PI-3K (P=0.125)、PKB (P=0.748) mRNA表达较对照组无显著差异；500 ng/mL gAd组IRS-1(P=0.031)、PI-3K(P=0.002)、PKB(P=0.01).GLUT-4(P=0.000)的表达均比对照组显著增加,且PI-3K (t=-3.66 P=0.022)、PKB (t=-4.161 P=0.014)、GLUT-4(t=-15.039,P=0.000)的表达均较250 ng/mL gAd组显著增加；1000 ng/mLgAd组IRS-1 (P=0.031). PI-3K (P=0.000)、PKB (P=0.000)、GLUT-4 (P=0.000)的表达均比对照组显著增加,且GLUT-4 (t=10.483, P=0.000) mRNA的表达较500 ng/mL gAd组显著增加。Western blot结果显示,gAd可增加3T3-L1脂肪细胞IR模型IRS-1磷酸化水平,且随着gAd浓度的增加,IRS-1磷酸化水平逐渐增加(F=360.345,r=0.968,P=0.000)。
结论
1.gAd可促进3T3-L1脂肪细胞IR模型葡萄糖的摄取。
2.gAd可能是通过促进AMPK Thr-172磷酸化,激活AMPK,增加CPT-I的活性,促进脂肪酸的氧化,改善3T3-L1脂肪细胞的IR。
3.gAd可增加胰岛素P13K通路IRS-1、PI3K、PKB、GLUT-4基因的表达,并使IRS-1磷酸化水平增加,改善3T3-L1脂肪细胞的IR。
Objective:
The study was to the role and mechanism of Globular domain of adiponectin (gAd) in improving Insulin resistance of the 3T3-L1 adipocytes.
Methods:
Culturing and differentiating 3T3-L1 cells, use oil red O for lipids when the cells were matured. After dialysis of gAd, determine protein concentration by Coomassie brilliant blue. Insulin resistance model of 3T3-L1 adipocytes was prepared with PA. Intervention the adipocytes which have been generated IR with different concentrations of gAd (250 ng/mL、500 ng/mL、1000 ng/mL) for 5h. Blank control group, the cell culture medium glucose content was detected with the glucose oxidize method, the mRNA expression of IRS-1, P13K, PKB, GLUT-4, AMPK, CPT-Ⅰwere detected with real-time quantitative PCR method. Phosphorylation AMPK Thr-172 and IRS-1 was detected by Western blot. SPSS 17.0 statistical analysis software was used to establish a database and analysis of the data, which data were expressed as mean±standard deviation (x±s), and the test level was a= 0.05.
Results:
1. Different concentrations of PA (0.25mmol/L,0.5mmol/L, 1.Ommol/L) effect on 3T3-L1 adipocytes for 24h can inhibited glucose uptake. Compared with the control group, the rate of glucose uptake in all experimental groups decreased 5.25%,10.29%,14.54%. So 3T3-L1 adipocytes can generate IR by PA.1.0 mmol/L of PA can inhibit glucose uptake significantly.
2. Different concentrations of gAd (250 ng/mL,500 ng/mL,1000 ng/mL) acting in 3T3-L1 cells which have generated IR, can stimulate glucose uptake significantly (F=35.499, r=-0.883, P=0.005), Compared with the control group,250ng/mL of gAd can besignificantly enhanced glucose uptake (p=0.000).
3. Different concentrations of gAd gradually increased the mRNA expression levels of AMPK (F=359.374, r=0.986, P=0.000), CPT-I (F=180.234, r=0.973, P=0.000) and in a dose-dependent manner. The experimental group and control group were significantly different (P<0.01), between groups in all experimental groups had significant differences (P <0.01). The results of Western blot illustrate that AMPK Thr-172 phosphorylation levels increased gradually followed by the concentration of gAd (F=269.407, r=0.982, P=0.000).
4. Affect of gAd on IR 3T3-L1 adipocyte models of insulin P13K pathway
Compared with the control group,250 ng/mL gAd group mRNA expression levels of GLUT-4 (P=0.02)increased than the control group, but the IRS-1, PI3K, PKB have no significant difference compared with the control group; 500 ng/mL gAd Group mRNA expression levels of IRS-1 (P=0.031), P13K (P=0.002), PKB (P=0.01), GLUT-4 (P=0.000) significantly increased compared with controls, and the mRNA expression levels of P13K (t=-3.66 P=0.022), PKB (t= 4.161 P=0.014), GLUT-4 (t=-15.039, P=0.000) significantly increased compared with 250 ng/ mL gAd; 1000 ng/mL gAd group mRNA expression levels of IRS-1 (P=0.031), P13K (P= 0.000), PKB (P=0.000), GLUT-4 (P=0.000), was significantly increased compared with controls (P＜0.01), and mRNA expression levels of GLUT-4 (t=10.483, P=0.000), significantly increased compared with 500 ng/mL gAd group. The results of Western blot illustrate that IRS-1 phosphorylation levels increased gradually followed by the concentration of gAd (F=360.345, r=0.968, P=0.000).
Conclusions:
1. GAd can promote glucose uptake of 3T3-L1 adipocyte model which have generated IR.
2. The mechanism of gAd improve insulin resistance may be increase AMPK Thr-172 phosphorylation, activation of AMPK, thus lift the inhibition on CPT-Ⅰ, increase free fatty acid oxidation.
3. GAd can improve insulin resistance by gradually increased the mRNA expression levels of IRS-1、PI3K、PKB、GLUT-4,and increase IRS-1 phosphorylation levels.
引文
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[33]易屏,陆付耳,陈广等.游离脂肪酸诱导3T3-L1脂肪细胞胰岛素抵抗的分子机制[J].中国糖尿病杂志,2008,16(4)：221-224.
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[35]Andreelli F, Foretz M, Knauf C, et al. Liver adenosine monophosphate-activated kinase-alpha2 catalytic subunit is a key target for thecontrol of hepatic glucose production by adiponectin and leptin but not insulin[J]. Endocrinology.2006,147(5):2432-2441.
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[1]Lara-Castro C, Luo N, Wallace P, et al. Adiponectin multimeri complexes and themetabolic syndrome trait cluster[J]. Diabetes,2006,55(1):249-259.
[2]Tray hum P, Wood IS. Adipokines:inflammation and the pleiotropic role of white adipose tissue[J].Br J Nutr,2004,92(3):347-355.
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[5]Wang Y, Lam KS, Xu JY, et al. Adiponectin inhibits cell prolifertion by interacting with several growth factors in an oligomerizati-dependent manner[J]. J Biol Chem,2005,280 (18)18341-18347.
[6]Lenchik L, Register TC, Hsu FC, et al. Adiponectin as a novel determinant of bone mineral density and visceral fat[J]. Bone,2003,33(4):646-651.
[7]Tomas E, Tsao TS, Saha AK, et al. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain:Acetyl-CoA carboxylase inhibition and AMP-activated protein kinas activation [J]. Proc Natl Acad Sci U S A,2002,99(25):16309-16313.
[8]Motoshima H, Wu X, Mahadev K, et al. Adiponectin suppresses proliferation and superoxide generation and enhances eNOS activity in endothelial cells treated with oxidized LDL[J]. Biochem Biophys Res Commun,2004,315(2):264-271.
[9]Scherer PE, Williams S, Fogliano M, et al. A novel serum protein similar to C1qproduced exclusively in adipocytes[J]. J Biol Chem,1995,270(45):26746-26749.
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[13]SchererPE, W illiamsS, FoglianoM, et al. A novel serum protein similar toC1q, produced exclusively in adipocytes[J]. JBiolChem,1995,270(45):26746-26749.
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[15]Shanmugam N,Reddy MA,Guha M, et al. High glucose-in-duced expression of proinflammatory cytokine and chemokine genes inmonocytic cells[J]. Diabetes 2003,52(5):1256-1264.
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[1]Lara-Castro C, Luo N, Wallace P, et al. Adiponectin multimeri complexes and themetabolic syndrome trait cluster[J]. Diabetes,2006,55(1):249-259.
[2]Tray hum P, Wood IS. Adipokines:inflammation and the pleiotropic role of white adipose tissue[J].Br J Nutr,2004,92(3):347-355.
[3]Ouchi N, Ohishi M, Kihara S, et al. Association of hypoadiponectinemia with impaired vaso reactivity [J]. Hypertension,2003,42(3):231-234.
[4]Musso G, Gambino R, Durazzo M, et al. Adipokines in NASH:postprandial lipid metabolism as a link between adiponectin and liver disease [J]. Hepatology,2005, 42(5):1175-1183.
[5]Wang Y, Lam KS, Xu JY, et al. Adiponectin inhibits cell prolifertion by interacting with several growth factors in an oligomerizati-dependent manner[J]. J Biol Chem,2005,280 (18)18341-18347.
[6]Lenchik L, Register TC, Hsu FC, et al. Adiponectin as a novel determinant of bone mineral density and visceral fat[J]. Bone,2003,33(4):646-651.
[7]Tomas E, Tsao TS, Saha AK, et al. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain:Acetyl-CoA carboxylase inhibition and AMP-activated protein kinas activation [J]. Proc Natl Acad Sci U S A,2002,99(25):16309-16313.
[8]Motoshima H, Wu X, Mahadev K, et al. Adiponectin suppresses proliferation and superoxide generation and enhances eNOS activity in endothelial cells treated with oxidized LDL[J]. Biochem Biophys Res Commun,2004,315(2):264-271.
[9]Scherer PE, Williams S, Fogliano M, et al. A novel serum protein similar to C1qproduced exclusively in adipocytes[J]. J Biol Chem,1995,270(45):26746-26749.
[10]Motoshima H, Wu X, Mahadev K, et al. Adiponectin suppresses proliferation and superoxide generation and enhances eNOS activity in endothelial cells treated with oxidized LDL [J].Biochem Biophys Res Commun.2004,315(2):264-271.
[11]Lara-Castro C, Luo N, Wallace P, et al. Adiponectin multimeric complexes and the metabolic syndrome trait cluster [J].Diabetes.2006,55(1):249-259.
[12]Trayhurn P, Wood IS. Adipokines:inflammation and the pleiotropic role of white adipose tissue [J]. Br J Nutr.2004,92(3):347-355.
[13]SchererPE, W illiamsS, FoglianoM, et al. A novel serum protein similar toC1q, produced exclusively in adipocytes[J]. JBiolChem,1995,270(45):26746-26749.
[14]Yamauchi T, Kamon J, Ito Y, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects[J]. Nature,2003,423(6941):762-769.
[15]Shanmugam N,Reddy MA,Guha M, et al. High glucose-in-duced expression of proinflammatory cytokine and chemokine genes inmonocytic cells[J]. Diabetes 2003,52(5):1256-1264.
[16]陈家伦.胰岛素信号转导及临床意义(上)[J].国外医学内分泌学分册,2002,22(1)：1-4.
[17]Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism[J].Nature 2001,414(6865):799-806.
[18]Hu XB, Zhang YJ, Zhang HT, et al. Cloning and expression of adiponectin and its globular domain, and measurement of the biological activityin vivo[J]. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai).2003,35(11):1023-1028.
[19]Mao X, Kikani CK, Riojas RA, et al.APPLl binds to adiponectin receptors and mediates adiponectin signaling and function[J].Nat Cell Biol,2006.8(5):516-523.
[20]W u XD, M otoshima H, M ahadev K.et al. Involvement of AM P-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocyte[J]. Diabetes,2003,2(6):1355-1363
[21]Ceddia RB, Somwar R, M aida A, et al. Globular adiponectin increases GI UT4 translocation and glucose uptake but reduces glycogen synthesis in rat skeletal muscle cells[J]. Diabetologia,2005,48(1):132-139.
[22]Yu C,Chen Y,Cline GW,et al.Mechanism by whick fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle[J].J Biol Chem 2002,277(52):50230-50236.
[23]Kahn BB, Pedersen O. Suppression of GLUT4 expressionin skeletal muscle of rats that are obese from high feeding but not from high carbohydrate feeding or genetic obesity [J]. Endocrinology,1993,132 (1):13-22.
[24]易屏,陆付耳,陈广等.游离脂肪酸诱导3T3-L1脂肪细胞胰岛素抵抗的分子机制[J].中国糖尿病杂志,2008,16(4)：221-224.
[25]Yoon MJ,Lee GY,Chung JJ,et al.Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase,p38 mitogen activated protein kinase,and peroxisome proliferator activated receptora[J].Diabetes,2006,55(9):2562-2570.
[26]Yamauchi T,Nio Y,Maki T,et al.Targeted disruption of AdipoRl and AdipoR2 causes abrogation of adiponectinbinding and metabolic actions[J].Nat Med,2007,13(3):332-339.
[27]Son BK,Akishita M,Iijima K,et al.Adiponectin antagonizes stimulatory effect of tumor necrosis factor-alpha on vascular smoothmuscle cell calcification:Regulation of growth.Arrest-specific.gene 6-mediated survival pathway by adenosine 5-monophosphate-activated protein kinase[J].Endocrinology,2008,149(4):16-46.
[28]KimDH,BurgessAP,Li M,et al.Heme oxygenase-mediated increases in adiponectin decrase fot content and inflammatory cytokinestumor necrosis factor-alpha and interleukin-6 in Zucker rats and reduce adipogenesis in hunm mesenchymal stem cells [J]. Pharmacol Exp Ther,2008,325(3):8-33.