缺氧的脂肪细胞与巨噬细胞条件培养基对骨骼肌细胞胰岛素作用的影响
|
摘要
目的：
应用脂肪细胞和巨噬细胞条件培养基以及饱和脂肪酸孵育骨骼肌细胞,检测胰岛素刺激的骨骼肌葡萄糖转运子4(GLUT4)的转位和胰岛素信号分子的磷酸化水平,研究肥胖和缺氧对骨骼肌胰岛素作用的影响,探讨肥胖导致周身胰岛素抵抗的机制。
方法：
1.脂肪细胞和巨噬细胞分别进行常氧和缺氧(1%02,5%CO2,94%N2)培养,制备条件培养基。
2.用脂肪细胞和巨噬细胞的条件培养基孵育骨骼肌细胞,采用偶联抗体的吸光度分析法测定骨骼肌GLUT4转位,采用(?)Vestern Blot法测定胰岛素信号分子的磷酸化水平。
3.用饱和脂肪酸棕榈酸孵育骨骼肌细胞,采用偶联抗体的吸光度分析法测定骨骼肌中GLUT4转位,采用(?)Vestern Blot法测定胰岛素信号分子的磷酸化水平。
4.采用ELISA法测定脂肪细胞和巨噬细胞条件培养基内TNF-α的水平。
5.采用Real-time PCR法,测定常氧和缺氧处理的脂肪细胞脂联素mRNA、 TNF-a mRNA和巨噬细胞TNF-a mRNA水平。
6.采用Transwell系统观察常氧和缺氧培养的脂肪细胞对巨噬细胞的趋化作用。
7.本研究的数据采用SPSS13.0软件进行统计学分析。
结果：
1.缺氧处理脂肪细胞和巨噬细胞,GLUT1蛋白表达增加。
2.常氧处理的脂肪细胞条件培养基孵育骨骼肌细胞,在C2C12和L6两种骨骼肌细胞中,基础状态和胰岛素刺激状态下GLUT4转位与对照组相比无显著性差异；缺氧处理的脂肪细胞条件培养基孵育骨骼肌细胞骨骼肌细胞在基础状态下GLUT4转位与对照组相比有显著增加(p<0.05,p<0.01),而胰岛素刺激的GLUT4转位与对照组相比增加无显著性差异,C2C12骨骼肌细胞胰岛素刺激GLUT4转位增加的倍数与对照组相比呈下降趋势,但无显著性差异,而在L6细胞中则显著下降(p<0.05)。
3.常氧处理的巨噬细胞条件培养基孵育C2C12骨骼肌细胞,与对照组相比,基础状态和胰岛素刺激状态下GLUT4转位有上升趋势,但无显著性差异。缺氧处理的巨噬细胞条件培养基孵育骨骼肌细胞,与对照组相比,基础状态下GLUT4转位有显著性升高(p<0.05),胰岛素刺激状态下GLUT4转位有增加趋势,但无显著性差异。两组胰岛素刺激GLUT4转位增加的倍数与对照组相比均呈下降趋势,但无显著性差异。
4.常氧处理的脂肪细胞条件培养基孵育C2C12骨骼肌细胞,与对照组相比,基础状态下Akt磷酸化水平有升高的趋势,但无显著性差异,胰岛素刺激的Akt磷酸化水平与对照组相比无显著性差异。缺氧处理的脂肪细胞条件培养基孵育C2C12骨骼肌细胞,与对照组相比,基础状态下Akt磷酸化水平有升高的趋势,但无显著性差异,胰岛素刺激的Akt磷酸化水平与对照组相比无显著性差异。
5.常氧处理的巨噬细胞条件培养基孵育C2C12骨骼肌细胞,与对照组相比,基础状态下Akt磷酸化水平有升高的趋势,但无显著性差异,胰岛素剌激的Akt磷酸化水平与对照组相比无显著性差异。缺氧处理的巨噬细胞条件培养基孵育C2C12骨骼肌细胞,与对照组相比,基础状态下Akt磷酸化水平有升高趋势,但无显著性差异,而胰岛素刺激的Akt磷酸化水平与对照组相比无显著性差异。
6.棕榈酸孵育骨骼肌细胞,可使骨骼肌细胞在基础状态下GLUT4转位和对照组相比无明显改变,而在胰岛素刺激下的GLUT4转位和对照组相比显著降低(p<0.05)。溶剂组BSA孵育的骨骼肌细胞,胰岛素增加骨骼肌细胞Akt的磷酸化水平,而棕榈酸孵育则使胰岛素刺激的Akt磷酸化水平显著性降低。胰岛素增加S6K的磷酸化水平,而棕榈酸孵育不影响胰岛素刺激的S6K的磷酸化以及IRS1$636/639磷酸化水平
7.缺氧处理的脂肪细胞和巨噬细胞条件培养基中TNF-a水平显著升高(p<0.01)。
8.缺氧处理的脂肪细胞脂联素mRNA水平降低(p<0.01),缺氧处理的脂肪细胞和巨噬细胞TNF-α mRNA水平显著升高(p<0.01)。
9.缺氧处理的脂肪细胞吸引巨噬细胞迁移增加。
结论：
1.缺氧培养箱培养细胞,可造成脂肪细胞和巨噬细胞缺氧,模拟肥胖者脂肪组织缺氧,制备条件培养基。
2.常氧处理的脂肪细胞条件培养基孵育骨骼肌细胞可造成骨骼肌细胞胰岛素刺激的GLUT4转位增加的倍数呈下降的趋势,但无显著性差异。而缺氧处理的脂肪细胞条件培养基孵育骨骼肌细胞可造成骨骼肌细胞胰岛素抵抗。
3.常氧处理和缺氧处理的巨噬细胞条件培养基孵育骨骼肌细胞使骨骼肌细胞胰岛素刺激的GLUT4转位增加的倍数呈下降的趋势,但无显著性差异。
4.饱和脂肪酸孵育可造成骨骼肌细胞胰岛素抵抗,其机制可能不涉及S6K。
5.脂肪细胞在缺氧状态下脂联素表达水平显著下降,TNF-α表达水平显著增加。巨噬细胞在缺氧状态下,TNF-α表达水平显著增加。这些因子可能参与条件培养基导致骨骼肌胰岛素抵抗的机制。
6.脂肪细胞缺氧可吸引更多的巨噬细胞,可能参与肥胖导致周身胰岛素抵抗的机制。
Objective:
To study the roles of obesity and hypoxia on insulin effect in skeletal muscle cells and to exlpore the mechanism of insulin resistance in obesity, GLUT4translocation and phosphorylation of insulin signaling molecules in skeletal muscle cells were determined under incubation with conditioned medium (CM) from adipocytes, macrophages or saturated fatty acid, respectively.
Methods:
1To prepare CM from adipocytes and macrophages cultured under normoxia and hypoxia (1%O2,5%CO2,94%N2) condition, respectively.
2To determine GLUT4translocation under basal and insulin condition by absorptiometric analysis and to determinate phosphorylation of insulin signaling molecules under basal and insulin condition by Western Blot in skeletal muscle cells incubated with or without CM from adipocytes and macrophages.
3To determine GLUT4translocation under basal and insulin condition with absorptiometric analysis and to determinate phosphorylation of insulin signaling molecules under basal and insulin condition by Western Blot in skeletal muscle cells with or without palmitate incubation.
4To determine TNF-a level in CM from adipocytes and macrophages by ELISA.
5To determine levels of adiponectin mRNA and TNF-a mRNA of adipocytes and level of TNF-a mRNA of macrophages under normoxia and hypoxia by Real-time PCR.
6To observe the influence on macrophage chemotactic movement to adipocytes with transwell system.
7To statistical analyze the data with SPSS software13.0.
Results:
1The GLUT1increased in adipocytes and macrophages under hypoxia treatment.
2Compared to control group, GLUT4translocation in basal and insulin condition showed no significant difference in C2C12and L6skeletal muscle cells incubated with CM from normoxia-treated adipocytes. Compared to control group, GLUT4 translocation in basal condition increased significantly (p＜0.05, p＜0.01) and GLUT4translocation under insulin condition had no significant difference in C2C12and L6skeletal muscle cells incubated with CM from hypoxia-treated adipocytes. Compared to control group, the fold increase above basal of GLUT4translocation after insulin stimulation showed decrease tendency, but no significant difference in C2C12skeletal muscle cells, but decreased significantly in L6skeletal muscle cells (p＜0.05) incubated with CM from hypoxia-treated adipocytes.
3Compared to control group, GLUT4translocation under basal and insulin condition showed increase tendency, but no significant difference in C2C12skeletal muscle cells incubated with CM from normoxia-treated macrophages. Compared to control group, the GLUT4translocation under basal condition increased significantly (p＜0.05), and the translocation under insulin condition had an increase tendency but no significant difference in skeletal muscle cells incubated with CM from hypoxia-treated macrophages. Compared to control group, the fold increase above basal of GLUT4translocation after insulin stimulation had a decrease tendency, but no significant difference in skeletal muscle cells incubated with CM from normoxia-treated and hypoxia-treated macrophages, respectively.
4Compared to control group, the phosphorylation of Akt under basal condition had an increase tendency but no significant difference and the phosphorylation of Akt under insulin condition had no significant difference in C2C12skeletal muscle cells incubated with CM from normoxia-treated adipocytes. Compared to control group, the phosphorylation of Akt under basal condition had an increase tendency but no significant difference and the phosphorylation of Akt under insulin condition had no significant difference in C2C12skeletal muscle cells incubated with CM from hypoxia-treated adipocytes.
5Compared to control group, the phosphorylation of Akt under basal condition had an increase tendency but no significant difference, and the phosphorylation of Akt under insulin condition had no significant difference in C2C12skeletal muscle cells incubated with CM from normoxia-treated and hypoxia treated macrophages.
6Compared to control group, the GLUT4translocation under basal condition showed no significant difference and the GLUT4translocation under insulin condition showed a significant decrement in skeletal muscle cells with palmitate incubation. Compared to basal condition, the phosphorylation of Akt under insulin condition incresed in vehicle group. Compared to vehicle group, the phosphorylation of Akt under insulin condition had a significant decrement and the phosphorylation of S6K and IRS1S636/639under insulin condition had no significant difference in skeletal muscle cells with palmitate incubation.
7TNF-a increased in CM from hypoxia-treated adipocytes and macrophages.
8The mRNA of adiponectin decreased in hypoxia-treated adipocytes, the mRNA of TNF-a increased in hypoxia-treated adipocytes and macrophages.
9Compared to nomorxia-treated group, macrophages migration increased in hypoxia-treated group.
Conclusions
1Adipocytes and macrophages response to hypoxia treatment. CM from adipocytes or macrophages can be made in this way to mimic the hypoxia state of adipose tissue in obesity.
2The fold increase above basal of GLUT4translocation after insulin stimulation shows decrease tendency, but no significant difference in skeletal muscle cells incubated with CM from normoxia-treated adipocytes compared to control group. Incubation of CM from hypoxia-treated adipocytes causes insulin resistance in skeletal muscle cells.
3The fold increase above basal of GLUT4translocation after insulin stimulation shows decrease tendency, but no significant difference in skeletal muscle cells incubated with CM from normoxia-treated and hypoxia-treated macrophages compared to control group.
4Incubation with palmitate causes insulin resistance in a S6K-independent mechanism in skeletal muscle cells.
5. Expression of adiponectin decreased and expression of TNF-a increased in hypoxia-treated adipocytes. Expression of TNF-a increased in hypoxia-treated macrophages. Adiponectin and TNF-a may involve in the mechanism of insulin resistance in skeletal muscle cells caused by CM from hypoxia-treated adipocytes.
6. Adipocytes under hypoxia condition attract more macrophages, which may play a role in the process of obesity to whole body insulin resistance.
应用脂肪细胞和巨噬细胞条件培养基以及饱和脂肪酸孵育骨骼肌细胞,检测胰岛素刺激的骨骼肌葡萄糖转运子4(GLUT4)的转位和胰岛素信号分子的磷酸化水平,研究肥胖和缺氧对骨骼肌胰岛素作用的影响,探讨肥胖导致周身胰岛素抵抗的机制。
方法：
1.脂肪细胞和巨噬细胞分别进行常氧和缺氧(1%02,5%CO2,94%N2)培养,制备条件培养基。
2.用脂肪细胞和巨噬细胞的条件培养基孵育骨骼肌细胞,采用偶联抗体的吸光度分析法测定骨骼肌GLUT4转位,采用(?)Vestern Blot法测定胰岛素信号分子的磷酸化水平。
3.用饱和脂肪酸棕榈酸孵育骨骼肌细胞,采用偶联抗体的吸光度分析法测定骨骼肌中GLUT4转位,采用(?)Vestern Blot法测定胰岛素信号分子的磷酸化水平。
4.采用ELISA法测定脂肪细胞和巨噬细胞条件培养基内TNF-α的水平。
5.采用Real-time PCR法,测定常氧和缺氧处理的脂肪细胞脂联素mRNA、 TNF-a mRNA和巨噬细胞TNF-a mRNA水平。
6.采用Transwell系统观察常氧和缺氧培养的脂肪细胞对巨噬细胞的趋化作用。
7.本研究的数据采用SPSS13.0软件进行统计学分析。
结果：
1.缺氧处理脂肪细胞和巨噬细胞,GLUT1蛋白表达增加。
2.常氧处理的脂肪细胞条件培养基孵育骨骼肌细胞,在C2C12和L6两种骨骼肌细胞中,基础状态和胰岛素刺激状态下GLUT4转位与对照组相比无显著性差异；缺氧处理的脂肪细胞条件培养基孵育骨骼肌细胞骨骼肌细胞在基础状态下GLUT4转位与对照组相比有显著增加(p<0.05,p<0.01),而胰岛素刺激的GLUT4转位与对照组相比增加无显著性差异,C2C12骨骼肌细胞胰岛素刺激GLUT4转位增加的倍数与对照组相比呈下降趋势,但无显著性差异,而在L6细胞中则显著下降(p<0.05)。
3.常氧处理的巨噬细胞条件培养基孵育C2C12骨骼肌细胞,与对照组相比,基础状态和胰岛素刺激状态下GLUT4转位有上升趋势,但无显著性差异。缺氧处理的巨噬细胞条件培养基孵育骨骼肌细胞,与对照组相比,基础状态下GLUT4转位有显著性升高(p<0.05),胰岛素刺激状态下GLUT4转位有增加趋势,但无显著性差异。两组胰岛素刺激GLUT4转位增加的倍数与对照组相比均呈下降趋势,但无显著性差异。
4.常氧处理的脂肪细胞条件培养基孵育C2C12骨骼肌细胞,与对照组相比,基础状态下Akt磷酸化水平有升高的趋势,但无显著性差异,胰岛素刺激的Akt磷酸化水平与对照组相比无显著性差异。缺氧处理的脂肪细胞条件培养基孵育C2C12骨骼肌细胞,与对照组相比,基础状态下Akt磷酸化水平有升高的趋势,但无显著性差异,胰岛素刺激的Akt磷酸化水平与对照组相比无显著性差异。
5.常氧处理的巨噬细胞条件培养基孵育C2C12骨骼肌细胞,与对照组相比,基础状态下Akt磷酸化水平有升高的趋势,但无显著性差异,胰岛素剌激的Akt磷酸化水平与对照组相比无显著性差异。缺氧处理的巨噬细胞条件培养基孵育C2C12骨骼肌细胞,与对照组相比,基础状态下Akt磷酸化水平有升高趋势,但无显著性差异,而胰岛素刺激的Akt磷酸化水平与对照组相比无显著性差异。
6.棕榈酸孵育骨骼肌细胞,可使骨骼肌细胞在基础状态下GLUT4转位和对照组相比无明显改变,而在胰岛素刺激下的GLUT4转位和对照组相比显著降低(p<0.05)。溶剂组BSA孵育的骨骼肌细胞,胰岛素增加骨骼肌细胞Akt的磷酸化水平,而棕榈酸孵育则使胰岛素刺激的Akt磷酸化水平显著性降低。胰岛素增加S6K的磷酸化水平,而棕榈酸孵育不影响胰岛素刺激的S6K的磷酸化以及IRS1$636/639磷酸化水平
7.缺氧处理的脂肪细胞和巨噬细胞条件培养基中TNF-a水平显著升高(p<0.01)。
8.缺氧处理的脂肪细胞脂联素mRNA水平降低(p<0.01),缺氧处理的脂肪细胞和巨噬细胞TNF-α mRNA水平显著升高(p<0.01)。
9.缺氧处理的脂肪细胞吸引巨噬细胞迁移增加。
结论：
1.缺氧培养箱培养细胞,可造成脂肪细胞和巨噬细胞缺氧,模拟肥胖者脂肪组织缺氧,制备条件培养基。
2.常氧处理的脂肪细胞条件培养基孵育骨骼肌细胞可造成骨骼肌细胞胰岛素刺激的GLUT4转位增加的倍数呈下降的趋势,但无显著性差异。而缺氧处理的脂肪细胞条件培养基孵育骨骼肌细胞可造成骨骼肌细胞胰岛素抵抗。
3.常氧处理和缺氧处理的巨噬细胞条件培养基孵育骨骼肌细胞使骨骼肌细胞胰岛素刺激的GLUT4转位增加的倍数呈下降的趋势,但无显著性差异。
4.饱和脂肪酸孵育可造成骨骼肌细胞胰岛素抵抗,其机制可能不涉及S6K。
5.脂肪细胞在缺氧状态下脂联素表达水平显著下降,TNF-α表达水平显著增加。巨噬细胞在缺氧状态下,TNF-α表达水平显著增加。这些因子可能参与条件培养基导致骨骼肌胰岛素抵抗的机制。
6.脂肪细胞缺氧可吸引更多的巨噬细胞,可能参与肥胖导致周身胰岛素抵抗的机制。
Objective:
To study the roles of obesity and hypoxia on insulin effect in skeletal muscle cells and to exlpore the mechanism of insulin resistance in obesity, GLUT4translocation and phosphorylation of insulin signaling molecules in skeletal muscle cells were determined under incubation with conditioned medium (CM) from adipocytes, macrophages or saturated fatty acid, respectively.
Methods:
1To prepare CM from adipocytes and macrophages cultured under normoxia and hypoxia (1%O2,5%CO2,94%N2) condition, respectively.
2To determine GLUT4translocation under basal and insulin condition by absorptiometric analysis and to determinate phosphorylation of insulin signaling molecules under basal and insulin condition by Western Blot in skeletal muscle cells incubated with or without CM from adipocytes and macrophages.
3To determine GLUT4translocation under basal and insulin condition with absorptiometric analysis and to determinate phosphorylation of insulin signaling molecules under basal and insulin condition by Western Blot in skeletal muscle cells with or without palmitate incubation.
4To determine TNF-a level in CM from adipocytes and macrophages by ELISA.
5To determine levels of adiponectin mRNA and TNF-a mRNA of adipocytes and level of TNF-a mRNA of macrophages under normoxia and hypoxia by Real-time PCR.
6To observe the influence on macrophage chemotactic movement to adipocytes with transwell system.
7To statistical analyze the data with SPSS software13.0.
Results:
1The GLUT1increased in adipocytes and macrophages under hypoxia treatment.
2Compared to control group, GLUT4translocation in basal and insulin condition showed no significant difference in C2C12and L6skeletal muscle cells incubated with CM from normoxia-treated adipocytes. Compared to control group, GLUT4 translocation in basal condition increased significantly (p＜0.05, p＜0.01) and GLUT4translocation under insulin condition had no significant difference in C2C12and L6skeletal muscle cells incubated with CM from hypoxia-treated adipocytes. Compared to control group, the fold increase above basal of GLUT4translocation after insulin stimulation showed decrease tendency, but no significant difference in C2C12skeletal muscle cells, but decreased significantly in L6skeletal muscle cells (p＜0.05) incubated with CM from hypoxia-treated adipocytes.
3Compared to control group, GLUT4translocation under basal and insulin condition showed increase tendency, but no significant difference in C2C12skeletal muscle cells incubated with CM from normoxia-treated macrophages. Compared to control group, the GLUT4translocation under basal condition increased significantly (p＜0.05), and the translocation under insulin condition had an increase tendency but no significant difference in skeletal muscle cells incubated with CM from hypoxia-treated macrophages. Compared to control group, the fold increase above basal of GLUT4translocation after insulin stimulation had a decrease tendency, but no significant difference in skeletal muscle cells incubated with CM from normoxia-treated and hypoxia-treated macrophages, respectively.
4Compared to control group, the phosphorylation of Akt under basal condition had an increase tendency but no significant difference and the phosphorylation of Akt under insulin condition had no significant difference in C2C12skeletal muscle cells incubated with CM from normoxia-treated adipocytes. Compared to control group, the phosphorylation of Akt under basal condition had an increase tendency but no significant difference and the phosphorylation of Akt under insulin condition had no significant difference in C2C12skeletal muscle cells incubated with CM from hypoxia-treated adipocytes.
5Compared to control group, the phosphorylation of Akt under basal condition had an increase tendency but no significant difference, and the phosphorylation of Akt under insulin condition had no significant difference in C2C12skeletal muscle cells incubated with CM from normoxia-treated and hypoxia treated macrophages.
6Compared to control group, the GLUT4translocation under basal condition showed no significant difference and the GLUT4translocation under insulin condition showed a significant decrement in skeletal muscle cells with palmitate incubation. Compared to basal condition, the phosphorylation of Akt under insulin condition incresed in vehicle group. Compared to vehicle group, the phosphorylation of Akt under insulin condition had a significant decrement and the phosphorylation of S6K and IRS1S636/639under insulin condition had no significant difference in skeletal muscle cells with palmitate incubation.
7TNF-a increased in CM from hypoxia-treated adipocytes and macrophages.
8The mRNA of adiponectin decreased in hypoxia-treated adipocytes, the mRNA of TNF-a increased in hypoxia-treated adipocytes and macrophages.
9Compared to nomorxia-treated group, macrophages migration increased in hypoxia-treated group.
Conclusions
1Adipocytes and macrophages response to hypoxia treatment. CM from adipocytes or macrophages can be made in this way to mimic the hypoxia state of adipose tissue in obesity.
2The fold increase above basal of GLUT4translocation after insulin stimulation shows decrease tendency, but no significant difference in skeletal muscle cells incubated with CM from normoxia-treated adipocytes compared to control group. Incubation of CM from hypoxia-treated adipocytes causes insulin resistance in skeletal muscle cells.
3The fold increase above basal of GLUT4translocation after insulin stimulation shows decrease tendency, but no significant difference in skeletal muscle cells incubated with CM from normoxia-treated and hypoxia-treated macrophages compared to control group.
4Incubation with palmitate causes insulin resistance in a S6K-independent mechanism in skeletal muscle cells.
5. Expression of adiponectin decreased and expression of TNF-a increased in hypoxia-treated adipocytes. Expression of TNF-a increased in hypoxia-treated macrophages. Adiponectin and TNF-a may involve in the mechanism of insulin resistance in skeletal muscle cells caused by CM from hypoxia-treated adipocytes.
6. Adipocytes under hypoxia condition attract more macrophages, which may play a role in the process of obesity to whole body insulin resistance.
引文
[1]Wild S, Roglic G, Green A, et, al. Global prevalence of diabetes:estimates for the pera 2000 and projections for 2030 [J]. Diabetes Care,2004,27:1047-1053.
[2]Shulman BM, and Flier JS. Adipogenesis and obesity:Rounding out the big picture [J]. Cell,1996,87:377-389.
[3]Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue [J]. Nature,1994,372:425-432.
[4]Beltowski J. Adiponectin and resistin-new hormones of white adipose tissue [J]. Med Sci Monit,2003,9:RA55-RA61.
[5]Shimonura I, Funahashi T, Takahashi M. Enhanced expression of PAI-1 in visceral fat:possible contributor to vascular disease in obesity [J]. Nat Med,1996,2: 800-803
[6]Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-a:direct role in obesity-linked insulin resistance [J]. Science,1993, 259:87-91.
[7]Ahima RS, and Flier JS. Adipose tissue as an endocrine organ [J]. Trends Endocrinol Metab,2000,11:327-332.
[8]Sartipy P, and Loskutoff DJ. Monocyte chemoattractant protein 1 in obesity and insulin resistance [J]. Proc Natl Acad Sci USA,2003,100:7265-7270.
[9]Bloomgarden ZT. Obesity and diabetes [J].Diabetes Care,2000,23:1584-1590.
[10]Felber JP, Golay A. Pathways from obesity to diabetes [J]. Int J Obes Relat Metab Disord,2002,26(Suppl2):S39-S45.
[11]Finegood DT. Obesity, inflammation and type Ⅱ diabetes [J]. Int J Obes Relat Metab Disord,2003,27(Suppl 3):S4-S5.
[12]Boden Boden G, Lebed B, SchatzM et al. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance-in healthy subjects [J]. Diabetes,2001,507:1612-1617.
[13]Chao L, Marcus-Samuels B, Mason MM et al. Adipose tissue required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones [J]. J Clin Invest,2000,106(10):1221-1228.
[14]Franckhauser S, Munoz S, PujolA et al. Increased fatty acid re-esterification by PEPCK overexpression in adipose tissue leads to obesity without insulin resistance [J]. Diabetes,2002,513:624-630.
[15]Boden G, Chen X. Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes [J]. J Clin Invest,1995,96:1261-1268.
[16]Belfort R, Mandarino L, Kashyap S, et al. Dose-response effect of elevated plasma free fatty acid on insulin signaling [J]. Diabetes,2005,54:1640-1648.
[17]Pessin JE, SaltielAR. Signaling pathways in insulin action:Molecular targets of insulin resistance [J]. J Clin Invest,2000,1062:165-169.
[18]SaltielAR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism [J]. Nature,2001,414 (6865):799-806.
[19]Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance [J]. Nature,2002,420:333-336.
[20]Dresner A, Laurent D, Marcucci M, et al. Effects of free fatty acids on glucose transport and IRS- 1-associated phosphatidylinositol-3-kinase activity [J]. J Clin Invest,1999,103(2):253-259.
[21]Griffin MF, Marcuccci MJ, Cline GW, et al. Free fatty acid-induced insulin resistance is associated with activity of protein kinase C theta and alterations in the insulin signaling cascade [J]. Diabetes,1999,48:1270-1274.
[22]Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance [J]. J Clin. Invest,2003, 12:1821-1830.
[23]Weisberg SP, McCann D, Desai M, et,al. Obesity is associated with macrophage accumulation in adipose tissue [J]. J Clin Invest,2003,112:1796-1808.
[24]Hotamisligil G.S and Spiegelman BM. Tumor necrosis factor alpha:a key component of the obesity-diabetes link [J]. Diabetes,1994,43:1271-1278.
[25]Lyon CJ, Law RE, Hsueh WA. Minireview:adiposity, inflammation, and atherogenesis [J]. Endocrinology,2003,144:2195-2200.
[26]Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease [J]. Circ Res,2005,96:939-949.
[27]Cousin B, Munoz O, Andre M, et al. A role for preadipocytes as macrophage-like cells [J]. Faseb J,1999,13:305-312.
[28]Cancello R, Henegar C, Viguerie N, et al. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss [J]. Diabetes,2005,54:2277-2286.
[29]Hatomisgil GS, and Spiegelman BM. Tumor necrosis factor alpha:a key component of the obesity-diabetes link [J]. Diabetes,1994,43:1271-1278.
[30]Qi C, and Pekala PH. Tumor necrosis factor-alpha induced insulin resistance [J]. Proc Soc Exp Biol Med,2000,223(2):128-135.
[31]Vander PT, Romijn JA, Endert E, et al. Tumor necrosis factor mimics the metabolic response to acute infection in healthy humans [J]. Am J Physiol,1991, 261:E457-E465.
[32]Lang CH, Dobrescu C, Bagby GJ. Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output [J]. Endocrinology, 1992,130:43-52.
[33]Hofmann C, Lorenz K, Braithwaite SS, et al. Altered gene expression for tumor necrosis factor- and its receptors during drug and dietary modulation of insulin resistance [J]. Endocrinology,1994,34:264-270.
[34]Hamann A, Benecke H, Le Marchand-Brustel Y, et al. Characterization of insulin resistance and NIDDM in transgenic mice with reduced brown fat [J]. Diabetes, 1995,44:1266-1273.
[35]Uysal KT, Wiesbrock SM, Marino MW, et al. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function [J]. Nature,1997,389: 610-614.
[36]Ventre J, Doebber T, Wu M, et al. Targeted disruption of the tumor necrosis factor-alpha gene-metabolic consequences in obese and nonobese mice [J]. Diabetes,1997,46:1526-1531.
[37]Hotamisligil GS. Inflammation pathways and insulin activation [J].Obes Relat Metab Disord,2003,27(suppl 3):S53-S55.
[38]Souza SC, Palmer HJ, Kang YH, et al. TNF-alpha induction of lipolysis is mediated through activation of the exreacellular signal related kinase pathway in 3T3-L1 adipocytes [J]. J Cell Biochem,2003,89:1077-1086.
[39]Uysal KT, Wiesbrock SM, Marino MW, et al. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function [J]. Nature,1997,389: 610-614.
[40]Hotamisligil GS, Murray DL, Choy LN, et al. Tumor necrosis factor alpha inhibits signaling from the insulin receptor[J]. Proc Natl Acad Sci USA,1994,91: 4854-4858
[41]Hotamisligial GS, Peraldi P, Budavari A, et al. IRS-1 mediate inhibition of insulin receptor tyrosine kinase activity in TNF-a and obesity-induced insulin resistance [J].Science,1996,271(5249):665-668.
[42].Shi H, Tzameli I, Bjorbaek C, et al. Suppressor of cytokine signaling 3 is a physiological regulator of adipocyte insulin signaling [J]. J Biol Chem,2004,279: 34733-34740.
[43]Jager J, Gremeaux T, Cormont M, et al. Interleukin-1-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression[J]. Endocrinology,2007,148:241-251.
[44]Weigert C, Hennige AM, Lehmann R, et al. Direct cross-talk of interleukin-6 and insulin signal transduction via insulin receptor substrate-1 in skeletal muscle cells [J]. J Biol Chem,2006,281:7060-7067.
[45]. Weyer C, Funahashi T, Tanaka S, et al. Hypoadiponectinemia in obesity and type 2 diabetes:close association with insulin resistance and hyperinsulinemia [J]. J Clin Endocrinol Metab,2001,86:1930-1935.
[46]Pittas AG, Joseph NA, Greenberg AS. Adipocytokines and insulin resistance [J]. J Clin Endocrinol Metab,2004,89:447-452.
[47]. Ye J, Gao Z, Yin J, et al. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice [J]. Am J Physiol Endocrinol Metab,2007,293:E1118-E1128.
[48]Brook CG, Lloyd JK,Wolf OH. Relation between age of onset of obesity and size and number of adipose cells [J]. Br Med J,1972,2:25-27.
[49]. Helmlinger G, Yuan F, DellianM, et al. Interstitial pH and PO2 gradients in solid tumors in vivo:high-resolution measurements reveal a lack of correlation [J]. Nat Med,1997,3:177-182.
[50]Semenza GL. Surviving ischemia:a daptive responses mediated by hypoxia-inducible factorl [J]. J Clin Invest,2000,106:809-812.
[51]Hosogai N, Fukuhara A, Oshima K, et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation [J]. Diabetes,2007,56:901-911.
[52]Bi M, Naczki C, Koritzinsky M, et al. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth [J]. EMBO J,2005, 24(19):3470-3481.
[53].Wang B, Wood IS, Trayhurn P. Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes [J]. Pflugers Arch,2007,455:479-492.
[54]Ozcan U, Cao Q,Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes [J]. Science,2004,306:457-461.
[55]Nakatani Y, Kaneto H, Kawamori D, et al. Involvement of endoplasmic reticulum stress in insulin resistance and diabetes [J]. J Biol Chem,2005,280: 847-851.
[56]Voros G, Maquoi E, Demeulemeester D, et, al. Modulation of angiogenesis during adipose tissue development in murine models of obesity[J]. Endocrinology, 2005,146:4545-4554.
[57]Murdoch C, Muthana M, Lewis CE. Hypoxia regulates macrophage functions in inflammation [J].. J Immunol,2005,175,6257-6263.
[58]Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors[J]. Endocr Rev, 2005,26:439-451.
[59]Douen A, Burdett E, Ramlal T, et al. A characterization of glucose transporter-enriched memebranes from rat skeletal muscle:assessment of endothelial cell contamination and presents of sarcoplasmic reticulum and transverse tubules [J]. Endocrinology,1991,128:611-616.
[60]Foster LJ, Li D, Randhawa VK, et al. Insulin accelerates inter-endosomal GLUTS traffic via phosphatidylinositol 3-kinase and protein kinase B [J]. J Biol Chem,2001,276:44212-44221.
[61]Li D, Randhawa VK, Patel N, et al. Hyperosmolarity reduces GLUT4 endocytosis and increases its exocytosis from a VAMP2-independent pool in L6 muscle cells [J]. J Biol Chem,2001,276:22883-22891.
[62]Grimble RF.Inflammatory status and insulin resistance [J]. Curr Opin Clin Nutr Metab Care,2002,5(5):551-559.
[63]West DB, Prinz WA, Francendese AA, et al. Adipocyte blood flow is decreased in obese Zucker rats [J]. Am J Physiol Regul Integr Comp Physiol,1987,253: R228-R233.
[64]Vincent MA, Clerk LH, Rattigan S, Clark MG, Barrett EJ. Active role for the vasculature in the delivery of insulin to skeletal muscle [J]. Clin Exp Pharmacol Physiol,2005,32:302-307.
[65]Bluher M, Wilson-Fritch L, Leszyk J, et al.. Role of insulin action and cell size on protein expression patterns in adipocytes [J]. J Biol Chem,2004,279: 31902-31909.
[66]Lolmede K, Durand SFV, Galitzky J,et al. Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes [J].Int J Obes Relat Metab Disord,2003,27:1187-1195.
[67]Miyazawa-Hoshimoto S, Takahashi K, Bujo H, et al. Elevated serum vascular endothelial growth factor is associated with visceral fat accumulation in human obsese subjects [J]. Diabetologia,2003,46(11):1483-1488.
[68]Papandreou I, Cairns RA, Fontana L, et al. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption [J]. Cell Metab, 2006,3:187-197.
[69]Shi H, Kokoeva MV, Inouye K, et al. TLR4 links innate immunity and fatty acid-induced insulin resistance [J]. J Clin Invest,2006,16:3015-3025.
[70]Hatomisgil GS, Peraldi P, Budavari A, et,al. IRS-lmediated inhibition of insulin receptor thyrosine kinase activity in TNF-alpha and obesity-induced insulin resistance [J]. Science,1996,271(5249):665-668.
[71]Curat CA, Miranville A, Sengenes C, et al. From blood monocytes to adipose tissue-resident macrophages:induction of diapedesis by human mature adipocytes [J]. Diabetes,2004,53:1285-1292.
[72]Tauman R, Ivanenko A, O'Brien LM, et al. Plasma C-reactive protein levels among children with sleep-disordered breathing [J]. Pediatrics,2004,113:e564-e569.
[73]West DB, Prinz WA, Francendese AA, et al. Adipocyte blood flow is decreased in obese Zucker rats [J]. Am J Physiol Regul Integr Comp Physiol,1987,253: R228-R233.
[74]Shi H, Kokoeva MV, Inouye K, et al. TLR4 links innate immunity and fatty acid-induced insulin resistance [J]. J Clin Invest,2006,116(11):3015-3025.
[75]Tremblay F, Krebs M, Dombrowski L, et al. Over activation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability [J]. Diabetes,2005,54 (9):2674-2684.
[76]Plomgaard P, Bouzakri K, Krogh-Madsen R, et al. Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation [J]. Diabetes,2005,54(10):2939-2945.
[77]. Kim JK, Fillmore JJ, Sunshine MJ, et al. PKC-θ koncknot mice are protected from fat-induced insulin resisitance [J]. J Clin Invest,2004,114:823-827.
[78]Le YJ, Corry PM. Hypoxia-induced bFGF gene expression is mediated through the JNK signal transduction pathway [J]. Mol Cell Biochem,1999,202:1-8.
[1]Trayhurn P, Wood IS. Adipokines:inflammation and the pleiotropic role of white adipose tissue [J].Br J Nutr,2004,92:347-355.
[2]Shulman BM, and Flier JS. Adipogenesis and obesity:Rounding out the big picture [J]. Cell,1996,87:377-389.
[3]Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue [J]. Nature,1994,372:425-432.
[4]Beltowski J. Adiponectin and resistin-new hormones of white adipose tissue [J]. Med Sci Monit,2003,9:RA55-RA61.
[5]Shimonura I, Funahashi T, Takahashi M. Enhanced expression of PAI-1 in visceral fat:possible contributor to vascular disease in obesity [J]. Nat Med,1996,2: 800-803.
[6]Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-a:direct role in obesity-linked insulin resistance [J]. Science, 1993,259:87-91.
[7]Ahima RS, and Flier JS. Adipose tissue as an endocrine organ [J]. Trends Endocrinol Metab,2000,11:327-332.
[8]Sartipy P, and Loskutoff DJ. Monocyte chemoattractant protein 1 in obesity and insulin resistance [J]. Proc Natl Acad Sci USA,2003,100:7265-7270.
[9]Bloomgarden ZT. Obesity and diabetes [J]. Diabetes Care,2000,23:1584-1590.
[10]Felber JP, Golay A. Pathways from obesity to diabetes. Int J Obes Relat Metab Disord,2002,26(Suppl 2):S39-S45.
[11]Finegood DT. Obesity, inflammation and type II diabetes [J]. Int J Obes Relat Metab Disord,2003,27(Suppl 3):S4-S5.
[12]Hotamisligil G.S and Spiegelman BM. Tumor necrosis factor alpha:a key component of the obesity-diabetes link [J]. Diabetes,1994,43:1271-1278.
[13]Lyon CJ, Law RE, Hsueh WA. Minireview:adiposity, inflammation, and atherogenesis [J]. Endocrinology,2003,144:2195-2200.
[14]Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease [J]. Circ Res,2005,96:939-949.
[15]Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance[J]. J Clin. Invest,2003,12: 1821-1830.
[16]Weisberg SP, McCann D, Desai M, et,al. Obesity is associated with macrophage accumulation in adipose tissue [J]. J Clin Invest,2003,12:1796-1808.
[17]Curat CA, Miranville A, Sengenes C, et al. From blood monocytes to adipose tissue-resident macrophages:induction of diapedesis by human mature adipocytes [J]. Diabetes,2004,53:1285-1292.
[18]Cancello R, Henegar C, Viguerie N, et al. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss[J]. Diabetes,2005,54: 2277-2286.
[19]Cousin B, Munoz O, Andre M, et al. A role for preadipocytes as macrophage-like cells [J]. Faseb J,1999,13:305-312.
[20]Baggiolini M. Chemokines and leukocyte traffic [J]. Nature,1998,392:565-568.
[21]Kanda H, Tateya S, Tamori Y, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity [J]. J Clin Invest,2006,116:1494-1505.
[22]Coenen KR, Gruen ML, Chait A, et al. Diet-induced increases in adiposity, but not plasma lipid, promote macrophage infiltration into white adipose tissue [J]. Diabetes,2007,56:564-573.
[23]Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization [J]. J Clin Invest,2007,117:175-184.
[24]Lee JY, Sohn KH, Rhee SH, et al. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4 [J]. J Biol Chem,2001,276:16683-16689.
[25]Lee JY, Plakidas A, Lee WH, et al. Differential modulation of Toll-like receptors by fatty acids:preferential inhibition by n-3 polyunsaturated fatty acids [J]. J Lipid Res,2003,44:479-486.
[26]Shi H, Kokoeva MV, Inouye K, et al.TLR4 links innate immunity and fatty acid-induced insulin resistance [J]. J Clin Invest,2006,116(11):3015-3025.
[27]Suganami T, Tanimoto-Koyama K, Nishida J, et al. Roll of the Toll-like receptor 4/NF-κB pathway in saturated fatty acid- induced inflammatory changes in the interaction between adipocytes and macrophages [J]. Arterioscler Thromb Vasc Biol,2007,27:84-91.
[28]Suganami T, Mieda T, Itoh M, et al. Attenuation of obesity-induced adipose tissue inflammation in C3H/HeJ mice carrying a Toll-like receptor mutation [J]. Bioche Biophysi Res Commun,2007,354:45-49.
[29]Poggi M, Bastelica D, Gual P, et al. C3H/HeJ mice carrying a toll like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet [J]. Diabetologia,2007,50:1267-1276.
[30]Tsukumo DM, Carnalho-Filho MA, Carvalheira JB, et al. Loss-of-function mutation in Toll-like receptor 4 prevents diet -induced obesity and insulin resistance [J]. Diabetes,2007,56:1986-1998.
[31]Davis JE, Gabler NK, Walker-Daniels J, et al. Tlr-4 in deficiency selectively protects against obesity induced by diets high in saturated fat [J]. Obsity (Silver Spring),2008,16:1248-1255.
[32]Todoric J, Loffler M, Huber J, et al. Adipose tissue inflammation induced by high-fat diet in obese diabetic mice is prevented by n-3 polyunsaturated fatty acids [J]. Diabetologia,2006,49:2109-2119.
[33]Saraswathi V, Gao L, Morrow JD, et al Fish oil increases cholesterol storage in white adipose tissue with concomitant decreases in inflammation, hepatic steatosis, and atherosclerosis in mice [J]. J Nutr,2007,137:1776-1782.
[34]Frankenberry KA, Somasundar P, McFadden DW, et al. Leptin induces cell migration and the expression of growth factors in human prostate cancer cells [J]. Am J Surg,2004,188:560-565.
[35]Goetze S, Bungenstock A, Czupalla C, et al. Leptin induces endothelial cell migration through Akt, which is inhibited by PPARτ-ligands [J]. Hypertension, 2002,40:748-754.
[36]Oda A, Taniguchi T, Yokoyama M. Leptin stimulates rat aortic smooth muscle cell proliferation and migration [J]. Kobe J Med Sci,2001,47:141-150.
[37]Ottonello L, Gnerre P, Bertolotto M, et al. Leptin as a uremic toxin interferes with neutrophil chemotaxis [J]. J Am Soc Nephrol,2004,15:2366-2372.
[38]Wolk R, Deb A, Caplice NM,et al. Leptin receptor and functional effects of leptin in human endothelial progenitor cells [J]. Atherosclerosis,2005,183: 131-139.
[39]Gruen ML, Hao M, Piston DW, et al. Leptin requires canonical migratory signaling pathways for induction of monocyte and macrophage chemotaxis [J]. Am J Physiol Cell Physiol,2007,293:C1481-C1488.
[40]Hosogai N, Fukuhara A, Oshima K, et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation [J]. Diabetes,2007,56:901-911.
[41]Ye J, Gao Z, Yin J, et al. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice [J]. Am J Physiol Endocnnol Metab,2007,293:E1118-E1128.
[42]Pang C, Gao Z, Yin J, et al. Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity [J]. Am J Physiol Endocrinol Metab,2008,295:E313-E322.
[43]Voros G, Maquoi E, Demeulemeester D, et, al. Modulation of angiogenesis during adipose tissue development in murine models of obesity [J]. Endocrinology,2005,146:4545-4554.
[44]Wang B, Wood IS, Trayhurn P. Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes [J]. Pflugers Arch,2007,455:479-492.
[45]Wang B, Wood I, Trayhurn P. Hypoxia induces leptin gene expression and secretion in human preadipocytes:differential effects of hypoxia on adipokine expression by preadipocytes [J]. J.Endocrinol,2008,198:127-134.
[46]Hosogai N, Fukuhara A, Oshima K, et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation [J]. Diabetes,2007,56:901-911.
[47]Cinti S, Mitchell G, Barbatelli G, et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans [J]. J Lipid Res,2005,46:2347-2355.
[48]Strissel KJ, Stancheva Z, Miyoshi H, et al. Adipocyte death, adipose tissue remodeling, and obesity complications [J]. Diabetes,2007,56:2910-2918.
[49]Yoshimura T, Robinson EA, Tanaka S, et al. Purification and amino acid analysis of two human glioma-derived monocytes chemoattractants [J]. J Exp Med,1989, 169:1449-1459.
[50]Matsushima K, Larsen CG, DuBois GC,et al. Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line [J]. J Exp Med,1989,169:1485-1490.
[51]Rollins BJ. Chemokines [J]. Blood,1997,90:909-928.
[52]Sartipy P, and Loskutoff DJ. Monocyte chemoattractant protein 1 in obesity and insulin resistance [J]. Proc Natl Acad Sci USA,2003,100:7265-7270.
[53]Kanda H, Tateya S, Tamori Y, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity [J]. J Clin Invest,2006,116(6):1494-1505.
[54]Weisberg SP, Hunter D, Huber R, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding [J]. J Clin Invest,2006,116:115-124.
[55]Huber J, Liefer FW, Zeyda M, et al. CC chemokine and CC chemokine receptor profiles in visceral and subcutaneous adipose tissue are altered in human obesity [J]. J Clin Endocrinol Metab,2008,93:3215-3221.
[56]Inouye KE, Shi H, Howard JK, et al. Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue [J]. Diabetes,2007,56:2242-2250.
[57]Kirk EA, Sagawa ZK, McDonald TO, et al. Macrophage chemoattractant protein-1 deficiency fails to restrain macrophage infiltration into adipose tissue[J]. Diabetes,2008,57:1254-1261.
[58]Chen A, Mumick S, Zhang, et al. Diet induction of monocyte chemoattractant protein-1 and its impact on obesity [J]. Obes Res,2005,13:1311-1320.
[59]Fernandez-Real JM, Ricart W. Insulin resistance and chronic cardiovascular inflammatory [J]. Endocr Rev,2003,24:278-301.
[60]Suganami T, Nishida J, Ogawa Y. A Paracrine Loop Between Adipocytes and Macrophages Aggravates Inflammatory Changes Role of Free Fatty Acids and Tumor Necrosis Factor [J]. J Arterioscler Thromb Vasc Biol,2005,25:2062-2068.
[61]Lam TT, Van De Werve G, and Giacca A. Free fatty acids increase basal hepatic glucose production and induce hepatic insulin resistance at different sites [J]. Am J Physio Endocrino Metab,2003,284:E281-E290.
[62]Boden G. Free fatty acids produce insulin resistance and active the proinflammatory nuclear factor-κB, pathway in fat liver [J]. Diabetes,2005,54: 34658-34665.
[63]Dresner A, Laurent D, Marcucci M, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3- kinase activity [J]. J Clin Invest,1999,130:253-259.
[64]Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance [J]. Nature,2002,420:333-336.
[65]Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB [J]. Nat Med,2005,11: 183-190.
[66]Yu C, Chen Y, Cline GW, et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle [J]. J BiolChem,2002,277,50230-50236.
[67]Pickersgill L, Litherland GJ, Greenberg AS, et al. Key role for ceramides in mediating insulin resistance in human muscle cells [J]. J Biol Chem,2007, 282(17):12583-12589.
[68]Lee JS, Pinnamaneni SK, Eo SJ, et al. Saturated, but not n-6 polyunsaturated, fatty acids induce insulin resistance:role of intramuscular accumulation of lipid metabolites [J]. J Appl Physiol,2006,100:1467-1474.
[69]Shi H, Kokoeva MV, Inouye K, et al. TLR4 links innate immunity and fatty acid-induced insulin resistance [J]. J Clin Invest,2006,16:3015-3025.
[70]Hatomisgil GS, AND Spiegelman BM. Tumor necrosis factor alpha:a key component of the obesity-diabetes link [J]. Diabetes,1994,43,1271-1278.
[71]Qi C, and Pekala PH. Tumor necrosis factor -alpha induced insulin resistance [J]. Proc Soc Exp Biol Med,2000,223(2):128-135.
[72]Hatomisgil GS, Peraldi P, Budavari A, et,al. IRS-1 mediated inhibition of insulin receptor thyrosine kinase activity in TNF-alpha and obesity-induced insulin resistance [J]. Science,1996,271(5249):665-668.
[73]Hotamisligil GS:Inflammatory pathways and insulin action [J]. Int J Obes Relat Metab Disord,2003,27(Suppl 3):S53-S55.
[74]Vander PT, Romijn JA, Endert E, et al. Tumor necrosis factor mimics the metabolic response to acute infection in healthy humans [J]. Am J Physiol,1991, 261:E457-E465.
[75]Uysal KT, Wiesbrock SM, Marino MW, et al. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function [J]. Nature,1997,389: 610-614.
[76]Uysal, KT, Wiesbrock, SM, and Hotamisligil, GS. Functional analysis of tumor necrosis factor (TNF) receptors in TNF-alpha-mediated insulin resistance in genetic obesity [J]. Endocrinology,1998,139:4832-4838.
[77]Ventre J, Doebber T, Wu M, et al. Targeted disruption of the tumor necrosis factor-alpha gene:metabolic consequences in obese and nonobese mice [J]. Diabetes,1997,46:1526-1531.
[78]Moller, D.E. Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes [J]. Trends Endocrinol Metab,2000,11:212-217.
[79]Keller P, Keller C, Carey AL, et al. Interleukin-6 production by contracting human skeletal muscle:autocrine regulation by IL-6 [J]. Biochem Biophys Res Commun,2003,310:550-554.
[80]Festa A, D'Agostino Jr R, Tracy RP, et,al. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes:the insulin resistance atherosclerosis study [J]. Diabetes,2002,51: 1131-1137.
[81]Gabay C, Kushner I:Acute-phase proteins and other systemic responses to inflammation [J]. N Engl J Med,1999,340:448-454.
[82]Senn JJ, Klover PJ, Nowak IA, et al. lnterleukin-6 induces cellular insulin resistance in hepatocytes [J]. Diabetes,2002,51:3391-3399.
[83]Kim HJ, Higashimori T, Park SY, et al. Differential effects of interleukin-6 and-10 on skeletal muscle and liver insulin action in vivo [J]. Diabetes,2004,53: 1060-1067.
[84]Weigert C, Hennige AM, Brodbeck K, et al. Interleukin-6 acts as insulin sensitizer on glycogen synthesis in human skeletal muscle cells by phosphorylation of Ser473 of Akt [J]. Am J Physiol Endocrinol Metab,2005,289: E251-E257
[85]Carey AL, Febbraio MA. Interleukin-6 and insulin sensitivity:friend or foe? [J] Diabetologia,2004,47:1135-1142.
[86]Henrike S, Daniela DS, Ulrike K. Monocyte Chemotactic Protein-1 Is a Potential Player in the Negative Cross-Talk between Adipose Tissue and Skeletal Muscle [J]. Endocrinology,2006,147:2458-2467.
[87]Franckhauser S, Elias I, Rotter Sopasakis V, et al. Overexpression of IL-6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice [J]. Diabetologia,2008,51:1306-1316.
[88]Pedersen BK, Febbraio MA. Point:Interleukin-6 does have a beneficial role in insulin sensitivity and glucose homeostasis [J]. J Appl Physiol,2007,102: 814-816.
[89]Muoio DM, Dohm GL, Fiedorek JR, et al. Leptin directly alters lipid partitioning in skeletal muscle [J]. Diabetes,1997,46:1360-1363.
[90]Kamohaha S, Burcelin R, Halaas JL, et al. Acute stimulation of glucose metabolism in mice by leptin treatment [J]. Nature,1997,389:374-377.
[91]Unger RH, Zhou YT, and Orci L. Regulation of fatty acid homeostasis in cells: novel role of leptin [J]. Proc Natl Acad Sci USA,1999,96:2327-2332.
[92]Monikoshi Y, Haque MS and Shimazu T. Microinjection of leptin into the ventromedia hypothamamus increases glucose uptake in peripheral tissues in rats [J]. Diabetes,1999,48:287-291.
[93]Loffreda S, Yang SQ, Lin HZ, et al. Leptin regulates proinflammatory immune responses [J]. FASEB J,1998,12:57-65.
[94]Curat CA, Miranville A, Sengenes C, et al. From blood monocytes to adipose tissue-resident macrophages:induction of diapedesis by human mature adipocytes [J]. Diabetes,2004.53:1285-1292.
[95]Petersen KF, Oral EA, Dufour S, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy [J]. J Clin Invest,2002,109: 1345-1350.
[96]Pelleymounter MA, Cullen MJ, Baker MB, et al. Effects of the obese gene product on body weight regulation in ob/ob mice [J]. Science,1995,269: 540-543.
[97]Monikoshi Y, Kim YB, Peroni OD, et al. Leptin stimulates fatty- acid oxidation by activating AMP-activated protein linase [J]. Nature,2002,415:339-343.
[98]Buhl ES, Jessen N, Pold R, Ledet T, et al. Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying feature of the insulin resistance syndrome [J]. Diabetes,2002,51(7):2199-2206.
[99]Kurth EJ, Hirshman MF, Goodyear LJ, el al.5'AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle [J]. Diabetes,1999,48: 1667-1671.
[100]Steppan CM, Bailey ST, Bhat S, et al.The hormone resistin links obesity to diabetes[J].Nature,2001,09(6818):307-312.
[101]Josef V Silha, Michal Krsek, Jan V Skrha, et al. Plasma resistin, adiponectin and leptin levels in lean and obese subjects:correlations with insulin resistance[J]. European Journal of Endocrinology,003,149(4):331-335.
[102]Levy JR, Davenport B, Clore JN, et al. Lipid metabolism and resistin gene expression in insulin- resistant Fischer 344 rats [J]. Am J Physiol Endocrinol Metab,2002,282(3):626-633.
[103]Lee JH, Chan JL, Yiannakouris N, et al. Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administratinn:cross-sectional and interventional studies in normal, insulin resistant and diabetic subiects [J]. J Clin Endocrinol Metab 2003, 88(10):4848-4856.
[104]Milan G, Granzotto M, Scarda A, et al. Resistin and adiponectin expression in visceral fat of obese rats:effect of weight loss [J]. Obes Res,2002,10(11): 1095-1103.
[105]Kawanami D, Maemura K, Takeda N, et al. Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells:a new insight into adipocytokine-endothelial cell interactions [J]. Biochem Biophys Res Commun,2004,314: 415-419.
[106]Rajala MW, Obici S, Scherer PE, et al. Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production [J]. J Clin Invest,2003,111:225-230.
[107]Steppan CM, Bailey ST, Bhat S,,et al.The hormone resistin links obesity to diabetes [J]. Nature,2001,409:307-312.
[108]Savage DB, Sewter CP, Klenk ES, et al. Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-γ action in humans [J]. Diabetes,2001,50(10):2199-2202.
[109]Volarova de Court B, Degawa-Yamauchi M, Considine RV, et,al High serum resistin is associated with an increase in adiposity but not a worsening of insulin resistance in Pima Indians [J]. Diabetes,2004,53:1279-1284.
[110]Degawa-Yamauchi M, Bovenkerk JE, Juliar BE, et al. Serum resistin (FIZZ3) protein is increased in obese humans [J]. J Clin Endocrinol Metab,2003,88: 5452-5455.
[111]Satoh H, Nguyen MT, Miles PD, et al. Adenovirus-mediated chronic "hyper-resistinemia" leads to in vivo insulin resistance in normal rats [J]. J Clin Invest,2004,114(2):224-231.
[112]Weyer C, Funahashi T, Tanaka S, et al. Hypoadiponectinemia in obesity and type 2 diabetes:close association with insulin resistance and hyperinsulinemia [J]. J Clin Endocrinol Metab,2001,86:1930-1935.
[113]Pittas AG, Joseph NA, Greenberg AS.Adipocytokines and insulin resistance [J]. J Clin Endocrinol Metab,2004,89:447-452.
[114]Ohnuma H, Igarashi M, Tominaga M, et al. Decreased serum levels of adiponectin are a risk factor for the progression to type 2 diabetes in the Japanese Population:the Funagata study [J]. Diabetes Care,2003,26:2015-2020.
[115]Duncan BB, Schmidt MI, Pankow JS, et al. Adiponectin and the development of type 2 diabetes:the Atherosclerosis Risk in Communities Study [J]. Diabetes, 2004,53:2473-2478.
[116]Lindsay RS, Funahashi T, Hanson RL, et al. Adiponectin and development of type 2 diabetes in the Pima Indian population [J]. Lancet,2002,360:57-58.
[117]Snehalatha C, Mukesh B, Simon M, et al. Plasma adiponectin is an independent predictor of type 2 diabetes in Asian indians [J]. Diabetes Care,2003,26: 3226-3229
[118]Spranger J, Kroke A, Mohlig M, et al. Adiponectin and protection against type 2 diabetes mellitus [J].Lancet,2003,361:226-228.
[2]Shulman BM, and Flier JS. Adipogenesis and obesity:Rounding out the big picture [J]. Cell,1996,87:377-389.
[3]Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue [J]. Nature,1994,372:425-432.
[4]Beltowski J. Adiponectin and resistin-new hormones of white adipose tissue [J]. Med Sci Monit,2003,9:RA55-RA61.
[5]Shimonura I, Funahashi T, Takahashi M. Enhanced expression of PAI-1 in visceral fat:possible contributor to vascular disease in obesity [J]. Nat Med,1996,2: 800-803
[6]Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-a:direct role in obesity-linked insulin resistance [J]. Science,1993, 259:87-91.
[7]Ahima RS, and Flier JS. Adipose tissue as an endocrine organ [J]. Trends Endocrinol Metab,2000,11:327-332.
[8]Sartipy P, and Loskutoff DJ. Monocyte chemoattractant protein 1 in obesity and insulin resistance [J]. Proc Natl Acad Sci USA,2003,100:7265-7270.
[9]Bloomgarden ZT. Obesity and diabetes [J].Diabetes Care,2000,23:1584-1590.
[10]Felber JP, Golay A. Pathways from obesity to diabetes [J]. Int J Obes Relat Metab Disord,2002,26(Suppl2):S39-S45.
[11]Finegood DT. Obesity, inflammation and type Ⅱ diabetes [J]. Int J Obes Relat Metab Disord,2003,27(Suppl 3):S4-S5.
[12]Boden Boden G, Lebed B, SchatzM et al. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance-in healthy subjects [J]. Diabetes,2001,507:1612-1617.
[13]Chao L, Marcus-Samuels B, Mason MM et al. Adipose tissue required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones [J]. J Clin Invest,2000,106(10):1221-1228.
[14]Franckhauser S, Munoz S, PujolA et al. Increased fatty acid re-esterification by PEPCK overexpression in adipose tissue leads to obesity without insulin resistance [J]. Diabetes,2002,513:624-630.
[15]Boden G, Chen X. Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes [J]. J Clin Invest,1995,96:1261-1268.
[16]Belfort R, Mandarino L, Kashyap S, et al. Dose-response effect of elevated plasma free fatty acid on insulin signaling [J]. Diabetes,2005,54:1640-1648.
[17]Pessin JE, SaltielAR. Signaling pathways in insulin action:Molecular targets of insulin resistance [J]. J Clin Invest,2000,1062:165-169.
[18]SaltielAR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism [J]. Nature,2001,414 (6865):799-806.
[19]Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance [J]. Nature,2002,420:333-336.
[20]Dresner A, Laurent D, Marcucci M, et al. Effects of free fatty acids on glucose transport and IRS- 1-associated phosphatidylinositol-3-kinase activity [J]. J Clin Invest,1999,103(2):253-259.
[21]Griffin MF, Marcuccci MJ, Cline GW, et al. Free fatty acid-induced insulin resistance is associated with activity of protein kinase C theta and alterations in the insulin signaling cascade [J]. Diabetes,1999,48:1270-1274.
[22]Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance [J]. J Clin. Invest,2003, 12:1821-1830.
[23]Weisberg SP, McCann D, Desai M, et,al. Obesity is associated with macrophage accumulation in adipose tissue [J]. J Clin Invest,2003,112:1796-1808.
[24]Hotamisligil G.S and Spiegelman BM. Tumor necrosis factor alpha:a key component of the obesity-diabetes link [J]. Diabetes,1994,43:1271-1278.
[25]Lyon CJ, Law RE, Hsueh WA. Minireview:adiposity, inflammation, and atherogenesis [J]. Endocrinology,2003,144:2195-2200.
[26]Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease [J]. Circ Res,2005,96:939-949.
[27]Cousin B, Munoz O, Andre M, et al. A role for preadipocytes as macrophage-like cells [J]. Faseb J,1999,13:305-312.
[28]Cancello R, Henegar C, Viguerie N, et al. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss [J]. Diabetes,2005,54:2277-2286.
[29]Hatomisgil GS, and Spiegelman BM. Tumor necrosis factor alpha:a key component of the obesity-diabetes link [J]. Diabetes,1994,43:1271-1278.
[30]Qi C, and Pekala PH. Tumor necrosis factor-alpha induced insulin resistance [J]. Proc Soc Exp Biol Med,2000,223(2):128-135.
[31]Vander PT, Romijn JA, Endert E, et al. Tumor necrosis factor mimics the metabolic response to acute infection in healthy humans [J]. Am J Physiol,1991, 261:E457-E465.
[32]Lang CH, Dobrescu C, Bagby GJ. Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output [J]. Endocrinology, 1992,130:43-52.
[33]Hofmann C, Lorenz K, Braithwaite SS, et al. Altered gene expression for tumor necrosis factor- and its receptors during drug and dietary modulation of insulin resistance [J]. Endocrinology,1994,34:264-270.
[34]Hamann A, Benecke H, Le Marchand-Brustel Y, et al. Characterization of insulin resistance and NIDDM in transgenic mice with reduced brown fat [J]. Diabetes, 1995,44:1266-1273.
[35]Uysal KT, Wiesbrock SM, Marino MW, et al. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function [J]. Nature,1997,389: 610-614.
[36]Ventre J, Doebber T, Wu M, et al. Targeted disruption of the tumor necrosis factor-alpha gene-metabolic consequences in obese and nonobese mice [J]. Diabetes,1997,46:1526-1531.
[37]Hotamisligil GS. Inflammation pathways and insulin activation [J].Obes Relat Metab Disord,2003,27(suppl 3):S53-S55.
[38]Souza SC, Palmer HJ, Kang YH, et al. TNF-alpha induction of lipolysis is mediated through activation of the exreacellular signal related kinase pathway in 3T3-L1 adipocytes [J]. J Cell Biochem,2003,89:1077-1086.
[39]Uysal KT, Wiesbrock SM, Marino MW, et al. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function [J]. Nature,1997,389: 610-614.
[40]Hotamisligil GS, Murray DL, Choy LN, et al. Tumor necrosis factor alpha inhibits signaling from the insulin receptor[J]. Proc Natl Acad Sci USA,1994,91: 4854-4858
[41]Hotamisligial GS, Peraldi P, Budavari A, et al. IRS-1 mediate inhibition of insulin receptor tyrosine kinase activity in TNF-a and obesity-induced insulin resistance [J].Science,1996,271(5249):665-668.
[42].Shi H, Tzameli I, Bjorbaek C, et al. Suppressor of cytokine signaling 3 is a physiological regulator of adipocyte insulin signaling [J]. J Biol Chem,2004,279: 34733-34740.
[43]Jager J, Gremeaux T, Cormont M, et al. Interleukin-1-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression[J]. Endocrinology,2007,148:241-251.
[44]Weigert C, Hennige AM, Lehmann R, et al. Direct cross-talk of interleukin-6 and insulin signal transduction via insulin receptor substrate-1 in skeletal muscle cells [J]. J Biol Chem,2006,281:7060-7067.
[45]. Weyer C, Funahashi T, Tanaka S, et al. Hypoadiponectinemia in obesity and type 2 diabetes:close association with insulin resistance and hyperinsulinemia [J]. J Clin Endocrinol Metab,2001,86:1930-1935.
[46]Pittas AG, Joseph NA, Greenberg AS. Adipocytokines and insulin resistance [J]. J Clin Endocrinol Metab,2004,89:447-452.
[47]. Ye J, Gao Z, Yin J, et al. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice [J]. Am J Physiol Endocrinol Metab,2007,293:E1118-E1128.
[48]Brook CG, Lloyd JK,Wolf OH. Relation between age of onset of obesity and size and number of adipose cells [J]. Br Med J,1972,2:25-27.
[49]. Helmlinger G, Yuan F, DellianM, et al. Interstitial pH and PO2 gradients in solid tumors in vivo:high-resolution measurements reveal a lack of correlation [J]. Nat Med,1997,3:177-182.
[50]Semenza GL. Surviving ischemia:a daptive responses mediated by hypoxia-inducible factorl [J]. J Clin Invest,2000,106:809-812.
[51]Hosogai N, Fukuhara A, Oshima K, et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation [J]. Diabetes,2007,56:901-911.
[52]Bi M, Naczki C, Koritzinsky M, et al. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth [J]. EMBO J,2005, 24(19):3470-3481.
[53].Wang B, Wood IS, Trayhurn P. Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes [J]. Pflugers Arch,2007,455:479-492.
[54]Ozcan U, Cao Q,Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes [J]. Science,2004,306:457-461.
[55]Nakatani Y, Kaneto H, Kawamori D, et al. Involvement of endoplasmic reticulum stress in insulin resistance and diabetes [J]. J Biol Chem,2005,280: 847-851.
[56]Voros G, Maquoi E, Demeulemeester D, et, al. Modulation of angiogenesis during adipose tissue development in murine models of obesity[J]. Endocrinology, 2005,146:4545-4554.
[57]Murdoch C, Muthana M, Lewis CE. Hypoxia regulates macrophage functions in inflammation [J].. J Immunol,2005,175,6257-6263.
[58]Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors[J]. Endocr Rev, 2005,26:439-451.
[59]Douen A, Burdett E, Ramlal T, et al. A characterization of glucose transporter-enriched memebranes from rat skeletal muscle:assessment of endothelial cell contamination and presents of sarcoplasmic reticulum and transverse tubules [J]. Endocrinology,1991,128:611-616.
[60]Foster LJ, Li D, Randhawa VK, et al. Insulin accelerates inter-endosomal GLUTS traffic via phosphatidylinositol 3-kinase and protein kinase B [J]. J Biol Chem,2001,276:44212-44221.
[61]Li D, Randhawa VK, Patel N, et al. Hyperosmolarity reduces GLUT4 endocytosis and increases its exocytosis from a VAMP2-independent pool in L6 muscle cells [J]. J Biol Chem,2001,276:22883-22891.
[62]Grimble RF.Inflammatory status and insulin resistance [J]. Curr Opin Clin Nutr Metab Care,2002,5(5):551-559.
[63]West DB, Prinz WA, Francendese AA, et al. Adipocyte blood flow is decreased in obese Zucker rats [J]. Am J Physiol Regul Integr Comp Physiol,1987,253: R228-R233.
[64]Vincent MA, Clerk LH, Rattigan S, Clark MG, Barrett EJ. Active role for the vasculature in the delivery of insulin to skeletal muscle [J]. Clin Exp Pharmacol Physiol,2005,32:302-307.
[65]Bluher M, Wilson-Fritch L, Leszyk J, et al.. Role of insulin action and cell size on protein expression patterns in adipocytes [J]. J Biol Chem,2004,279: 31902-31909.
[66]Lolmede K, Durand SFV, Galitzky J,et al. Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes [J].Int J Obes Relat Metab Disord,2003,27:1187-1195.
[67]Miyazawa-Hoshimoto S, Takahashi K, Bujo H, et al. Elevated serum vascular endothelial growth factor is associated with visceral fat accumulation in human obsese subjects [J]. Diabetologia,2003,46(11):1483-1488.
[68]Papandreou I, Cairns RA, Fontana L, et al. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption [J]. Cell Metab, 2006,3:187-197.
[69]Shi H, Kokoeva MV, Inouye K, et al. TLR4 links innate immunity and fatty acid-induced insulin resistance [J]. J Clin Invest,2006,16:3015-3025.
[70]Hatomisgil GS, Peraldi P, Budavari A, et,al. IRS-lmediated inhibition of insulin receptor thyrosine kinase activity in TNF-alpha and obesity-induced insulin resistance [J]. Science,1996,271(5249):665-668.
[71]Curat CA, Miranville A, Sengenes C, et al. From blood monocytes to adipose tissue-resident macrophages:induction of diapedesis by human mature adipocytes [J]. Diabetes,2004,53:1285-1292.
[72]Tauman R, Ivanenko A, O'Brien LM, et al. Plasma C-reactive protein levels among children with sleep-disordered breathing [J]. Pediatrics,2004,113:e564-e569.
[73]West DB, Prinz WA, Francendese AA, et al. Adipocyte blood flow is decreased in obese Zucker rats [J]. Am J Physiol Regul Integr Comp Physiol,1987,253: R228-R233.
[74]Shi H, Kokoeva MV, Inouye K, et al. TLR4 links innate immunity and fatty acid-induced insulin resistance [J]. J Clin Invest,2006,116(11):3015-3025.
[75]Tremblay F, Krebs M, Dombrowski L, et al. Over activation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability [J]. Diabetes,2005,54 (9):2674-2684.
[76]Plomgaard P, Bouzakri K, Krogh-Madsen R, et al. Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation [J]. Diabetes,2005,54(10):2939-2945.
[77]. Kim JK, Fillmore JJ, Sunshine MJ, et al. PKC-θ koncknot mice are protected from fat-induced insulin resisitance [J]. J Clin Invest,2004,114:823-827.
[78]Le YJ, Corry PM. Hypoxia-induced bFGF gene expression is mediated through the JNK signal transduction pathway [J]. Mol Cell Biochem,1999,202:1-8.
[1]Trayhurn P, Wood IS. Adipokines:inflammation and the pleiotropic role of white adipose tissue [J].Br J Nutr,2004,92:347-355.
[2]Shulman BM, and Flier JS. Adipogenesis and obesity:Rounding out the big picture [J]. Cell,1996,87:377-389.
[3]Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue [J]. Nature,1994,372:425-432.
[4]Beltowski J. Adiponectin and resistin-new hormones of white adipose tissue [J]. Med Sci Monit,2003,9:RA55-RA61.
[5]Shimonura I, Funahashi T, Takahashi M. Enhanced expression of PAI-1 in visceral fat:possible contributor to vascular disease in obesity [J]. Nat Med,1996,2: 800-803.
[6]Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-a:direct role in obesity-linked insulin resistance [J]. Science, 1993,259:87-91.
[7]Ahima RS, and Flier JS. Adipose tissue as an endocrine organ [J]. Trends Endocrinol Metab,2000,11:327-332.
[8]Sartipy P, and Loskutoff DJ. Monocyte chemoattractant protein 1 in obesity and insulin resistance [J]. Proc Natl Acad Sci USA,2003,100:7265-7270.
[9]Bloomgarden ZT. Obesity and diabetes [J]. Diabetes Care,2000,23:1584-1590.
[10]Felber JP, Golay A. Pathways from obesity to diabetes. Int J Obes Relat Metab Disord,2002,26(Suppl 2):S39-S45.
[11]Finegood DT. Obesity, inflammation and type II diabetes [J]. Int J Obes Relat Metab Disord,2003,27(Suppl 3):S4-S5.
[12]Hotamisligil G.S and Spiegelman BM. Tumor necrosis factor alpha:a key component of the obesity-diabetes link [J]. Diabetes,1994,43:1271-1278.
[13]Lyon CJ, Law RE, Hsueh WA. Minireview:adiposity, inflammation, and atherogenesis [J]. Endocrinology,2003,144:2195-2200.
[14]Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease [J]. Circ Res,2005,96:939-949.
[15]Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance[J]. J Clin. Invest,2003,12: 1821-1830.
[16]Weisberg SP, McCann D, Desai M, et,al. Obesity is associated with macrophage accumulation in adipose tissue [J]. J Clin Invest,2003,12:1796-1808.
[17]Curat CA, Miranville A, Sengenes C, et al. From blood monocytes to adipose tissue-resident macrophages:induction of diapedesis by human mature adipocytes [J]. Diabetes,2004,53:1285-1292.
[18]Cancello R, Henegar C, Viguerie N, et al. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss[J]. Diabetes,2005,54: 2277-2286.
[19]Cousin B, Munoz O, Andre M, et al. A role for preadipocytes as macrophage-like cells [J]. Faseb J,1999,13:305-312.
[20]Baggiolini M. Chemokines and leukocyte traffic [J]. Nature,1998,392:565-568.
[21]Kanda H, Tateya S, Tamori Y, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity [J]. J Clin Invest,2006,116:1494-1505.
[22]Coenen KR, Gruen ML, Chait A, et al. Diet-induced increases in adiposity, but not plasma lipid, promote macrophage infiltration into white adipose tissue [J]. Diabetes,2007,56:564-573.
[23]Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization [J]. J Clin Invest,2007,117:175-184.
[24]Lee JY, Sohn KH, Rhee SH, et al. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4 [J]. J Biol Chem,2001,276:16683-16689.
[25]Lee JY, Plakidas A, Lee WH, et al. Differential modulation of Toll-like receptors by fatty acids:preferential inhibition by n-3 polyunsaturated fatty acids [J]. J Lipid Res,2003,44:479-486.
[26]Shi H, Kokoeva MV, Inouye K, et al.TLR4 links innate immunity and fatty acid-induced insulin resistance [J]. J Clin Invest,2006,116(11):3015-3025.
[27]Suganami T, Tanimoto-Koyama K, Nishida J, et al. Roll of the Toll-like receptor 4/NF-κB pathway in saturated fatty acid- induced inflammatory changes in the interaction between adipocytes and macrophages [J]. Arterioscler Thromb Vasc Biol,2007,27:84-91.
[28]Suganami T, Mieda T, Itoh M, et al. Attenuation of obesity-induced adipose tissue inflammation in C3H/HeJ mice carrying a Toll-like receptor mutation [J]. Bioche Biophysi Res Commun,2007,354:45-49.
[29]Poggi M, Bastelica D, Gual P, et al. C3H/HeJ mice carrying a toll like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet [J]. Diabetologia,2007,50:1267-1276.
[30]Tsukumo DM, Carnalho-Filho MA, Carvalheira JB, et al. Loss-of-function mutation in Toll-like receptor 4 prevents diet -induced obesity and insulin resistance [J]. Diabetes,2007,56:1986-1998.
[31]Davis JE, Gabler NK, Walker-Daniels J, et al. Tlr-4 in deficiency selectively protects against obesity induced by diets high in saturated fat [J]. Obsity (Silver Spring),2008,16:1248-1255.
[32]Todoric J, Loffler M, Huber J, et al. Adipose tissue inflammation induced by high-fat diet in obese diabetic mice is prevented by n-3 polyunsaturated fatty acids [J]. Diabetologia,2006,49:2109-2119.
[33]Saraswathi V, Gao L, Morrow JD, et al Fish oil increases cholesterol storage in white adipose tissue with concomitant decreases in inflammation, hepatic steatosis, and atherosclerosis in mice [J]. J Nutr,2007,137:1776-1782.
[34]Frankenberry KA, Somasundar P, McFadden DW, et al. Leptin induces cell migration and the expression of growth factors in human prostate cancer cells [J]. Am J Surg,2004,188:560-565.
[35]Goetze S, Bungenstock A, Czupalla C, et al. Leptin induces endothelial cell migration through Akt, which is inhibited by PPARτ-ligands [J]. Hypertension, 2002,40:748-754.
[36]Oda A, Taniguchi T, Yokoyama M. Leptin stimulates rat aortic smooth muscle cell proliferation and migration [J]. Kobe J Med Sci,2001,47:141-150.
[37]Ottonello L, Gnerre P, Bertolotto M, et al. Leptin as a uremic toxin interferes with neutrophil chemotaxis [J]. J Am Soc Nephrol,2004,15:2366-2372.
[38]Wolk R, Deb A, Caplice NM,et al. Leptin receptor and functional effects of leptin in human endothelial progenitor cells [J]. Atherosclerosis,2005,183: 131-139.
[39]Gruen ML, Hao M, Piston DW, et al. Leptin requires canonical migratory signaling pathways for induction of monocyte and macrophage chemotaxis [J]. Am J Physiol Cell Physiol,2007,293:C1481-C1488.
[40]Hosogai N, Fukuhara A, Oshima K, et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation [J]. Diabetes,2007,56:901-911.
[41]Ye J, Gao Z, Yin J, et al. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice [J]. Am J Physiol Endocnnol Metab,2007,293:E1118-E1128.
[42]Pang C, Gao Z, Yin J, et al. Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity [J]. Am J Physiol Endocrinol Metab,2008,295:E313-E322.
[43]Voros G, Maquoi E, Demeulemeester D, et, al. Modulation of angiogenesis during adipose tissue development in murine models of obesity [J]. Endocrinology,2005,146:4545-4554.
[44]Wang B, Wood IS, Trayhurn P. Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes [J]. Pflugers Arch,2007,455:479-492.
[45]Wang B, Wood I, Trayhurn P. Hypoxia induces leptin gene expression and secretion in human preadipocytes:differential effects of hypoxia on adipokine expression by preadipocytes [J]. J.Endocrinol,2008,198:127-134.
[46]Hosogai N, Fukuhara A, Oshima K, et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation [J]. Diabetes,2007,56:901-911.
[47]Cinti S, Mitchell G, Barbatelli G, et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans [J]. J Lipid Res,2005,46:2347-2355.
[48]Strissel KJ, Stancheva Z, Miyoshi H, et al. Adipocyte death, adipose tissue remodeling, and obesity complications [J]. Diabetes,2007,56:2910-2918.
[49]Yoshimura T, Robinson EA, Tanaka S, et al. Purification and amino acid analysis of two human glioma-derived monocytes chemoattractants [J]. J Exp Med,1989, 169:1449-1459.
[50]Matsushima K, Larsen CG, DuBois GC,et al. Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line [J]. J Exp Med,1989,169:1485-1490.
[51]Rollins BJ. Chemokines [J]. Blood,1997,90:909-928.
[52]Sartipy P, and Loskutoff DJ. Monocyte chemoattractant protein 1 in obesity and insulin resistance [J]. Proc Natl Acad Sci USA,2003,100:7265-7270.
[53]Kanda H, Tateya S, Tamori Y, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity [J]. J Clin Invest,2006,116(6):1494-1505.
[54]Weisberg SP, Hunter D, Huber R, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding [J]. J Clin Invest,2006,116:115-124.
[55]Huber J, Liefer FW, Zeyda M, et al. CC chemokine and CC chemokine receptor profiles in visceral and subcutaneous adipose tissue are altered in human obesity [J]. J Clin Endocrinol Metab,2008,93:3215-3221.
[56]Inouye KE, Shi H, Howard JK, et al. Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue [J]. Diabetes,2007,56:2242-2250.
[57]Kirk EA, Sagawa ZK, McDonald TO, et al. Macrophage chemoattractant protein-1 deficiency fails to restrain macrophage infiltration into adipose tissue[J]. Diabetes,2008,57:1254-1261.
[58]Chen A, Mumick S, Zhang, et al. Diet induction of monocyte chemoattractant protein-1 and its impact on obesity [J]. Obes Res,2005,13:1311-1320.
[59]Fernandez-Real JM, Ricart W. Insulin resistance and chronic cardiovascular inflammatory [J]. Endocr Rev,2003,24:278-301.
[60]Suganami T, Nishida J, Ogawa Y. A Paracrine Loop Between Adipocytes and Macrophages Aggravates Inflammatory Changes Role of Free Fatty Acids and Tumor Necrosis Factor [J]. J Arterioscler Thromb Vasc Biol,2005,25:2062-2068.
[61]Lam TT, Van De Werve G, and Giacca A. Free fatty acids increase basal hepatic glucose production and induce hepatic insulin resistance at different sites [J]. Am J Physio Endocrino Metab,2003,284:E281-E290.
[62]Boden G. Free fatty acids produce insulin resistance and active the proinflammatory nuclear factor-κB, pathway in fat liver [J]. Diabetes,2005,54: 34658-34665.
[63]Dresner A, Laurent D, Marcucci M, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3- kinase activity [J]. J Clin Invest,1999,130:253-259.
[64]Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance [J]. Nature,2002,420:333-336.
[65]Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB [J]. Nat Med,2005,11: 183-190.
[66]Yu C, Chen Y, Cline GW, et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle [J]. J BiolChem,2002,277,50230-50236.
[67]Pickersgill L, Litherland GJ, Greenberg AS, et al. Key role for ceramides in mediating insulin resistance in human muscle cells [J]. J Biol Chem,2007, 282(17):12583-12589.
[68]Lee JS, Pinnamaneni SK, Eo SJ, et al. Saturated, but not n-6 polyunsaturated, fatty acids induce insulin resistance:role of intramuscular accumulation of lipid metabolites [J]. J Appl Physiol,2006,100:1467-1474.
[69]Shi H, Kokoeva MV, Inouye K, et al. TLR4 links innate immunity and fatty acid-induced insulin resistance [J]. J Clin Invest,2006,16:3015-3025.
[70]Hatomisgil GS, AND Spiegelman BM. Tumor necrosis factor alpha:a key component of the obesity-diabetes link [J]. Diabetes,1994,43,1271-1278.
[71]Qi C, and Pekala PH. Tumor necrosis factor -alpha induced insulin resistance [J]. Proc Soc Exp Biol Med,2000,223(2):128-135.
[72]Hatomisgil GS, Peraldi P, Budavari A, et,al. IRS-1 mediated inhibition of insulin receptor thyrosine kinase activity in TNF-alpha and obesity-induced insulin resistance [J]. Science,1996,271(5249):665-668.
[73]Hotamisligil GS:Inflammatory pathways and insulin action [J]. Int J Obes Relat Metab Disord,2003,27(Suppl 3):S53-S55.
[74]Vander PT, Romijn JA, Endert E, et al. Tumor necrosis factor mimics the metabolic response to acute infection in healthy humans [J]. Am J Physiol,1991, 261:E457-E465.
[75]Uysal KT, Wiesbrock SM, Marino MW, et al. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function [J]. Nature,1997,389: 610-614.
[76]Uysal, KT, Wiesbrock, SM, and Hotamisligil, GS. Functional analysis of tumor necrosis factor (TNF) receptors in TNF-alpha-mediated insulin resistance in genetic obesity [J]. Endocrinology,1998,139:4832-4838.
[77]Ventre J, Doebber T, Wu M, et al. Targeted disruption of the tumor necrosis factor-alpha gene:metabolic consequences in obese and nonobese mice [J]. Diabetes,1997,46:1526-1531.
[78]Moller, D.E. Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes [J]. Trends Endocrinol Metab,2000,11:212-217.
[79]Keller P, Keller C, Carey AL, et al. Interleukin-6 production by contracting human skeletal muscle:autocrine regulation by IL-6 [J]. Biochem Biophys Res Commun,2003,310:550-554.
[80]Festa A, D'Agostino Jr R, Tracy RP, et,al. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes:the insulin resistance atherosclerosis study [J]. Diabetes,2002,51: 1131-1137.
[81]Gabay C, Kushner I:Acute-phase proteins and other systemic responses to inflammation [J]. N Engl J Med,1999,340:448-454.
[82]Senn JJ, Klover PJ, Nowak IA, et al. lnterleukin-6 induces cellular insulin resistance in hepatocytes [J]. Diabetes,2002,51:3391-3399.
[83]Kim HJ, Higashimori T, Park SY, et al. Differential effects of interleukin-6 and-10 on skeletal muscle and liver insulin action in vivo [J]. Diabetes,2004,53: 1060-1067.
[84]Weigert C, Hennige AM, Brodbeck K, et al. Interleukin-6 acts as insulin sensitizer on glycogen synthesis in human skeletal muscle cells by phosphorylation of Ser473 of Akt [J]. Am J Physiol Endocrinol Metab,2005,289: E251-E257
[85]Carey AL, Febbraio MA. Interleukin-6 and insulin sensitivity:friend or foe? [J] Diabetologia,2004,47:1135-1142.
[86]Henrike S, Daniela DS, Ulrike K. Monocyte Chemotactic Protein-1 Is a Potential Player in the Negative Cross-Talk between Adipose Tissue and Skeletal Muscle [J]. Endocrinology,2006,147:2458-2467.
[87]Franckhauser S, Elias I, Rotter Sopasakis V, et al. Overexpression of IL-6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice [J]. Diabetologia,2008,51:1306-1316.
[88]Pedersen BK, Febbraio MA. Point:Interleukin-6 does have a beneficial role in insulin sensitivity and glucose homeostasis [J]. J Appl Physiol,2007,102: 814-816.
[89]Muoio DM, Dohm GL, Fiedorek JR, et al. Leptin directly alters lipid partitioning in skeletal muscle [J]. Diabetes,1997,46:1360-1363.
[90]Kamohaha S, Burcelin R, Halaas JL, et al. Acute stimulation of glucose metabolism in mice by leptin treatment [J]. Nature,1997,389:374-377.
[91]Unger RH, Zhou YT, and Orci L. Regulation of fatty acid homeostasis in cells: novel role of leptin [J]. Proc Natl Acad Sci USA,1999,96:2327-2332.
[92]Monikoshi Y, Haque MS and Shimazu T. Microinjection of leptin into the ventromedia hypothamamus increases glucose uptake in peripheral tissues in rats [J]. Diabetes,1999,48:287-291.
[93]Loffreda S, Yang SQ, Lin HZ, et al. Leptin regulates proinflammatory immune responses [J]. FASEB J,1998,12:57-65.
[94]Curat CA, Miranville A, Sengenes C, et al. From blood monocytes to adipose tissue-resident macrophages:induction of diapedesis by human mature adipocytes [J]. Diabetes,2004.53:1285-1292.
[95]Petersen KF, Oral EA, Dufour S, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy [J]. J Clin Invest,2002,109: 1345-1350.
[96]Pelleymounter MA, Cullen MJ, Baker MB, et al. Effects of the obese gene product on body weight regulation in ob/ob mice [J]. Science,1995,269: 540-543.
[97]Monikoshi Y, Kim YB, Peroni OD, et al. Leptin stimulates fatty- acid oxidation by activating AMP-activated protein linase [J]. Nature,2002,415:339-343.
[98]Buhl ES, Jessen N, Pold R, Ledet T, et al. Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying feature of the insulin resistance syndrome [J]. Diabetes,2002,51(7):2199-2206.
[99]Kurth EJ, Hirshman MF, Goodyear LJ, el al.5'AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle [J]. Diabetes,1999,48: 1667-1671.
[100]Steppan CM, Bailey ST, Bhat S, et al.The hormone resistin links obesity to diabetes[J].Nature,2001,09(6818):307-312.
[101]Josef V Silha, Michal Krsek, Jan V Skrha, et al. Plasma resistin, adiponectin and leptin levels in lean and obese subjects:correlations with insulin resistance[J]. European Journal of Endocrinology,003,149(4):331-335.
[102]Levy JR, Davenport B, Clore JN, et al. Lipid metabolism and resistin gene expression in insulin- resistant Fischer 344 rats [J]. Am J Physiol Endocrinol Metab,2002,282(3):626-633.
[103]Lee JH, Chan JL, Yiannakouris N, et al. Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administratinn:cross-sectional and interventional studies in normal, insulin resistant and diabetic subiects [J]. J Clin Endocrinol Metab 2003, 88(10):4848-4856.
[104]Milan G, Granzotto M, Scarda A, et al. Resistin and adiponectin expression in visceral fat of obese rats:effect of weight loss [J]. Obes Res,2002,10(11): 1095-1103.
[105]Kawanami D, Maemura K, Takeda N, et al. Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells:a new insight into adipocytokine-endothelial cell interactions [J]. Biochem Biophys Res Commun,2004,314: 415-419.
[106]Rajala MW, Obici S, Scherer PE, et al. Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production [J]. J Clin Invest,2003,111:225-230.
[107]Steppan CM, Bailey ST, Bhat S,,et al.The hormone resistin links obesity to diabetes [J]. Nature,2001,409:307-312.
[108]Savage DB, Sewter CP, Klenk ES, et al. Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-γ action in humans [J]. Diabetes,2001,50(10):2199-2202.
[109]Volarova de Court B, Degawa-Yamauchi M, Considine RV, et,al High serum resistin is associated with an increase in adiposity but not a worsening of insulin resistance in Pima Indians [J]. Diabetes,2004,53:1279-1284.
[110]Degawa-Yamauchi M, Bovenkerk JE, Juliar BE, et al. Serum resistin (FIZZ3) protein is increased in obese humans [J]. J Clin Endocrinol Metab,2003,88: 5452-5455.
[111]Satoh H, Nguyen MT, Miles PD, et al. Adenovirus-mediated chronic "hyper-resistinemia" leads to in vivo insulin resistance in normal rats [J]. J Clin Invest,2004,114(2):224-231.
[112]Weyer C, Funahashi T, Tanaka S, et al. Hypoadiponectinemia in obesity and type 2 diabetes:close association with insulin resistance and hyperinsulinemia [J]. J Clin Endocrinol Metab,2001,86:1930-1935.
[113]Pittas AG, Joseph NA, Greenberg AS.Adipocytokines and insulin resistance [J]. J Clin Endocrinol Metab,2004,89:447-452.
[114]Ohnuma H, Igarashi M, Tominaga M, et al. Decreased serum levels of adiponectin are a risk factor for the progression to type 2 diabetes in the Japanese Population:the Funagata study [J]. Diabetes Care,2003,26:2015-2020.
[115]Duncan BB, Schmidt MI, Pankow JS, et al. Adiponectin and the development of type 2 diabetes:the Atherosclerosis Risk in Communities Study [J]. Diabetes, 2004,53:2473-2478.
[116]Lindsay RS, Funahashi T, Hanson RL, et al. Adiponectin and development of type 2 diabetes in the Pima Indian population [J]. Lancet,2002,360:57-58.
[117]Snehalatha C, Mukesh B, Simon M, et al. Plasma adiponectin is an independent predictor of type 2 diabetes in Asian indians [J]. Diabetes Care,2003,26: 3226-3229
[118]Spranger J, Kroke A, Mohlig M, et al. Adiponectin and protection against type 2 diabetes mellitus [J].Lancet,2003,361:226-228.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |