抗胰島素激素的調節與作用之探討

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劉奇偉(Chi-wei Liu) 查詢紙本館藏

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論文名稱

抗胰島素激素的調節與作用之探討
(Studies on the regulation and action of resistin hormone)

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摘要(中)

脂肪細胞現今已知可以表達及分泌許多種具有生物活性的胜肽，這些生物活性的胜肽在內分泌水平下可調控糖尿病、肥胖、癌症以及其它生物醫學相關的疾病。抗胰島素激素是富含半胱氨酸的賀爾蒙，最早自囓齒類動物脂肪組織分離並且發現它會連接肥胖和第二型糖尿病的發生。本文的總體目標是探討抗胰島素激素的調節與作用機制。第一章研究中，我們發現FOXO1轉錄因子可藉由直接結合抗胰島素激素啟動子進而刺激脂肪細胞抗胰島素激素基因的表達。第二章結果指出在3T3-L1脂肪細胞中，環境雌激素(例如辛基苯酚，壬基苯酚，雙酚A)對抗胰島素激素基因表達有不同的影響。在動物實驗中顯示，辛基苯酚會增加在附睾附近脂肪組織中抗胰島素激素基因表達，並且會增加血液中抗胰島素激素和血糖的含量。我們發現在動物實驗中支持體外細胞實驗的結果。此外，此章節也證實在3T3-L1脂肪細胞中處理各自的雌激素受體α和β的活化劑(例如propylpyrazoletriol和diarylpropionitrile)，發現雌激素受體α和β的活化劑會隨著劑量和時間刺激抗胰島素激素基因表達。第三章研究中指出在PC-3攝護腺癌細胞中抗胰島素激素會刺激抑制細胞激素訊號（SOCS）的基因表現，特別會刺激SOCS-1、-2、-3、-4、-5、-6基因的表達但不會影響SOCS-7和CIS-1基因的表現。抗胰島素激素透過toll-like受體4（TLR4）、細胞外信號調節激酶、p38促分裂原活化蛋白激酶、C-Jun N-末端激酶和Janus激酶2，但不透過TLR2刺激SOCS基因的表現。正如先前研究發現抗胰島素激素、FOXO1轉錄因子和SOCS皆可功能性調節糖尿病、肥胖和癌症，本研究的結果有助於解釋抗胰島素激素調節這些生物醫學疾病、環境雌激素影響代謝和生殖障礙所透過的機制。

摘要(英)

Adipocytes are now known to express and secrete a variety of bioactive peptides that regulate diabetes, obesity, cancer, and other biomedical diseases at the endocrine levels. Resistin is a cysteine-rich hormone that was first isolated from adipose tissues and found to link obesity to Type 2 diabetes in rodents. The overall objective of this dissertation was thus to examine the regulation and actions of resistin. The first chapter shows that the forkhead transcription factor FOXO1 stimulates the expression of the adipocyte resistin gene via the direct binding of resistin promoter. The second chapter shows that environmental estrogens, such as octylphenol, nonylphenol and bisphenol A, had different effects on resistin gene expression in 3T3-L1 adipocytes. In vivo experiments showed that octylphenol increased resistin expression in epididymal adipose tissue and serum levels of resistin and glucose supports its in vitro effect. Furthermore, this chapter demonstrated that the agonist of the respective estrogen receptor alpha and beta, such as propylpyrazoletriol and diarylpropionitrile, dose- and time-dependently stimulated resistin gene expression in 3T3-L1 adipocytes. The third chapter shows that resistin stimulated the expression of suppressor of cytokine signaling (SOCS) genes, particularly SOCS-1, -2, -3, -4, -5, and -6 but not SOCS-7 and CIS-1 genes, in human PC-3 prostate cancer cell via the toll-like receptor 4 (TLR4), extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and Janus kinase 2 but not TLR2 pathways. As resistin, FOXO1, and SOCS all function to regulate diabetes, obesity, and cancer, the results of this study may help explain the mechanism through which resistin modulates the processes of these biomedical diseases and environmental hormone-mediated metabolic and reproductive disorders.

關鍵字(中)

★ 抗胰島素激素
★ 辛基苯酚
★ FOXO1轉錄因子
★ 細胞激素抑制者

關鍵字(英)

★ resistin
★ octylphenol
★ FOXO1 transcription factor
★ suppressor of cytokine signaling

論文目次

Chinese Abstract ....................... i
English Abstract ....................... ii
Declaration ....................... iii
Acknowledgment ....................... iv
Table of Contents ....................... v
List of Tables ....................... ix
List of Figures ....................... x
Abbreviation ....................... xiii

1. Chapter One Forkhead transcription factor FOXO1 regulates activity of resistin gene promoter............1
1-1. Introduction....................................3
1-2. Materials and Methods...........................5
1-2.1. Chemical reagents...............................5
1.2.2. Cell culture....................................5
1-2.3. Plasmid constructions...........................6
1-2.4. Transient transfection and luciferase reporter
assay...........................................7
1-2.5. Confocal laser scanning microscopy..............8
1-2.6. Chromatin immunoprecipitation (ChIP) assay......8
1-2.7. RNA amalysis....................................9
1-2.8. Western blot analysis...........................11
1-2.9. Statistical analysis............................12
1-3. Results and Discussion..........................13
1-3.1. FOXO1 factor activated the resistin gene
promoter........................................13
1-3.2. FoxO1 and resistin expressed high mRNA levels
during differentiation of fat cells.............15
1-3.3. Dominant-negative FoxO1 reduced resistin mRNA
expression and promoter activity................16
1-3.4. FoxO1 bound the resistin gene promoter..........16
1-4. Conclusions.....................................19
1-5. References......................................20

2. Chapter Two Environmental estrogens and estrogen receptor activators modulate resistin hormone...........26
2-1. Introduction....................................28
2-2. Materials and Methods...........................31
2-2.1. Chemical reagents...............................31
2.2.2. Cell culture....................................31
2-2.3. In vivo experiments.............................31
2-2.4. Real-time PCR...................................32
2-2.5. Statistical analysis............................33
2-3. Results and Discussion..........................34
2-3.1. Environmental estrogens affect the expression of adipocyte resistin..............................34
2-3.2. Environmental estrogens affect the expression of adipocyte leptin and adiponectin genes..........34
2-3.3. Octylphenol affects tissue and serum levels of
resistin, adiponectin, and leptin in vivo.......36
2-3.4. The octylphenol-stimulated expression of the
resistin gene in vivo is associated with glucose
homeostasis.....................................38
2-3.5. Estrogen receptor activators affect the expression
of adipocyte resistin, adiponectin, and leptin
gene............................................39
2-4. Conclusions.....................................44
2-5. References......................................45

3. Chapter Three Resistin hormone stimulates the expression of suppressors of cytokine suppressors of cytokine signaling (SOCSs) genes through the toll-like receptor 4 pathway.................................................52
3-1. Introduction....................................54
3-2. Materials and Methods...........................57
3-2.1. Chemical reagents...............................57
3.2.2. Cell culture and treatment......................57
3-2.3. Cell proliferation assay........................57
3-2.4. RT-PCR and Real-time PCR........................58
3-2.5. Statistical analysis............................59
3-3. Results and Discussion..........................60
3-3.1. Resistin stimulated expression of SOCSs genes...60
3-3.2. The effect of resistin on SOCSs mRNA expression
may requires new mRNA synthesis or alters mRNA
stability.......................................60
3-3.3. Resistin affects SOCSs mRNA expression via the
TLR4 pathway....................................61
3-3.4. ERK MEK, JNK MAPK, p38 MAPK, PI3K, and JAK-2
are involved in the resistin-stimulated increase
of SOCSs mRNA...................................62
3-3.5. The effects of resistin on SOCSs mRNA expression
are cell type specific..........................63
3-3.6. Resistin stimulated growth of PC-3 prostate cancer
cells...........................................64
3-3.7. Resistin signaling molecules are involved in the
resistin-stimulated growth of PC-3 prostate cancer
cells...........................................64
3-4. Conclusions.....................................66
3-5. References......................................67

Tables 1-5.............................................77
Fiqures 1-27............................................82
Appendix 1. The respective dissociation curves for adiponectin, resistin, FoxO1, aP2, and GAPDH indicated the specificity of real-time PCR anslysis...................121
Appendix 2. The parallelism of titration curves for adiponectin, resistin, FoxO1, aP2, and GAPDH indicated the respective efficiency of their real-time PCR anslysis...122
Appendix 3. The respective end-point RT-PCR analysis for adiponectin, resistin, FoxO1, aP2, and GAPDH indicated
the specificity and exponential change..................123
Appendix 4. The control for amplification of genomic DNA was that an equivalent amount of total RNA was not performedwith a reaction of reverse transcription but amplified in the PCR reaction of adiponectin, resistin, FoxO1, aP2, and GAPDH...................................124
Appendix 5. The different FoxO1 mutants affected activity of resistin gene promoter...............................125
Appendix 6. Using RT-PCR and real-time PCR to investigate the expression of FoxO3, FoxO4, and FoxO6 genes during
differentiation of C3H10T1/2 and 3T3-L1 preadipocytes
to adipocytes...........................................126
Appendix 7. Chromatin immunoprecipitation analysis indicated the association of FoxO1 transcription factor with resistin promoter in C3H10T1/2 and Day 2 differentiating adipocytes..............................128
Appendix 8. The differences in structures of the SOCS family members. (KIR, kinase inhibitory region; SH2 domain, Src homology 2 domain)..................................129
Appendix 9. A respective dissociation curve for SOCS-1, SOCS-2, SOCS-3, SOCS-4, SOCS-5, SOCS-6, SOCS-7, CIS-1,
and GAPDH indicates the specificity of real-time PCR
anslysis................................................130
Appendix 10. A parallelism of titration curves for SOCS-1, SOCS-2, SOCS-3, SOCS-4, SOCS-5, SOCS-6, SOCS-7, CIS-1,
and GAPDH indicates the respective efficiency of their
real-time PCR anslysis..................................131
Appendix 11. The control for amplification of genomic DNA was that an equivalent amount of total RNA was not performedwith a reaction of reverse transcription but amplified in the PCR reaction of SOCS-1, SOCS-2, SOCS-3, SOCS-4, SOCS-5, SOCS-6, SOCS-7, CIS-1, and GAPDH gene...132
Appendix 12. The effect of different inhibitors on cell viability of PC-3 prostate cancer cells after 2.5 and 24 h of treatments...........................................133
Appendix 13. The control for amplification of genomic DNA for the PCR reaction of resistin and GAPDH genes........134
Appendix 14. The control for amplification of genomic DNADNA for the PCR reaction of Resistin and GAPDH genes
in the presence and absence of ET-1.....................135
Appendix 15. SOCS family genes expressed in PC-3 and LNCaP-FGC prostate cancer cells, and U-937 leukemia cells.....138

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chapter 2
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指導教授

高永旭(Yung-hsi Kao)

審核日期

2015-1-16

推文