抗胰島素激素的調節與作用之探討

Studies on the regulation and action of resistin hormone

劉奇偉(Chi-wei Liu)

指導教授 ： 高永旭

國立中央大學/理學院/生命科學系/博士(2015年)

摘要

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。

關鍵字

抗胰島素激素 ； 辛基苯酚 ； FOXO1轉錄因子 ； 細胞激素抑制者

並列摘要

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.

並列關鍵字

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

參考文獻

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Chapter 1

2. Kim K.H., Zhao L., Moon Y., Kang C., Sul H.S., 2004. Dominant inhibitory adipocyte-specific secretory factor (ADSF)/resistin enhances adipogenesis and improves insulin sensitivity. Proc. Natl. Acad. Sci. U.S.A. 101, 6780–6785.

3. Mcternan P.G., Mcternan C.L., Chetty R., Jenner K., Fisher F.M., Lauer M.N., Crocker J., Barnett A.H., Kumar S., 2002. Increased resistin gene and protein expression in human abdominal adipose tissue. J. Clin. Endocrinol. Metab. 87, 2407–2410.

5. Pizzuti A., Argiolas A., Paola R.D., Baratta R., Rausea A., Bozzali M., Vigneri R., Dallapiccola B., Trischitta V., Frittitta L., 2002. An ATG repeat in the 30 untranslated region of the human resistin gene is associated with a decreased risk of insulin resistance. J. Clin. Endocrinol. Metab. 87, 4403–4406.