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姓名	黃詠亭(Yung-Ting Huang)  查詢紙本館藏	畢業系所	生命科學系
論文名稱	調控小鼠脂肪細胞釋放阻抗素之訊息傳導路徑 (Effects of Distinct Signal Pathways on Resistin Release in Murine Adipocytes)
相關論文	★ PDE抑制劑與cAMP訊號傳導對類風濕性關節炎小鼠模型中CD4+ T細胞釋放IFN-g與IL-17A之調控 ★ PDE4和cAMP訊號傳導於小鼠骨髓細胞分化為樹突細胞之角色 ★ 利用斑馬魚研究肝臟疾病和肝癌之發生：B型肝炎病毒X抗原，黃麴毒素，p53突變，src和edn1的致癌作用及其協同效應 ★ 環狀核苷酸磷酸二酯酶4對LPS/TLR4訊息傳導誘導小鼠巨噬細胞表現IFN-β的影響 ★ 抑制環狀核苷酸磷酸二酯酶 3 (PDE3)對 3T3-L1 脂肪細胞內蛋白質表現之影響 ★ 環狀核苷酸磷酸二酯酶4B對小鼠樹突細胞分化與CXCR4表現之調控 ★ 利用聚乙烯亞胺輸送環狀核苷酸磷酸二酯酶4B之專一性反義寡核苷酸可抑制LPS刺激小鼠巨噬細胞釋放TNF-α ★ PDE4與PDE3抑制劑對膠原蛋白誘發DBA/1小鼠關節炎及釋放發炎激素IFN-γ與IL-17A的協同調控作用 ★ 環狀核苷酸磷酸二酯酶4B對內毒素誘導巨噬細胞 產生IL-1Ra和樹突細胞表現TLRs之影響 及其對乾癬症生成之潛在角色 ★ 環狀核苷酸磷酸二脂酶4B對內毒素刺激小鼠樹突細胞表現NOD1與CXCR4的影響 ★ TDAG8 participates in different phases of neuropathic pain by regulating distinct pathways of substance P ★ Innovative Mind-Body Intervention Day Easy Exercise Increases Peripheral Blood CD34+ Cells and Attenuates Back Pain in Adults ★ Viscolin對不同免疫細胞發炎反應的影響 ★ 環狀腺苷單磷酸與其它訊息傳遞因子對脂肪細胞釋放阻抗素之影響 ★ 環狀核苷酸磷酸二酯酶4B對於小鼠T細胞功能之調節 ★ 巨噬細胞中抑制PDE4對LPS誘導發炎反應之調控
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摘要(中)	阻抗素(resistin)是一種與胰島素抗性和能量平衡有關的脂肪素。研究指出， isoproterenol (ISO，一種β adrenergic receptor agonist)可降低3T3-L1脂肪細胞內resistin mRNA的表現量，但目前對於ISO是否會調控resistin的釋放以及其活化cAMP訊息傳導的機制仍不明瞭。本研究利用ELISA方法分析不同藥劑處理3T3-L1脂肪細胞或小鼠腹腔脂肪細胞對resistin釋放之影響。結果顯示ISO或forskolin皆可抑制兩種脂肪細胞對resistin的釋放，且ISO對resistin釋放的抑制作用可完全被PKA抑制劑Rp-8-CPT-cAMPS回復。進一步使用dibutyryl-cAMP (dbcAMP)處理3T3-L1脂肪細胞或小鼠腹腔脂肪細胞，結果顯示僅小鼠脂肪細胞的resistin釋放有明顯抑制作用。第三型環狀核苷酸磷酸二酯酶(PDE3)是脂肪細胞內降解cAMP的酵素，負責調節細胞內cAMP濃度及其訊息傳遞路徑。將cAMP類似物dbcAMP與PDE3抑制劑cilostazol共同處理3T3-L1脂肪細胞，可使resistin的釋放量明顯下降，PKA抑制劑能將此抑制作用完全回復。此外，我們發現利用PKA活化劑6-Bnz-cAMP處理兩種脂肪細胞可抑制resistin的釋放，而Epac活化劑8-pCPT-2'-O-Me-cAMP則無此作用。這些結果顯示，在脂肪細胞中cAMP抑制resistin釋放是經由活化PKA而非Epac路徑所致。本研究亦發現，TNF-alpha與PI3K抑制劑LY294002均可降低resistin的釋放，但其抑制作用不會被PKA抑制劑回復，顯示TNF-alpha與PI3K抑制劑的抑制作用不是經由活化PKA訊息傳導所致。再者，本研究利用胰島素刺激3T3-L1脂肪細胞以活化PI3K，結果顯示其對resistin的釋放無顯著影響，然而胰島素會阻斷LY294002對resistin的抑制作用，使resistin釋放回升，由此我們推測當PI3K被抑制時，胰島素可經由活化其他路徑以增加resistin的釋放。我們也發現，AMPK促進劑AICAR與AMPK抑制劑Compound C皆會抑制脂肪細胞釋放resistin，此不相容結果之原因仍不甚明瞭。綜合本研究結果，脂肪細胞釋放resistin可被多種訊息傳遞路徑及分子所調控，包括cAMP/PDE3/PKA、PI3K、TNF-alpha?receptor及AMPK等。
摘要(英)	Resistin is an adipokine which is implicated in adipogenesis, insulin resistance, and inflammation. Its mRNA expression in mouse adipocytes is demonstated to be down-regulated by the cAMP-elevating agent isoproterenol (ISO), a β-adrenergic receptor agonist, but the mechanism underlying this cAMP signaling remains undefined. In this study, treatment of mouse primary and 3T3-L1 adipocytes with ISO, revealed that the resistin release was significantly reduced. Additionally, this response was reversed by the PKA inhibitor Rp-8-CPT-cAMPS. This decrease in the resistin release was mimicked by the treatment of the cells with the PKA activator 6-Bnz-cAMP, whereas the Epac activator 8-pCPT-2’’-O-Me-cAMP did not alter the resistin release. These results indicated that the PKA activation mediates the ISO/cAMP-induced reduction of resistin release. The resistin release was also significantly suppressed when 3T3-L1 adipocytes were incubated with a combination of the cAMP-specific phosphodiestrase PDE3 inhibitor cilostazol and dibutyryl-cAMP (dbcAMP). Like the ISO-induced signaling, this decrease was also reversed by the PKA inhibitor, indicating that the decrease of resistin release by dbcAMP and PDE3 inhibitor is also mediated by PKA activation. Treatment of adipocytes with TNF-alpha and PI3K inhibitor LY294002 also showed a significant decrease in resistn release, but such effect was not reversed by the PKA inhibitor, suggesting that signal pathways other than cAMP signaling are involved in resistin production. Moreover, insulin alone was found no effect on resistin release in 3T3-L1 adipocytes, but it could block the inhibitory effect of PI3K inhibitor, suggesting that a PI3K-independent pathway may mediate the insulin action. Taken together, these results demonstrated that in mouse adipocytes the resistin release is regulated by distinct signal pathways including cAMP/PDE3/PKA, TNF-alpha?receptor, and PI3K signaling.
關鍵字(中)	★ 腫瘤壞死因子 ★ 脂肪細胞 ★ 環狀核苷酸磷酸二酯酶 ★ 環狀腺苷單磷酸 ★ 磷酸肌醇三激酶 ★ 阻抗素	關鍵字(英)	★ adipocyte ★ PI3K ★ TNF-alpha ★ resistin ★ cAMP ★ PDE
論文目次	目錄 中文摘要 i Abstract ii 誌謝 iii 目錄 iv 圖目錄 vi 縮寫檢索表 vii 第一章 緒論 1 1-1 脂肪組織 1 1-2 阻抗素(Resistin) 1 1-2-1 Resistin的發現 1 1-2-2 Resistin的分子特性 2 1-2-3 Resistin表現與釋放的調控 2 1-3 cAMP與脂肪細胞 3 1-4 cAMP訊息傳導路徑 4 1-5 環狀核苷酸磷酸二酯酶(Cyclic nucleotide phosphodiesterases；PDE) 5 1-6 PDE3家族 6 1-7 cAMP與Resistin 7 1-8 AMP-activated protein kinase (AMPK) 7 第二章 研究動機與目的 9 第三章 材料與方法 11 3-1 材料 11 3-1-1 實驗小鼠 11 3-1-2 細胞株 11 3-1-3 實驗藥材 11 3-2 方法 12 3-2-1 3T3-L1細胞培養 12 3-2-2 3T3-L1細胞分化 12 3-2-3 3T3-L1脂肪細胞的處理 13 3-2-4 分離小鼠初代脂肪細胞 13 3-2-5 小鼠初代脂肪細胞的處理 14 3-2-6 細胞萃取液之製備 14 3-2-7 蛋白質定量 15 3-2-8 PDE酵素活性檢測 15 3-2-9 酵素免疫分析法(Enzyme-linked immunosorbent assay，ELISA) 16 第四章 實驗結果 17 4-1 cAMP訊息傳導對脂肪細胞釋放resistin之影響 17 4-1-1 Isoproterenol、forskolin和dibutyryl-cAMP對3T3-L1脂肪細胞釋放resistin之影響 17 4-1-2 Isoproterenol、forskolin和dibutyryl-cAMP對小鼠初代脂肪細胞釋放resistin之影響 17 4-1-3 cAMP訊息傳導路徑與脂肪細胞釋放resistin之關係 18 4-1-4 PDE與cAMP 類似物dbcAMP對脂肪細胞釋放resistin之影響 18 4-1-5 Dibutyryl-cAMP和cilostazol對脂肪細胞釋放resistin之訊息傳導 19 4-2 Tumor Necrosis Factor-alpha (TNF-a)對脂肪細胞釋放resistin之影響 20 4-3 PI3K對脂肪細胞釋放resistin之影響 20 4-4 AMP-activated protein kinase (AMPK)對脂肪細胞釋放resistin之影響 21 4-5 Isoproterenol、dibutyryl-cAMP和resistin對3T3-L1脂肪細胞內PDE活性之影響 22 第五章 討論 24 5-1 cAMP訊息傳導對脂肪細胞釋放resistin之影響 24 5-2 TNF-alpha對脂肪細胞釋放resistin之影響 27 5-3 PI3K對脂肪細胞釋放resistin之影響 27 5-4 AMP-activated protein kinase (AMPK)對脂肪細胞釋放resistin之影響 29 第六章 圖與圖解 30 參考文獻 41 附錄 49 圖目錄 圖一、cAMP調節劑對脂肪細胞釋放resistin之影響 30 圖二、PKA活化劑、Epac活化劑和PKA抑制劑對ISO抑制脂肪細胞釋放resistin之影響 31 圖三、dbcAMP和cilostazol對脂肪細胞釋放resistin之影響 32 圖四、dbcAMP和cilostazol共同處理不同時間對脂肪細胞釋放resistin之影響 33 圖五、dbcAMP和cilostazol共同處理對3T3-L1脂肪細胞釋放resistin之影響 34 圖六、cilostazol和dbcAMP抑制脂肪細胞釋放resistin之訊息傳導路徑 35 圖七、TNF-?對脂肪細胞釋放resistin的抑制作用並非藉由PKA之活化 36 圖八、胰島素對脂肪細胞釋放resistin之影響 37 圖九、PI3K抑制劑對脂肪細胞釋放resistin之抑制作用不被PKA所調控 38 圖十、AMPK活性對3T3-L1脂肪細胞釋放resistin之影響 39 圖十一、Isoproterenol、dbcAMP和resistin對3T3-L1脂肪細胞內PDE活性之影響 40
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指導教授	金秀蓮(S.-L. Catherine Jin)	審核日期	2012-7-30
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