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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 莊立民(Lee-Ming Chuang) | |
| dc.contributor.author | Siow-Wey Hee | en |
| dc.contributor.author | 許曉薇 | zh_TW |
| dc.date.accessioned | 2021-06-14T16:52:42Z | - |
| dc.date.available | 2012-10-05 | |
| dc.date.copyright | 2011-10-05 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-08-12 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/40598 | - |
| dc.description.abstract | 近期有越來越多研究指出Nocturnin (Noc, Ccrn4l)可以調控脂肪代謝及脂肪細胞分化。本篇論文我們探討在早期脂肪細胞分化過程中，Noc所參與調控的角色。首先我們發現Noc是唯一在脂肪細胞分化過程中，會呈現雙週期表現情形的已知去腺嘧啶酶 (deadenylase)；而另四個Pan2, Parn, Ccr4, and Caf1去腺嘧啶酶則相對下降或沒變化。而利用Noc-silenced 3T3-L1前驅脂肪細胞及Noc基因剔除小鼠胚胎纖維母細胞primary mouse embryonic fibroblasts (MEFs)，顯示出早期瞬間表現的Noc會調控複製擴增（mitotic clonal expansion）過程及影響cyclin D1的表現。進一步我們利用Noc¬-depleted 3T3-L1 脂肪細胞微陣列分析（microarray），證實大部份差異表現的基因是跟細胞生長及增生有關。在脂肪細胞早期分化期間，Noc會與mRNA 去穩定因子 tristetraprolin (TTP) 作結合。經由篩選TTP的標的基因，我們發現在Noc- / -小鼠的脂肪組織中， Polo-like kinase3 （Plk3）mRNA的表現量明顯上升。而Noc的表現也可進一步抑制Plk3在3T3- L1前脂肪細胞的表現。
另外，在人類的脂肪組織中，NOC mRNA 與空腹胰島素(fasting insulin)及血中胰島素抗性指標（HOMA- IR）呈現負相關性，而與adiponectin mRNA及血中濃度呈正相關性; 同時，NOC mRNA 也與TTP mRNA呈正相關性．另外，PLK3 mRNA表現量與體重指數 (BMI) 不相關，但其位於皮下脂肪（SAT）的表現量顯著高於腹部脂肪 （VAT）。此外，無論是VAT或SAT 的PLK3 mRNA表現量都與adiponectin mRNA及adiponectin血清濃度呈強烈正相關，另外在校正過年齡、性別及BMI後，SAT PLK3 mRNA仍與空腹胰島素(fasting insulin)及血中胰島素抗性指標呈現負相關性．透過本篇論文的研究，我們對於Noc調控脂肪細胞分化的機制有更明確的闡述，也強化了Noc在胰島素於脂肪組織調控代謝功能的重要性。同時，我們的研究結果顯示PLK3與胰島素的敏感性有強烈的相關性。 | zh_TW |
| dc.description.abstract | The deadenylase nocturnin (Noc, Ccrn4l) has been recently found to regulate lipid metabolism and to control preadipocyte differentiation. Here we showed that among the five deadenylases tested; only Noc exhibited a biphasic expression during adipocyte differentiation, while the expression levels of other deadenylases, including Pan2, Parn, Ccr4, and Caf1 were relatively unchanged or reduced during adipogenesis. The immediate early-expressed Noc during 3T3-L1 adipogenesis was involved in regulating mitotic clonal expansion and cyclin D1 expression, as demonstrated in Noc-silenced 3T3-L1 cells and Noc-/- primary mouse embryonic fibroblasts (MEFs). Transcriptional profiling of Noc¬-depleted 3T3-L1 adipocytes revealed that most of the differentially expressed genes were related to cell growth and proliferation. An mRNA destabilizer, tristetraprolin (TTP), was further identified as an interacting partner of Noc during early adipogenesis. Screening of TTP mRNA targets in adipose tissue of Noc-/- mice revealed that the Polo-like kinase 3 (Plk3) mRNA expression was significantly upregulated. Ectopic expression of Noc further decreases Plk3 expression in 3T3-L1 preadipocytes.
In human adipose tissue, NOC mRNA level negatively associated with both fasting serum insulin and HOMA-IR, and positively associated with both adiponectin mRNA levels and circulating adiponectin levels. Moreover, NOC mRNA levels were also positively correlated with TTP mRNA levels in human adipose tissues. We further found that PLK3 mRNA levels were not associated with BMI, but were significant higher in subcutaneous adipose tissues (SAT) comparing to visceral adipose tissues (VAT). Furthermore, PLK3 mRNA levels in both VAT and SAT were strongly positively correlated with adiponectin gene expression as well as serum concentrations. The SAT PLK3 mRNA expressions were negatively correlated with fasting insulin levels and HOMA-IR even after adjustment of age, sex and BMI. Taken together, these results suggest the role of Noc in the modulation of early adipogenesis as well as systemic insulin sensitivity. Our findings also suggest that PLK3 is associated with systemic insulin sensitivity. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-14T16:52:42Z (GMT). No. of bitstreams: 1 ntu-100-D91448003-1.pdf: 1340061 bytes, checksum: aa15fc6084379ca580a0f1dfb443abf8 (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | Table of Contents
口試委員會審定書 1 誌謝 II 中文摘要 III Abstract IV Table of Contents V 1. Introduction 1.1 Circadian rhythms 1 1.2 Molecular clock components 1 1.3 Peripheral clock 1 1.4 Potential role for the circadian clock in metabolism 2 1.5 Adipose tissue 3 1.6 Adipocyte differentiation 3 1.7 Mitotic clonal expansion 3 1.8 Adipogenic transcription factors 3 1.9 Nocturnin (Ccrn4l, Noc) 4 1.10 Tristetraprolin 4 1.11 Polo-like kinase (Plk) family 4 1.12 Polo-like kinase 3 (Plk3) 5 1.13 Experimental rationale 5 2. Material and Methods 7 2.1 Materials 7 2.2 Plasmids 7 2.3 Targeted disruption of the Noc gene 7 2.4 Animals 8 2.5 Cell Culture 8 2.6 Oil red O staining 9 2.7 Lentivirus production and infection of 3T3-L1 cells 9 2.8 Reverse transcription and quantitative real-time PCR 9 2.9 Microarray analysis 9 2.10 Glucose transport assays 10 2.11 Bromodeoxyuridine incorporation assay 10 2.12 Immunoprecipitation and Western blot analysis 10 2.13 Study of human adipose tissues and metabolic phenotypes 11 2.14 Statistics 11 3. Results 12 3.1 Biphasic expression of Noc during 3T3-L1 adipogenesis 12 3.2 Noc knockdown accelerates the adipocyte differentiation process 12 3.3 Noc-/- embryonic fibroblast exhibit enhanced adipocyte differentiation 13 3.4 Effect of Noc knockdown on gene expression in 3T3-L1 adipocytes 13 3.5 Ectopic expression of Noc results in impaired adipogenesis 14 3.6 Depletion of Noc partially impedes MCE of adipogenesis 14 3.7 Noc interacts with TTP during early 3T3-L1 adipogenesis 15 3.8 NOC correlated with TTP, APM1 mRNA expression and metabolic parameters in human adipose tissues 15 3.9 Difference in PLK3 mRNA levels between VAT and SAT 16 3.10 Correlations between PLK3 and adiponectin gene expression in human adipose tissues 16 3.11 Correlations between PLK3 mRNA levels in human adipose tissue and metabolic phenotypes 17 4. Discussion 18 5. Tables 27 6. Figures 45 7. References 63 8. Appendix 74 | |
| dc.language.iso | en | |
| dc.subject | nocturnin | zh_TW |
| dc.subject | 脂肪細胞 | zh_TW |
| dc.subject | 胰島素抗性 | zh_TW |
| dc.subject | 代謝性症候群 | zh_TW |
| dc.subject | 晝夜節律 | zh_TW |
| dc.subject | metabolic syndrome | en |
| dc.subject | insulin resistance | en |
| dc.subject | adipocyte | en |
| dc.subject | nocturnin | en |
| dc.subject | circadian rhythm | en |
| dc.title | Nocturnin基因在脂肪細胞分化、肥胖與代謝所扮演的角色 | zh_TW |
| dc.title | The role of Nocturnin in adipogenesis,
obesity and metabolic disorders | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 呂勝春(Sheng-Chung Lee),黃青真(Ching-jang Huang),陳玉怜(Yuh-Lien Chen),張?仁(Ching-Jin Chang) | |
| dc.subject.keyword | 晝夜節律,nocturnin,脂肪細胞,胰島素抗性,代謝性症候群, | zh_TW |
| dc.subject.keyword | circadian rhythm,nocturnin,adipocyte,insulin resistance,metabolic syndrome, | en |
| dc.relation.page | 74 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2011-08-12 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| 顯示於系所單位： | 分子醫學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-100-1.pdf 未授權公開取用 | 1.31 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。