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系統識別號 U0026-2407201401221500
論文名稱(中文) Toll-like Receptor 2在葡萄糖代謝及能量恆定上之角色
論文名稱(英文) Role of Toll-like Receptor 2 in Glucose Metabolism and Energy Homeostasis
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 2
出版年 103
研究生(中文) 郭力華
研究生(英文) Li-Hua Kuo
學號 S58961418
學位類別 博士
語文別 英文
論文頁數 124頁
口試委員 指導教授-蔡曜聲
召集委員-蔡少正
口試委員-任卓穎
口試委員-林淑華
口試委員-蔡佩珍
口試委員-謝博軒
中文關鍵字 發炎  胰島素阻抗  Toll-like receptor 2 
英文關鍵字 Inflammation  insulin resistance  Toll-like receptor 2 
學科別分類
中文摘要 第二型糖尿病的特徵包含肥胖、發炎以及胰島素阻抗,目前研究指出肥胖會使發炎反應上升,進一步造成胰島素阻抗。然而,肥胖導致發炎反應產生的機制目前仍然所知有限。考量到先天免疫反應的分子Toll-like receptor 2 (TLR2)會辨識很多含有脂質的分子,我們假設脂質會活化TLR2、使之傳遞發炎訊息、並且進一步造成胰島素阻抗。首先,我們觀察到肥胖(ob/ob)小鼠中脂肪組織及肝臟中的TLR2表現量變得較高,這促使我們研究TLR2在胰島素阻抗中的角色,結果顯示,無論是餵食一般飼料或高脂飼料,TLR2缺失小鼠都有較好的葡萄糖清除能力及胰島素敏感性。第二,隨著年齡增加或餵食高脂飼料,TLR2缺失小鼠與野生型小鼠相比後較沒有肥胖的情形,而且活動力及消耗的能量也較高。第三,我們特別在TLR2缺失小鼠的肝臟當中發現,細胞外訊息調節激酶 (ERK)的活化程度降低,並且伴隨胰島素訊息傳遞分子的活化上升。進一步分析TLR2影響肝臟胰島素敏感性的機制,我們發現棕櫚酸可以透過TLR2活化巨噬細胞和肝臟細胞,間接或直接影響肝細胞中的胰島素訊息傳遞。最後,因為TLR2缺失小鼠肝臟當中發炎訊息及脂質堆積的減少,也改善了肝臟的葡萄糖代謝功能。基於上述結果,我們發現TLR2扮演連結脂質和肝臟發炎反應的橋樑,進而造成肝臟胰島素阻抗,而影響全身對於葡萄糖的恆定。
英文摘要 Type 2 diabetes consists major characteristics such as obesity, inflammation and insulin resistance. It has been shown that inflammation is elevated in the condition of obesity and leads to insulin resistance. However, the underlying mechanism linking obesity and inflammation is poorly understood. Considering that the innate immune molecule Toll-like receptor 2 (TLR2) recognizes a large number of lipid containing molecules, we hypothesized that TLR2 is activated by dietary lipids, transduces proinflammatory signals, and further contributes to insulin resistance. First, we observed elevated expression of proinflammatory cytokines and TLR2 in white adipose tissue and liver of ob/ob mice. This promoted us to study the role of TLR2 in insulin resistance, and we found that TLR2-deficient mice exhibited improved glucose tolerance and insulin sensitivity regardless of feeding them regular chow or a high-fat diet. Secondly, aged or high-fat fed TLR2-deficient mice were protected from obesity and adipocyte hypertrophy, accompanied with increased locomotor activity and energy expenditure. Thirdly, we found reduced extracellular signal-regulated kinase (ERK) activation and increased insulin signaling in TLR2-deficient mice in a liver-specific manner. To dissect the mechanism by which TLR2 influences hepatic insulin sensitivity, we revealed that the dietary lipid, palmitate, activates primary macrophages and hepatocytes, and may indirectly or directly interrupt hepatic insulin signaling through TLR2. Finally, we observed improved glucose metabolism in the liver of TLR2-deficient mice, and this may be contributed by attenuated inflammatory response as well as decreased hepatic triacylglyceride accumulation. Taken together, our work has identified TLR2 as a key bridge between the dietary lipid and hepatic inflammatory responses, leading to hepaitc insulin resistance and impaired glucose homeostasis.
論文目次 Abstract I
摘要 II
誌謝 III
Table of contents IV
List of figures VI
Abbreviations VII
Chapter 1: Introduction 1
1.1 Metabolic syndrome 1
1.2 Type 2 diabetes 1
1.3 Physiological effects of insulin on insulin responsive tissues 2
1.4 Insulin signaling in insulin resistance 4
1.5 Insulin resistance and inflammation 4
1.6 Nutrient excess and insulin resistance 5
1.7 Free fatty acid 6
1.8 Toll-like receptors 7
1.9 Toll-like receptor 2 7
1.10 FFA and TLR 8
1.11 TLRs and insulin resistance 9
1.12 NLRP3 inflammasome in insulin resistance 9
Chapter 2: Objective and specific aims 11
Chapter 3: Materials and Methods 13
3.1 Mice 13
3.2 Tissue collection and RNA analysis 13
3.3 Morphological analysis 13
3.4 Immunohistochemical staining 14
3.5 Glucose metabolic assays 14
3.6 Induction of adipogenesis from MEF 14
3.7 Lipid and cytokine assays 15
3.8 Metabolic analysis 15
3.9 Protein analysis 15
3.10 Isolation of mouse primary hepatocytes and glucose production assay 16
3.11 In vitro glucose uptake assay 16
3.12 Organ lipid content 17
3.13 Data analysis 17
Chapter 4: Results 18
4.1 Upregulation of TLR2 and inflammatory cytokines in WAT and liver of obese mice 18
4.2 Increased insulin sensitivity in Tlr2-/- mice 18
4.3 Decreased body weight and fat mass in Tlr2-/- mice 19
4.4 Lipid profile and cytokines in Tlr2-/- mice 21
4.5 Attenuated local inflammatory responses in Tlr2-/- mice 22
4.6 Attenuated inflammasome in Tlr2-/- mice 23
4.7 TLR2 influences downstream inflammatory mediators and insulin signaling in primary hepatocytes 24
4.8 Improved insulin signaling specifically in the liver of Tlr2-/- mice 26
4.9 Reduced triglyceride content and improved glucose metabolism in the liver of Tlr2-/- mice 27
4.10 Increased insulin sensitivity in Tlr2/Tlr4 DKO mice compared to Tlr4-/- mice 29
Chapter 5: Discussion 30
5.1 Which organ and cell is important in TLR2-induced insulin resistance? 30
5.2 Factors that activate TLR2 33
5.3 Could infection lead to type 2 diabetes? 34
5.4 Influences of TLR2 deficiency on lipid accumulation and insulin sensitivity in the liver 35
5.5 Regulation of ERK on insulin signaling 37
5.6 Influences of TLR2 deficiency on energy expenditure 39
5.7 Is TLR2 more important than TLR4 in insulin resistance? 40
Chapter 6: Conclusion 42
Reference 44
Figures 53
Tables 85
Table 1 List of primers used in this study 85
Appendices 87
Publications 124
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