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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/93672完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林甫容 | zh_TW |
| dc.contributor.advisor | Fu-Jung Lin | en |
| dc.contributor.author | 江忠霖 | zh_TW |
| dc.contributor.author | Chung-Lin Jiang | en |
| dc.date.accessioned | 2024-08-07T16:19:26Z | - |
| dc.date.available | 2024-08-08 | - |
| dc.date.copyright | 2024-08-07 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-07-26 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/93672 | - |
| dc.description.abstract | 如何減緩肥胖一直是公共健康的重要課題。隨著肥胖程度的加劇，第二型糖尿病和心血管疾病的風險也大幅提高。近年來，學者開始關注米色脂肪細胞對代謝調節的正面影響，並透過研究遺傳基因、環境、生活方式、飲食和藥物等因素，探索如何增強米色脂肪以抵抗代謝疾病。然而，米色脂肪的起源仍有很多未知。了解米色脂肪的發育起源將有助於發展治療代謝疾病的策略。本論文利用小鼠為實驗模式，從三個方面探討米色脂肪細胞的發育。第一個研究發現 ApoE 基因負向調節米色脂肪生成。ApoE 基因剔除小鼠具有低度的內源性生酮現象，生酮作用所生成的酮體（β-hydroxybutyrate，βHB）促進脂肪前驅細胞分化成米色脂肪細胞。這項發現連結 APOE 基因引發的肥胖易感性和米色脂肪發育之間的關聯性。第二個研究發現哺乳期仔鼠有別於成年鼠，具有自發性的營養性酮症，此生理現象我們定義為「哺乳期酮症（preweaning ketosis）」。生酮基因 Hmgcs2 缺陷或提早斷奶造成的生酮缺失則會損害米色脂肪細胞的分化，觸發肥胖易感性，並於成年後，對代謝表現的調節產生不利影響。此外，哺乳期增強生酮作用（enhanced ketogenesis during lactation）具有促進米色脂肪分化和米色脂肪的產熱功能。這些發現，確認提升哺乳期的血清 βHB 濃度能夠調節小鼠在哺乳期間的米色脂肪發育。第三個研究發現哺乳期以外源性方式增加血清 βHB 濃度，具有促進米色脂肪分化之作用，減緩 PO 子代的肥胖易感性，部分改善 PO 子代在代謝調節方面的表現。綜上所述，本論文發現哺乳階段的 βHB 具有調節米色脂肪發育的新功能。因此，βHB 可能可以作為一種有效的調節劑，有助於肥胖易感性族群抵抗肥胖的發展。 | zh_TW |
| dc.description.abstract | Obesity and metabolic diseases represent significant public health concerns. Recently, beige adipocytes have attracted much attention for their potential positive impact on metabolism. However, the developmental origin of beige adipocytes remains unclear. This study aimed to answer this question through three distinct aspects using mouse models. The first study examined the role of the ApoE gene in obesity. We found that ApoE deficiency induces beiging of white adipose tissue in mice by enhancing the production of the ketone body β-hydroxybutyrate (βHB) from adipose precursor cells. This discovery reinforces the link between APOE gene inheritance, obesity susceptibility, and beige fat development. The second study revealed a novel role of preweaning ketosis in regulating beige fat biogenesis and highlighted its significance in promoting healthy growth in newborns. Deficiency in preweaning ketosis impairs beige fat development and increases susceptibility to obesity, with adverse metabolic consequences in adulthood. The third study demonstrated that enhancing ketogenesis during lactation through exogenous ketone body supplementation can mitigate offspring susceptibility to obesity induced by parental obesity. These results indicate that elevated serum βHB concentration positively regulates beige fat development and improves metabolic outcomes. Overall, this study suggests that augmenting the development of beige adipocytes may offer a novel therapeutic approach for addressing obesity and its associated metabolic diseases. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-08-07T16:19:25Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-08-07T16:19:26Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 論文口試委員審定書 i
謝 辭 ii 中文摘要 iii 英文摘要 iv 目 次 v 圖 次 xiii 表 次 xvii 縮寫表 xviiii 緒 論 1 第一節 前言 1 第二節 文獻回顧 3 一、脂肪組織的發育、功能與涉及的代謝調節之回顧 3 二、酮體在哺乳動物扮演的功能之回顧 14 三、酮體在脂肪組織的代謝功能調節之回顧 21 第三節 研究假說及實驗架構 22 一、研究動機 22 二、研究假說 23 三、研究架構 24 第一章 E 型載脂蛋白缺陷小鼠透過脂肪前驅細胞的酮體產生途徑促進脂肪米色化 Apolipoprotein E deficiency in mice enhance adipose beiging by promoting adipose progenitor-mediated β-hydroxybutyrate production 30 第一節 摘要 30 第二節 前言 31 一、E 型載脂蛋白的基因型影響肥胖風險 31 二、小鼠脂肪組織 ApoE 影響代謝功能並參與肥胖與胰島素阻抗的病程發展 31 第三節 研究假說與實驗設計 33 第四節 材料與方法 33 一、試劑與耗材 33 二、小鼠飼養 33 三、小鼠基因型鑑定（genotyping） 34 四、產熱效率及能量代謝分析 35 五、各項代謝指標在血液與細胞培養基的濃度分析 35 六、初代細胞 35 七、組織化學及免疫染色 37 八、脂肪組織切片的脂肪細胞大小尺寸量化 37 九、脂肪組織切片的脂肪細胞型態之量化 38 十、脂肪組織切片的脂肪細胞標定的螢光蛋白之量化 38 十一、細胞存活率或毒性試驗分析 39 十二、油紅 O（Oil red O）染色 39 十三、葡萄糖攝取試驗 39 十四、脂肪酸利用試驗 40 十五、脂肪酸分解試驗 40 十六、粒線體耗氧、糖解作用與脂肪酸氧化功能 40 十七、粒線體數量之定量 42 十八、RNA 萃取、反轉錄 cDNA 和即時定量聚合酶連鎖反應（qPCR） 42 十九、蛋白質萃取和西方墨點法 43 二十、統計分析與數據整理 45 第五節 實驗結果 45 一、連續每天以腹腔注射 PPARγ 活化劑 WT 小鼠在 7 天後促進皮下脂肪米色化並不影響血酮濃度 45 二、Chow 飼養的 ApoE-/- 小鼠在 PPARγ 活化劑處理下並不影響體重與體組成的改變 46 三、PPARγ 活化劑處理的 ApoE-/- 小鼠具有較高的產熱效率及代謝率 46 四、ApoE-/- 小鼠具有脂肪米色化特徵並在 PPARγ 活化劑處理下增強其米色化效果 46 五、ApoE-/- 小鼠在低溫條件下飼養具有較強脂米色化效果 48 六、ApoE-/- 小鼠的皮下脂肪具有較小尺寸的脂肪細胞並增強其米色化效果 48 七、ApoE-/- 小鼠在 PPARγ 活化劑或冷暴露處理下促進棕色脂肪的脂肪細胞尺寸變大 49 八、ApoE-/- 小鼠的棕色脂肪組織不改變產熱基因表現 49 九、PPARγ 活化劑處理的 ApoE-/- 小鼠會促進脂肪分解 49 十、缺乏 ApoE 促進米色脂肪分化及功能 50 十一、缺乏 ApoE 促進脂肪前驅細胞以酮體 βHB 產生途徑誘導米色脂肪分化 50 十二、PPARγ 活化劑處理的 ApoE-/- 小鼠不影響血糖、血乳酸及血酮濃度的改變 52 十三、生酮抑制劑對 MEFs 的細胞毒性之影響 52 十四、ApoE-/- 脂肪前驅細胞部分依賴 Hmgcs2/βHB 途徑來調節米色脂肪分化的基因指標 52 十五、ApoE-/- 脂肪前驅細胞經由脂肪酸轉運蛋白 CD36 途徑的脂肪酸氧化作用來產生酮體 βHB 53 十六、脂肪細胞缺乏 ApoE 增強脂肪酸氧化作用、脂質分解及胰島素敏感性 54 十七、小鼠缺乏 ApoE 不改變皮下脂肪前驅細胞的數量 54 十八、ApoE-/- 前驅細胞增強的 Pparγ2 訊號可以被生酮抑制劑所破壞 55 十九、ApoE-/- 小鼠經由脂肪前驅細胞之酮體產生途徑增強米色脂肪分化來活化白色脂肪組織的產熱作用 55 第六節 討論 80 一、脂肪組織條件性剔除 ApoE 小鼠增強代謝作用 80 二、ApoE-/- 小鼠經由生成酮體來增強脂肪米色化 80 三、ApoE-/- 小鼠的脂肪前驅細胞活化脂肪酸轉運蛋白 CD36之脂肪酸氧化途徑來產生酮體 82 四、ApoE-/- 小鼠誘發的脂肪米色化作用連結人類 APOE4 基因型可能之應用 83 第七節 結論 86 第二章 生命早期的酮體訊號通過 H3K9/14Ac 和 H3K9Bhb 修飾的表觀遺傳變化調節米色脂肪分化 Early life ketone body signaling in promoting beige adipogenesis via H3K9/14Ac and H3K9Bhb epigenetic modifications 87 第一節 摘要 87 第二節 前言 88 一、母奶 MCFAs 成份與調節米色脂肪發育的關聯性 88 二、新生階段的內源性酮症現象可能參與米色脂肪發育之過程 88 第三節 研究假說與實驗設計 89 第四節 材料與方法 89 一、小鼠飼養 89 二、口服葡萄糖耐受性與胰島素耐受性試驗 90 三、量化肝臟脂肪堆積程度 91 四、低溫暴露下的體溫測量 91 五、細胞分離、培養與分化 91 六、流式細胞儀和細胞收選實驗 92 七、細胞免疫螢光染色 93 八、誘發胰島素阻抗下的葡萄糖攝取試驗 93 九、慢病毒感染 93 十、粒線體 DNA 之定量 94 十一、RNA-Seq 分析 94 十二、染色質免疫沉澱（ChIP）和 qPCR 95 十三、ChIP-Seq 分析 96 十四、統計分析與數據整理 97 十五、其他試驗方法 97 第五節 實驗結果 97 一、離乳前的中鏈脂肪酸缺乏促進成年肥胖 97 二、離乳前的中鏈脂肪酸缺乏加劇成年期的胰島素阻抗及下調脂肪功能指標 99 三、生酮酵素 Hmgcs2 缺陷小鼠具有高致死率 100 四、內源性酮症缺失抑制冷暴露誘發的脂肪米色化 100 五、內源性酮症缺失所抑制的產熱作用不依賴於棕色脂肪 102 六、內源性酮症缺失的皮下脂肪上調發炎途徑與下調脂肪代謝的基因群表現 103 七、增強哺乳期生酮（EKDL）促進成年小鼠增強冷暴露下的脂肪米色化 105 八、中年小鼠誘導營養性酮症會輕微促進冷暴露下的脂肪米色化 106 九、哺乳期為米色脂肪分化的關鍵時期 107 十、酮體 βHB 在米色脂肪分化途徑中的關鍵作用 109 十一、EKDL 於脂肪前驅細胞上調米色脂肪前驅細胞指標的基因和蛋白質表現 109 十二、哺乳期血酮變化影響脂肪前驅細胞分化後的脂肪細胞代謝功能 110 十三、哺乳期血酮變化調節米色脂肪前驅細胞的數量 111 十四、高表現 CD81 的米色脂肪前驅細胞調節米色脂肪分化 112 十五、EKDL 上調脂肪前驅細胞在米色脂肪分化途徑的發生 113 十六、EKDL 抑制脂肪前驅細胞的平滑肌相關訊號之途徑 115 十七、EKDL 對脂肪前驅細胞在 Hdac 家族表現之調節影響 116 十八、ChIP-seq 實驗的剪切 DNA 片段之結果 116 十九、EKDL 脂肪前驅細胞中 H3K9/14Ac 和 H3K9Bhb 的修飾標記高比例重疊於全基因組的啟動子區域 117 二十、EKDL 脂肪前驅細胞的 H3K9/14Ac 和 H3K9Bhb 依賴的轉錄基因 118 二十一、EKDL 脂肪前驅細胞的 H3K9/14Ac 和 H3K9Bhb 依賴的轉錄基因涉及的生物途徑 119 二十二、使用 MAnorm 方法分析 EKDL 脂肪前驅細胞中 H3K9/14Ac 和H3K9Bhb依賴的轉錄基因以及相關的生物途徑 119 二十三、EKDL 脂肪前驅細胞在特定途徑中的基因組之啟動子區域被表觀遺傳標記 H3K9Ac、H3K14Ac 和 H3K9Bhb 所修飾 120 二十五、EKDL 脂肪前驅細胞在特定細胞基因指標的表觀遺傳修飾與基因表現之影響 122 二十六、EKDL 脂肪前驅細胞的 Ppargc1a、Klf9 和 Vdr 啟動子區域被 H3K9/14Ac 及 H3K9Bhb 所修飾 122 二十七、βHB 於 MEFs 上調 Pparg 及 Ppargc1a 的基因表現 123 二十八、Bdh1 維持前驅細胞內 βHB 程度並正調節 Ppargc1a 表現與米色脂肪前驅細胞的基因指標 123 二十九、βHB 於 MEFs 上調整體組蛋白乙醯化和 β-羥基丁醯化修飾程度並使 Ppargc1a 啟動子區域發生修飾 123 三十一、EKDL 調節的米色脂肪分化需依賴 Pgc-1α 途徑 125 三十二、哺乳期提高血酮濃度促進米色脂肪分化以改善成年後飲食誘導的代謝紊亂 126 第六節 討論 169 一、哺乳期酮症的生理現象 169 二、母奶的 MCFAs 成份影響哺乳期酮症的發生 170 三、常規配方奶不含有 MCFAs 171 四、1,3BD 小鼠實驗模式與人體試驗的其他貢獻 172 五、EKDL 通過表觀遺傳記憶來調節米色脂肪分化 174 六、βHB 依賴的米色脂肪分化之關鍵轉錄因子 175 七、βHB 通過 Bdh1 依賴性調節脂肪前驅細胞表現 Pgc-1α 176 八、CD81+ 米色脂肪前驅細胞 176 第七節 結論 177 第三章 親代肥胖的子代小鼠在哺乳期增強生酮作用下促進米色脂肪分化並減緩成年後的代謝紊亂 Preweaning β-hydroxybutyrate elevation attenuates predisposition to metabolic dysregulation and impairs beige fat biogenesis in offspring of parents with high-fat diet-induced obesity 178 第一節 摘要 178 第二節 前言 179 一、親代肥胖（PO）的子代在代謝紊亂的高易感性與脂肪組織發育的關聯性 179 二、藉由酮體的促米色脂肪分化作用來抵抗代高肥胖易感性的可能性 180 第三節 研究假說與實驗設計 181 第四節 材料與方法 181 一、小鼠飼養 181 二、血液分析與血壓測量 183 三、流式細胞儀 183 四、慢病毒感染 183 五、RNA-Seq 分析 184 六、統計分析與數據整理 184 七、其他試驗方法 184 第五節 實驗結果 185 一、PO 的子代（Ob 子代）有早期體重過重現象 185 二、誘導 EKDL 的 Ob 子代在成年後具有抵抗飲食誘導的肥胖 185 三、誘導 EKDL 的 Ob 子代在成年後改變各代謝參數 187 四、誘導 EKDL 的 Ob 子代在成年後改變其代謝特徵 187 五、誘導 EKDL 的 Ob 子代在成年後增強脂肪米色化作用與產熱作用 188 六、誘導 EKDL 的 Ob 子代使脂肪前驅細胞增強米色脂肪分化與功能 189 七、鑑定仔鼠與中年小鼠的皮下脂肪內米色脂肪前驅細胞數量的分群與差異性 190 八、Ob 子代經由 EKDL 恢復損害的米色脂肪前驅細胞之活性 190 九、Ob 子代損害的米色脂肪分化可以經由 EKDL 誘導改變其米色脂肪分化的基因變化 191 十、有或無誘導 EKDL的 Ob 及 Ln 子代在皮下脂肪之前驅細胞的 RNA-seq 分析並以 ORA 方法顯示出的訊息途徑 192 十一、有或無誘導 EKDL的 Ob 及 Ln 子代在皮下脂肪之前驅細胞的 RNA-seq 分析並以 GSEA 方法顯示出的訊息途徑 194 十二、有或無誘導 EKDL 的 Ln 子代在皮下脂肪之前驅細胞的 RNA-seq 分析並以熱圖顯示出受調節的轉錄因子表現之排序 194 十三、Ln 與 Ob 子代在皮下脂肪之前驅細胞的 RNA-seq 分析並以熱圖顯示出受調節的轉錄因子表現之排序 195 十四、有或無誘導 EKDL 的 Ob 及 Ln 子代在皮下脂肪之前驅細胞的 RNA-seq 分析並以熱圖顯示出受調節的轉錄因子表現之排序 196 十五、EKDL 調節 Ob 子代的脂肪前驅細胞的 Ppargc1a、Klf9 和 Vdr 基因啟動子區域被 H3K9Bhb 所修飾 196 十六、Ob 子代的脂肪前驅細胞具有較高的 Hdac3 表現量且抑制 Hdac3 表現的脂肪前驅細胞在酮體 βHB 處理下能上調米色脂肪前驅細胞的基因指標 198 十七、母乳成份可能經由影響米色脂肪發育來活化白色脂肪組織的產熱功能 198 十八、誘導 EKDL 刺激脂肪前驅細胞活化 mTOR 活性訊號 199 十九、人類脂肪幹細胞處理 βHB 對 mTOR 活性與分化脂肪細胞後對代謝功能影響 200 二十、誘導 EKDL 對於 Ob 子代在代謝功能及米色脂肪生成之影響 200 第六節 討論 227 一、PO 子代造成的代謝特徵與酮體代謝動態之變化 227 二、EKDL 誘導的 PO 子代部分改善米色分化來抵抗成年後的代謝紊亂 228 三、βHB 可能透過多種途徑促進調節米色脂肪分化 229 四、βHB 在成熟脂肪細胞中脂肪米色化的影響 230 五、PO 調節子代的白色或米色脂肪分化 231 六、βHB 作為天然 Hdac 抑制劑的潛在應用性 231 第七節 結論 232 總討論 233 第一節 本研究之新穎性 233 第二節 本研究的實驗侷限性 236 第三節 可能的延伸性研究 237 總 結 240 參考文獻 242 附 錄 - 1 - | - |
| dc.language.iso | zh_TW | - |
| dc.subject | 米色脂肪生成 | zh_TW |
| dc.subject | 酮體 | zh_TW |
| dc.subject | 哺乳期酮症 | zh_TW |
| dc.subject | 肥胖易感性 | zh_TW |
| dc.subject | APOE 基因 | zh_TW |
| dc.subject | 親代肥胖 | zh_TW |
| dc.subject | preweaning ketosis | en |
| dc.subject | beige fat biogenesis | en |
| dc.subject | parental obesity | en |
| dc.subject | APOE | en |
| dc.subject | obesity susceptibility | en |
| dc.subject | β-hydroxybutyrate | en |
| dc.title | 以小鼠模式探討酮體在米色脂肪細胞分化之作用 與抗肥胖之潛力 | zh_TW |
| dc.title | Elucidating the Role of Ketone Bodies in Beige Adipogenesis and Their Potential Anti-Obesity Effects Using Mouse Models | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 王志豪;李弘元;阮琪昌;阮麗蓉;黃青真;蔡曜聲 | zh_TW |
| dc.contributor.oralexamcommittee | Chih-Hao Wang;Hung-Yuan Li;Chi-Chang Juan;Li-Jung Juan;Ching-jang Huang;Yau-Sheng Tsai | en |
| dc.subject.keyword | 米色脂肪生成,酮體,哺乳期酮症,肥胖易感性,APOE 基因,親代肥胖, | zh_TW |
| dc.subject.keyword | beige fat biogenesis,β-hydroxybutyrate,preweaning ketosis,obesity susceptibility,APOE,parental obesity, | en |
| dc.relation.page | 296 | - |
| dc.identifier.doi | 10.6342/NTU202401070 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2024-07-28 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 生化科技學系 | - |
| 顯示於系所單位： | 生化科技學系 | |
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| ntu-112-2.pdf 未授權公開取用 | 33.84 MB | Adobe PDF |
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