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系統識別號 U0026-3007201713190200
論文名稱(中文) 肥胖,脂聯素,與梗塞型腦中風預後 從實驗室到床邊—基礎與臨床研究
論文名稱(英文) Obesity, Adiponectin and Prognosis of Ischemic Stroke From Bench to Beside—Basic and Clinical Studies
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 105
學期 2
出版年 106
研究生(中文) 吳明修
研究生(英文) Ming-Hsiu Wu
學號 S98971071
學位類別 博士
語文別 英文
論文頁數 111頁
口試委員 指導教授-黃朝慶
指導教授-蔡坤哲
召集委員-蔡曜聲
口試委員-陳志弘
口試委員-邱仲慶
口試委員-張菁萍
口試委員-許重義
中文關鍵字 缺血性腦中風  肥胖  過重  身體質量指數  肥胖弔詭  存活  功能性預後  缺血性腦損傷  脂聯素  脂聯素受體  p38絲裂原活化蛋白激酶  飲食誘導肥胖  中大腦動脈梗塞  桿狀病毒 
英文關鍵字 ischemic stroke  obesity  overweight  body mass index (BMI)  obesity paradox  survival  functional outcome  ischemic cerebral injury  adiponectin (APN)  adiponectin receptor (AdipoR)  p38 MAPK  diet-induced obesity (DIO)  middle cerebral artery occlusion (MCAO)  baculovirus 
學科別分類
中文摘要 腦中風是全球死亡的第二大原因。肥胖是一個全球性的健康問題,肥胖增加了死亡,心血管疾病,與糖尿病的風險,並且是已知的腦中風危險因子。肥胖是身體的一種慢性炎症狀態,它伴隨有被活化的免疫細胞,較高的促發炎細胞因子,且會加劇缺血性腦損傷。
弔詭的是,相較於正常體重,過重和肥胖有較佳的生存預後,也被稱為肥胖弔詭。但研究結果顯示,肥胖弔詭於急性腦中風的預後並不一致,甚至相反。另一問題是,是否較低的死亡率會帶來較佳的功能性預後。
由脂肪組織分泌的脂聯素,是最強效的抗發炎脂肪細胞因子,具血管保護作用能抵抗動脈硬化。脂聯素的表達會因肥胖下降。脂聯素似乎不會增加腦中風風險。關於脂聯素和腦中風死亡的風險,現有的證據是相互矛盾的;對於功能性預後則不一致。
我論文的目的即為探討肥胖與脂聯素在缺血性腦中風所扮演的角色。
首先,於實驗室先以飲食誘導肥胖的大鼠接受大腦中動脈栓塞。而以桿狀病毒介導的脂聯素表現前處理,能減少因肥胖加劇的腦缺血損傷,為經由下調脂聯素受體1,上調脂聯素受體2,下調p38絲裂原活化蛋白激酶與胱天蛋白酶3,並以減輕腦梗塞範圍,神經功能缺損,腦血屏障破壞,與神經凋亡來表現。
其次,利用台灣中風登錄資料庫,以身體質量指數分層,分析19069位初次缺血性腦中風病人,發現體重與缺血性腦中風預後相關。且肥胖弔詭被部分證實在亞洲初次缺血性腦中風病人身上。與正常體重相較,僅過重,而非肥胖,有較佳的生存與功能性預後。過輕則死亡率上升且功能預後不佳。
最後,測量並分析229位因急性缺血性腦中風病人的血清脂聯素濃度,發現入院時高脂聯素血症有較差的3與12個月預後。若進一步測量其亞型,發現低血清高分子量脂聯素有較差的1,3,6與12個月預後。高血清球型脂聯素有較差的6個月預後。
我相信,由這些工作得到的結果,可以幫助釐清肥胖與脂聯素在腦缺血損傷的病理生理機轉,並為體重於急性缺血性腦中風照護提供做為臨床介入的線索。
英文摘要 Stroke is the second leading cause of death worldwide. Obesity is a pandemic health problem in the world, known to be associated with increased risk of death, cardiovascular disease, and diabetes mellitus, and a recognized risk factor for stroke.
Obesity is a chronic inflammatory status for the body, associated with activated immune cells and increasing pro-inflammatory cytokines, and could exacerbate ischemic cerebral injury.
Paradoxically, overweight and obesity are related to better survival benefit than normal weight which is termed as obesity paradox. It has been studied in acute stroke with inconsistent even conflicting results. Another question is whether the decreased mortality could lead to improved functional outcome.
Adiponectin (APN), secreted by adipose tissue, is the most anti-inflammatory adipokine and vasoprotective against atherosclerosis. The expression of adiponectin is dowregulated in obesity. Adiponectin seems not to increase stroke risk. Results from studies in assessing circulating adiponectin concentrations and the risk of stroke mortality are conflicting, and inconsistent in its relationship with functional outcome.
The aim of my thesis is to investigate the role of obesity and adiponectin in the pathogenesis and prognosis of ischemic stroke.
In the bench work, diet-induced obesity (DIO) rats received middle cerebral artery occlusion (MCAO). Pre-treatment with intra-striatal delivery of baculovirus-mediated APN expression reduced cerebral ischemic injury aggravated by obesity through down-regulation of adiponectin receptor 1 (AdipoR1) and up-regulation of adiponectin receptor 2 (AdipoR2), and down-regulation of p38 MAPK and caspase-3, as evidenced by reduced infarction volume, neurological deficits, blood-brain-barrier damage, and neuronal apoptosis.
With data from the Taiwan Stroke Registry (TSR), 19,069 first-ever acute ischemic stroke patients were recruited and stratified by body mass index (BMI), and it was found that body weight was related to the prognosis of acute ischemic stroke. Obesity paradox was partially demonstrated in Asian first-ever ischemic stroke patients. Only overweight, but not obese patients showed improved survival and functional outcome after stroke, when compared with the normal weight. Underweight had increased mortality and decreased functional outcome.
Clinically, 229 patients were recruited in Chi-Mei Medical Center, Liouying, and it was showed that admission hyperadiponectinemia was related to worse prognosis 3 and 12 months after acute ischemic stroke. With measurement of APN isoforms, low admission serum high molecular weight APN was related to worse prognosis 1, 3, 6 and 12 months after acute ischemic stroke. Also, high serum admission globular form APN was related to worse prognosis 6 months after acute ischemic stroke.
I believe that results from these works could help to elucidate mechanisms of obesity and APN in cerebral ischemic injury and provide evidence in relating body weight to clinical care of acute ischemic stroke.
論文目次 Chapter 1 Introduction 1
1.1 Obesity……….. 2
1.1.1 Prevalence 2
1.1.2 Definitions 2
1.1.3 Obesity and Inflammation: “inflamed” adipose tissue 3
1.1.4 Obesity and Cerebral Ischemic Injury 4
1.1.5 Obesity and Increased Risk of Morbidities and Mortality in General Population 5
1.1.6 Obesity and Increased Risk of Stroke 5
1.1.7 Obesity Paradox 6
1.1.8 Obesity Paradox and Stroke Outcome 6
1.2 Adiponectin…… 9
1.2.1 Structure and Biosynthesis 9
1.2.2 Physiological and Pathophysiological Roles in Human Diseases 9
1.2.3 Adiponectin and Cerebral Ischemic Injury 10
1.2.4 Adiponectin and Risk of Stroke 12
1.2.5 Expression Profiles of Adiponectin in Ischemic Stroke 12
1.2.6 Adiponectin and Prognosis of Ischemic Stroke 13
1.3 Adiponectin Receptors 15
1.3.1 Adiponectin Receptors in Cerebral Ischemic Injury: detrimental role of AdipoR1 activation 15
1.4 p38 and Cerebral Ischemic Injury 16
1.5 Thesis Aims…… 16

Chapter 2. Adiponectin alleviates cerebral ischemic injury aggravated by obesity through modulation of adiponectin receptors-p38 MAPK pathways 18
2.1 Background…… 18
2.2 Aims…………… 19
2.3 Materials and Methods 19
2.3.1 Subjects and Experimental Conditions 19
2.3.2 Ethics Statement 20
2.3.3 Animals and Stroke Model 20
2.3.4 Experimental Groups 20
2.3.5 Intrastriatal Injection of Recombinant Baculovirus Expressing Adiponectin… ……….21
2.3.6 Modified Neurological Severity Scores (NSS) 23
2.3.7 Western Blot 23
2.3.8 Immunofluorescence Staining 24
2.3.9 Cerebral Infarction Assessment 25
2.3.10 Evans Blue Extravasation 25
2.3.11 Brain Water Contents 26
2.3.12 Statistical Analysis 26
2.4 Results………… 26
2.4.1 Increasing Percentages of DAPI-NeuN-APN Specific Cells in Ischemic Brain Tissues by MCAO or Intracerebral Injection of Baculovirus-Mediated APN… 26
2.4.2 Increasing Percentages of APN-Containing Neurons Attenuates MCAO-Induced Infarct Size, Neurologic Deficits, and Brain Edema 27
2.4.3 Increasing Percentages of APN-Containing Neurons Reduces MCAO-induced Neuronal Apoptosis 28
2.4.4 Increasing Percentages of APN-Containing Neurons Attenuates MCAO-Induced Up-Regulated Expression of both AdipoR1 and p38 MAPK Proteins and Down-Regulated Expression of AdipoR2 28
2.5 Discussion…….. 30
2.6 Conclusion……. 32
Chapter 3. Body weight are related to the prognosis of acute ischemic stroke—obesity paradox: only the overweight, but not the obese have better survival and functional outcome than the normal weight 51
3.1 Background…… 51
3.2 Aim……………. 52
3.3 Patients and Methods 52
3.3.1 Data Source 52
3.3.2 Data Collection 53
3.3.3 Outcome Measures 53
3.3.4 Statistical Analysis 54
3.4 Results………… 54
3.4.1 Demographic and clinical characteristics in study subjects 54
3.4.2 Comparison of mortality among four BMI categories 55
3.4.3 Comparison of functional outcome among four BMI categories 56
3.4.4 Comparison of mortality among four BMI categories by admission NIHSS score… 57
3.4.5 Comparison of functional outcome among four BMI categories by admission NIHSS score 57
3.4.6 Odds ratio for outcome by BMI levels 58
3.5 Discussion…….. 58
3.6 Conclusion……. 63
Chapter 4. Blood adiponectin levels are related to the prognosis of acute ischemic stroke—total and isoforms all matter but differ 71
4.1 Background…… 71
4.2 Aim……………. 72
4.3 Patients and Methods 73
4.3.1 Patients 73
4.3.2 Data Collection 73
4.3.3 Adiponectin Measurement 73
4.3.4 Outcome Assays 74
4.3.5 Statistical Analysis 74
4.4 Results………… 75
4.4.1 High admission serum total APN was associated with unfavorable outcome after acute ischemic stroke. 75
4.4.2 Low admission serum HMW APN was associated with unfavorable outcome after acute ischemic stroke. 75
4.4.3 High admission serum globular APN was associated with unfavorable outcome after acute ischemic stroke. 76
4.5 Discussions…… 76
4.6 Conclusion……. 78
Chapter 5 General discussions, conclusions, and future perspectives 84
5.1 General Discussions 84
5.2 Conclusions…… 86
5.3 Future Perspectives 89
5.3.1 Repression of APN-AdipoR1 axis and activation of APN-AdipoR2 axis in cerebral ischemic injury 89
5.3.2 Body weight and prognosis of ischemic stroke: influence in secondary stroke and role of “pre-stroke” obesity 89
5.3.3 Adiponectin and isoforms as biomarkers in acute ischemic stroke 90
Bibliography 96
Thesis-Related Publications 109
Publications during graduate program 110

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