臺灣博碩士論文加值系統

肥胖已成為一個引人關注的全球公共衛生問題。穴位埋線治療（ACET）是一種新興的針灸療法，在減重方面受到歡迎。近來肥胖也被認為是一種炎症性疾病。研究已經證實，連續四周皮下注射大腸桿菌分泌的脂多醣（LPS）的小鼠會在這些小鼠中引起低度炎症導致肥胖。以前的研究曾報導一例ACET導致局部感染和治療後結節形成。了解ACET在LPS誘導的炎症中的作用是抑制還是促進也是對於穴位埋線安全性一項重要的研究。本研究的目的是通過雙盲，隨機和對照臨床試驗研究ACET對肥胖，脂質和相關激素的治療效果。LPS誘導的敗血症性休克模型也用於檢測ACET的安全性和ACET在炎症中的作用。
在臨床試驗中，治療組中40名受試者和40名對照組受試者完成了研究。治療組的參與者每週一次接受ACET，總治療時間為6週，以及偽ACET組。我們的研究顯示ACET可將體重從78.3±12.1公斤降至76.6±12.2公斤（p <0.001），腰圍從96.6±10.2公分降至91.7±11.2公分（p <0.001）。另外，埋線後甘油三酯水平從162.3±99.9 mg/dL明顯降低至142.7±92.9 mg/dL（p = 0.035）。相反的，偽ACET組在人體測量和生化數據方面沒有顯示出差異。在肥胖相關激素肽中，ACET組顯示瘦素水平和瘦素與脂聯素比率顯著降低。我們的研究表明，ACET可通過改善肥胖婦女的瘦素抵抗來減輕中心性肥胖婦女的體重和腰圍，並降低三酸甘油酯水平。
在動物實驗裡，我們也連續兩週給予ACET，然後在小鼠中給予LPS誘導敗血性休克。我們證明，ACET可以通過抑制NFκB信號途徑減弱LPS誘導的急性炎症基因表達，並上調IL-10等抗炎基因的表達。此外，經穴位埋線治療的小鼠再接受LPS誘導敗血症的存活率顯著提高，不僅由於炎性基因表達降低，而且也通過保存下丘腦AMP-活化蛋白激酶（AMPK）蛋白活性和肝磷酸烯醇式丙酮酸羧激酶（PEPCK）活性預防LPS誘導的低血糖症。
由上研究可證明，ACET是一種安全且節省時間的肥胖治療方法，可能是解決代謝紊亂患病率的新型替代方案。

Obesity has become a noticeable and worldwide public health problem recently. Recently, acupoint catgut embedding treatment (ACET), an extensive form of acupuncture, has become popular in weight reduction. Obesity has also been recognized recently as an inflammatory disease. It was demonstrated that mice injected with lipopolysaccharide (LPS) secreted from E. Coli subcutaneously for four consecutive weeks would cause a low degree of inflammation in these mice that lead to obesity. Previous study has reported a case of ACET resulted in local infection and tender nodule formation after treatment. Therefore, it is also important to find out the effect of ACET in LPS-induced sepsis is either attenuated or increased. The aim of this study is to investigate the therapeutic effects of ACET on obesity, lipid and related hormone peptides by a double-blinded, randomized and controlled clinical trial. In addition, LPS-induced septic shock model is also applied for examining the safety of ACET and the effect of ACET in inflammation.
In the clinical trial, 40 subjects in therapeutic arm with 40 subjects in control arm completed the study. Participants in therapeutic arm received ACET once a week with total treatment time 6 weeks as well as sham ACET group. Our study showed ACET can reduce weight from 78.3±12.1kg to 76.6±12.2kg（p<0.001）with waist circumference reduction from 96.6±10.2 to 91.7±11.2cm(p<0.001). Besides, triglyceride level obviously decreased from 162.3±99.9 mg/dL to 142.7±92.9 mg/dL (p=0.035) after catgut embedding. The sham group didn’t show difference in both anthropometric measurements and biochemical data. In obesity-related hormone peptide, ACET groups showed significant reduction in leptin level and leptin to adiponectin ratio. Our study demonstrated that ACET may reduce weight and waist circumference with triglyceride level in obese women through improving leptin resistance.
In addition, ACET was applied weekly twice before giving LPS induction in mice. We demonstrated that advanced performing ACET could attenuate LPS induced acute inflammatory gene expressions via NF-kB signaling and up-regulate anti-inflammatory gene expression such as IL-10. In addition, embedded mice are all survived from LPS induce mortality, due to not only decrease of inflammatory gene expression, but also prevention of LPS-induced hypoglycemia by preservation of hypothalamus AMP-activated protein kinase (AMPK) protein and hepatic phosphoenolpyruvate carboxykinase (PEPCK) protein levels.
ACET is a safe and time-saving treatment for obesity and could be a novel and alternative answer for solving the prevalence of metabolic disorders.

Content...........................................I
ABSTRACT...................................................................................................VI
中文摘要...................................................................................................VIII
List of Abbreviations......................................................................................X
List of Figures............................................................................................XII
List of Tables.............................................................................................XIII
Chapter 1 Introduction.....................................................................................1
1.1 Introduction of obesity................................................................................1
1.1.1 Definition of obesity................................................................................1
1.1.2 Prevalence of obesity................................................................................2
1.1.3 Etiology of obesity..................................................................................4
1.1.4 Relationship between obesity and obesity-related hormone.............................................6
1.1.5 Relationship between obesity and inflammation........................................................9
1.1.6 Lipopolysaccharide and inflammation..................................................................11
1.1.7 Anti-inflammatory agents and metabolic syndrome......................................................12
1.2 Introduction of obesity in view of traditional Chinese medicine........................................13
1.3 Introduction of complementery and alternative medicine application in obesity..........................15
1.3.1 Mechanism of acupuncture in treating obesity.........................................................16
1.4 Introduction of Acupoint Catgut Embedding Treatment (ACET).............................................19
1.4.1 Introduction of ACET history.........................................................................19
1.4.2 Introduction of ACET application in disease..........................................................20
1.4.3 Introduction of ACET application in obesity..........................................................21
1.4.4 Mechanism of ACET in obesity.........................................................................22
1.4.5 Relation between ACET and inflammation...............................................................23
1.5 Study motivation and aim of the study..................................................................24
1.5.1 Study motivation.....................................................................................24
1.5.2 Aim of the study.....................................................................................25
Chapter 2 Methods and Measurement..........................................................................26
2.1 Therapeutic effect of ACET in obesity..................................................................26
2.1.1 Study design and participants........................................................................26
2.1.2 Power calculation and sample size....................................................................27
2.1.3 Randomization and blindness..........................................................................28
2.1.4 ACET protocol........................................................................................28
2.1.5 ACET preparation.....................................................................................30
2.1.6 Primary outcome measurements.........................................................................30
2.1.7 Analysis of biochemical data and obesity-related hormone peptides....................................30
2.1.8 Measurement of quality of life.......................................................................32
2.1.9 Traditional Chinese Medicine constitution analysis of obese women....................................32
2.1.10 Statistical analysis................................................................................33
2.2 Part 2 ACET effect in lipopolysaccharide-induced septic shock..........................................33
2.2.1 Animal handling and procedures for ACET..............................................................33
2.2.2 LPS treatment and survival rate analysis.............................................................34
2.2.3 Pyruvate tolerance test..............................................................................35
2.2.4 Tissue sample collection.............................................................................35
2.2.5 Real-time RT-PCR.....................................................................................35
2.2.6 Western blotting.....................................................................................37
2.2.7 Cytokine protein array...............................................................................37
2.2.8 Statistics...........................................................................................38
Chapter 3 Results..........................................................................................39
3.1 Therapeutic effect of ACET in abdominally obese women..................................................39
3.1.1 Study participants recruitment.......................................................................39
3.1.2 ACET significantly reduces body weight and waist circumference in abdominally obese women............39
3.1.3 Blood triglyceride levels significantly decline after ACET...........................................41
3.1.4 Leptin to adiponectin ratio decreases in abdominally obese women following ACET......................41
3.1.5 ACET is more effective in reducing waist circumference...............................................42
3.1.6 Quality of life scores improve in obese women after ACET.............................................42
3.1.7 Distribution of TCM syndrome in obese women..........................................................43
3.1.8 Possible side effects of adverse events occur during treatment.......................................43
3.2 ACET effect on lipopolysaccharide-induced sepsis.......................................................44
3.2.1 ACET preserved mice survival after lipopolysaccharide-induced septic shock...........................44
3.2.2 LPS-stimulated inducible nitric oxide synthase gene expression via NF-kB signaling was attenuated by ACET..44
3.2.3 ACET treatment modulates the levels of LPS induced inflammatory response in the liver................45
3.2.4 Effects of ACET on serum inflammation cytokine profiles in the presence of LPS.......................46
3.2.5 Modulation of hypothalamus AMPK and hepatic PEPCK protein levels by ACET.............................47
Chapter 4 Discussion.......................................................................................48
4.1 Therapeutic effect of ACET in abdominally obese women..................................................48
4.1.1 ACET reduces body weight significantly in obese women ...............................................48
4.1.2 ACET improves abdominal obesity better than eletroacupuncture........................................49
4.1.3 ACET has lipid-lowering effect in obese women........................................................50
4.1.4 ACET has the potential of improving insulin resistance in obese women................................50
4.1.5 Leptin resistance can be improved by ACET............................................................51
4.1.6 ACET may decrease metabolic syndrome development by improving leptin to adiponectin ratio............52
4.1.7 ACET is a safe treatment in treating obesity.........................................................53
4.1.8 Spleen qi deficiency and liver qi stagnation are the most prevalent TCM syndrome groups in obese women 53
4.1.9 ACET is a safe and timesaving treatment for obesity..................................................55
4.2 ACET effect on lipopolysaccharide-induced septic shock.................................................55
4.2.1 ACET pretreatment could decrease the mortality rate of LPS-induced septic shock......................55
4.2.2 LPS stimulated inducible nitric oxide synthase gene expression via NFB signaling was attenuated by ACET.56
4.2.3 ACET possesses antinflammatory effect by upregulating anti-inflammatory cytokine gene IL-10 expression....57
4.2.4 TNF-alpha gene expression all revealed attenuation after LPS treatment with or without ACET..........58
4.2.5 ACET attenuates SOCS family expression which might be due to less inflammatory cytokine stimuli......59
4.2.6 ACET reduced inflammatory cytokine secretion and increased anti-inflammatory cytokine secretion......60
4.2.7 ACET prevents LPS-induced hypoglycemia by preservation of hypothalamus AMPK and hepatic PEPCK protein levels.60
4.3 Future work............................................................................................62
Chapter 5 Conclusion.......................................................................................63
References.................................................................................................65
Figures....................................................................................................75
Tables.....................................................................................................92
Appendix..................................................................................................101
Supplementary Figure 1:台北市立聯合醫院人體試驗委員會計畫執行許可書.......................................101
Supplementary Figure 2:美國臨床試驗註冊網站登錄資料.......................................................102
Supplementary Table 1:臺北市立聯合醫院中醫醫療部肥胖患者中醫體質證型問卷..................................103
Supplementary Table 2:WHO 生活品質量表....................................................................107
Supplementary Table 3: Informed consent form..............................................................108
Publication during Ph.D program............................................114

List of Figures
Figure 1: ACET protocol and survival rate analysis……………………………75
Figure 2: Trial profile and design………………………………………………………………77
Figure 3: Distribution of Chinese Medicine syndrome in obese women………………………………………………………………………………………………………………..78
Figure 4: The effect of ACET on LPS-mediated NF-B signaling activation and inducible nitric oxide (iNOS2) gene upregulation..…..80
Figure 5: ACET modulates the levels of LPS-induced IL-10 and SOCS (1-3) gene expression in the liver………………………………….………………..82
Figure 6: Effect of ACET on the serum cytokine profiles in response to LPS treatment………………………………………………………………………………………………85
Figure 7: ACET attenuates LPS-induced hypoglycemia via the modulation of hepatic PEPCK and hypothalamus AMPK protein levels…………………………………………………………………………………………………………………….88
Figure 8: A summary of dual beneficial effects of ACET on LPS induced septic shock………………………………………………………………………………………..91
List of Tables
Table 1: Demographic data of participants ……………………………………………92
Table 2: Within-group anthropometric, blood pressure, and laboratory data at baseline and after 6 weeks …………………………………….…93
Table 3: Obesity-related hormone at baseline and after 6 weeks………94
Table 4: The difference in anthropometric, blood pressure, and laboratory data at baseline and after 6 weeks ………………………………………..95
Table 5: Life quality scores change after catgut embedding treatment…………………………………………………………………………………………………………….96
Table 6: Within-group anthropometric, blood pressure, and laboratory data in patients with and without qi deficiency………………..97
Table 7: Within-group anthropometric, blood pressure, and laboratory data in patients with and without qi stagnation………………..98
Table 8: Comparison in life quality scores between patients with and without qi deficiency……………………………………………………………………………………….99
Table 9: Comparison in life quality scores between patients with and without qi stagnation…………………………………………………………………………………....100

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