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Beneficial effects of gingerenone A, a polyphenol present in ginger, on obesity and metabolic disorders : 생강의 폴리페놀 성분인 진저레논 에이의 비만과 대사성 질환 개선 효능

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dc.contributor.advisor이기원-
dc.contributor.author석수진-
dc.date.accessioned2017-07-13T17:37:45Z-
dc.date.available2017-07-13T17:37:45Z-
dc.date.issued2015-08-
dc.identifier.other000000066649-
dc.identifier.urihttps://hdl.handle.net/10371/120980-
dc.description학위논문 (박사)-- 서울대학교 대학원 : 협동과정 농업생물공학전공, 2015. 8. 이기원.-
dc.description.abstractThe World Health Organization (WHO), defines both overweight and obesity as potentially hazardous conditions of abnormal or excessive fat accumulation arising from an imbalance between energy intake and energy expenditure. Several studies have shown that excessive bodily adipose tissue is associated with metabolic disorders including type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. Therefore, the inhibition of adipose tissue expansion has been proposed as a promising strategy for the prevention and/or treatment of obesity.
Ginger is frequently used as an ingredient in nonprescription weight-loss products. Although several pharmacological effects of ginger extract on obesity and metabolic disease have been studied, the relative potencies of the major bioactive ginger compounds (6-gingerol (6G), 8-gingerol (8G), 10-gingerol (10G), 6-shogaol (6S) and gingerenone A (GA)) for the suppression of adipogenesis and lipid accumulation have not been clearly elucidated.
In the present study, I first compared the effect of the gingerols, 6S and GA on adipogenesis in 3T3-L1 preadipocytes. Our findings show that GA elicits the most potent inhibitory effect on adipogenesis in 3T3-L1 preadipocytes among the five ginger compounds. GA consistently inhibited the expression of adipogenesis- and lipogenesis-related proteins in a concentration-dependent manner. I next compared the effect of the compounds on lipid accumulation in fully differentiated 3T3-L1 adipocytes. The results revealed that only GA reduces lipid accumulation in mature adipocytes, by regulating fatty acid metabolism, showing that GA inhibits not only adipogenesis in preadipocytes but also lipid accumulation in mature adipocytes.
On the basis of these results, I further investigated the effect of GA on body weight gain induced by a high-fat diet (HFD). Consistent with the in vitro data, GA supplementation significantly attenuated HFD-induced obesity by reducing fat mass. Significant losses of fat mass can cause lipodystrophy, leading to ectopic lipid deposition, particularly in the liver. Thus, I chose to investigate serum and liver lipid profiles to examine the effect of GA on lipodystrophy. Circulating free fatty acids (FFAs) and hepatic triacylglycerol (TAG) content were ameliorated to some extent by treatment with GA when comparisons were made to the HFD-alone group. These results suggest that GA suppresses HFD-induced obesity by reducing adipose tissue mass, but does not affect lipodystrophy. To further investigate the mechanisms involved in the reduction of GA-induced fat mass, I evaluated fatty acid metabolism in epididymal adipose tissue (EWAT). The results showed that GA reduces the expression of lipolysis- and lipogenesis-related proteins, while increasing fatty acid oxidation- and mitochondrial biogenesis-related transcript levels via the activation of AMP-activated protein kinase (AMPK) in EWAT.
Adipose tissue inflammation caused by excessively hypertrophied fat mass has been closely associated with insulin resistance. I investigated whether the anti-obesity effect of GA might be influencing adipose tissue inflammation and glucose metabolism, and found that GA effectively suppressed adipose tissue inflammation by blocking macrophage recruitment and down-regulating expression of the pro-inflammatory cytokine, tumor necrosis factor α (TNF-α). Moreover, GA increased the expression levels of adiponectin, an adipokine with anti-inflammatory and insulin-sensitizing properties. Next, I examined the effect of GA on insulin resistance by conducting a hyperinsulinemic-euglycemic clamp experiment, as such effects on adipose tissue inflammation and adiponectin expression may also affect glucose metabolism. GA effectively improved glucose intolerance induced by high-fat feeding via an increase in whole-body glucose utilization.
In conclusion, I observed that GA suppressed the development of obesity and adipose tissue inflammation, while improving glucose intolerance induced by HFD in mice, highlighting GAs potential for development as a therapeutic agent for the treatment of obesity and its complications.
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dc.description.tableofcontentsChapter 1. Beneficial effects of ginger (Zingiber officinale Roscoe), on obesity and its complications: A Review 1
Abstract 2
1.1. Introduction 3
1.2. Beneficial effect of ginger and its constituents on obesity 4
1.2.1. Ginger and its constituents inhibit adipogenesis 4
1.2.2. Ginger and its constituents inhibit amylase and pancreatic lipase activity 5
1.2.3. Ginger and its constituents enhance fatty acid metabolism 6
1.3. Beneficial effects of ginger and its constituents on metabolic disorders 7
1.3.1. Ginger and its constituents improve hyperglycemia 7
1.3.2. Ginger and its constituents improve dyslipidemia 8
1.3.3. Ginger and its constituents improve obesity-related inflammation 10
1.4. Summary 11
1.5. Reference 12

Chapter 2. Gingerenone A, an active diarylheptanoid present in ginger, suppresses adipogenesis and lipid accumulation in 3T3-L1 cells 18
Abstract 19
2.1. Introduction 21
2.2. Materials and Methods 25
2.2.1. Chemicals and reagents 25
2.2.2. Cell culture and differentiation 26
2.2.3. Cell viability and cytotoxicity 26
2.2.4. ORO staining 27
2.2.5. Western blot analysis 28
2.2.6. Glycerol release 29
2.2.7. Statistical analysis 29
2.3. Results 31
2.3.1. GA exerts the most potent inhibitory effect on MDI-induced adipogenesis in 3T3-L1 preadipocytes among five bioactive compounds present in ginger 31
2.3.2. GA suppresses adipogenesis and down-regulates expression levels of adipogenic and lipogenic proteins 35
2.3.3. GA suppresses lipid accumulation in 3T3-L1 mature adipocytes 38
2.4. Discussion 43
2.5. Reference 46
Chapter 3. Gingerenone A suppresses high-fat diet-induced obesity in mice 52
Abstract 53
3.1. Introduction 54
3.2. Materials and Methods 57
3.2.1. Chemicals and reagents 57
3.2.2. Experimental animals and diets 57
3.2.3. Serum and liver biochemical analysis 58
3.2.4. Hematoxylin and eosin staining and adipocyte cell size assessment 59
3.2.5. Quantitative real-time polymerase chain reaction analysis 59
3.2.6. Immunoblotting 60
3.2.7. Statistical analysis 61
3.3. Results 62
3.3.1. GA attenuates HFD-induced body weight gain in mice 62
3.3.2. GA reduces HFD-induced enlarged fat mass by reducing adipocyte size 66
3.3.3. GA decreases circulating FFA levels. 71
3.3.4. GA regulates fatty acid metabolism and mitochondrial biogenesis via activation of AMPK in EWAT 74
3.4. Discussion 82
3.5. Reference 85

Chapter 4. Gingerenone A suppresses adipose tissue inflammation and improves glucose intolerance in mice fed with a high-fat diet 89
Abstract 90
4.1. Introduction 91
4.2. Materials and Methods 94
4.2.1. Chemicals and reagents 94
4.2.2. Culture of macrophages and 3T3-L1 adipocytes 94
4.2.3. Trans-well migration assay 95
4.2.4. Co-culture of adipocytes and macrophages 95
4.2.5. Quantitative real-time polymerase chain reaction (qRT-PCR) 96
4.2.6. Western blot analysis 97
4.2.7. Histological analysis 98
4.2.8. Experimental animals and diets 98
4.2.9. Intraperitoneal glucose tolerance test 100
4.2.10. Hyperinsulinemic-euglycemic clamp to assess insulin action in vivo 100
4.2.11. Biochemical analysis and calculation 101
4.2.12. Statistical analysis 102
4.3. Results 103
4.3.1. GA suppresses macrophage recruitment and modulates pro-inflammatory adipokines expression in vitro 103
4.3.2. GA administration inhibits HFD-induced macrophage infiltration into adipose tissue 107
4.3.3. GA reduces adipose tissue inflammation by regulating adipokines 111
4.3.4. GA improves glucose intolerance induced by HFD 114
4.4. Discussion 120
4.5. Reference 124

국문초록 128
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dc.formatapplication/pdf-
dc.format.extent2286557 bytes-
dc.format.mediumapplication/pdf-
dc.language.isoen-
dc.publisher서울대학교 대학원-
dc.subjectGingerenone A-
dc.subjectobesity-
dc.subjectadipose tissue inflammation-
dc.subjectglucose intolerance-
dc.subjectfatty acid metabolism-
dc.subject.ddc660-
dc.titleBeneficial effects of gingerenone A, a polyphenol present in ginger, on obesity and metabolic disorders-
dc.title.alternative생강의 폴리페놀 성분인 진저레논 에이의 비만과 대사성 질환 개선 효능-
dc.typeThesis-
dc.contributor.AlternativeAuthorSujin Suk-
dc.description.degreeDoctor-
dc.citation.pagesix, 132-
dc.contributor.affiliation농업생명과학대학 협동과정 농업생물공학전공-
dc.date.awarded2015-08-
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