Ameliorating Effects of Edible Sargassum fulvellum on HFD/STZ-Induced Type II Diabetes Model: Anti-Diabetic, Anti- Obesity, and Preventing Non-Alcoholic Fatty Liver Disease
- Alternative Title
- HFD/STZ 유발 제2형 당뇨병 모델에 대한 식용 Sargassum fulvellum의 개선 효과: 항당뇨병, 항비만 및 비알코올성 지방간 질환 예방
- Abstract
- 제2형 당뇨병(T2DM), 비만, 비알코올성 지방간 질환(NAFLD)과 같은 대사성 질환은 인슐린 저항성, 만성 염증, 대사 기능 장애와 밀접하게 연관된 상호 연결된 상태입니다. 본 연구는 Sargassum fulvellum 에틸 아세테이트 추출물(SF-ETAC)의 다중 표적 치료 가능성을 탐구하였습니다. SF-ETAC는 DPP-IV와 α-Glucisdase의 활성을 유의미하게 억제하고, GLP-1 활성을 증진시키며, 췌장 베타 세포 기능을 개선하고, SGLT1과 GLUT2와 같은 포도당 수송 단백질을 조절하여, 당뇨병 모델에서 포도당 내성과 인슐린 감수성을 개선하였으며, 이는 메트포르민과 유사한 효능을 보였습니다. 추가적으로, SF-ETAC는 AMPK를 활성화하고, PPARγ와 SREBP-1의 발현 억제를 통해 지방 형성을 억제하며, 지질 분해를 촉진하고, 갈색 지방 조직(BAT)의 기능을 보존하여 비만을 효과적으로 개선하였습니다. 또한, 염증성 사이토카인과 MAPK 경로 활성을 억제하여 전신 염증을 감소시켰습니다. NAFLD 모델에서는 간 DPP-IV 활성을 억제하고, 간 기능을 개선하며, 지방 생성 단백질 발현을 감소시키고, 지방산 산화를 촉진하였습니다. SF-ETAC의 생리활성 화합물인 fucosterol은 포도당 조절과 항염증 효과를 더욱 증폭시켰습니다. 이러한 연구 결과는 SF-ETAC가 T2DM, 비만 및 NAFLD의 다면적인 특성을 해결하며, 대사 증후군에 대해 보다 안전하고 통합적인 접근 방식을 제공하는 천연적이고 지속 가능한 치료제로서의 가능성을 제시합니다.
키워드: Sargassum fulvellum, DPP-IV 억제, AMPK 활성화, GLP-1, 대사 증후군, NAFLD, 비만, 당뇨병.|Metabolic disorders like T2DM, obesity, and NAFLD are interconnected conditions linked to insulin resistance, chronic inflammation, and metabolic dysfunction. This study explores the multi-targeted therapeutic potential of Sargassum fulvellum ethyl acetate extract (SF-ETAC). SF-ETAC significantly inhibited DPP-IV and α-glucosidase, enhanced GLP-1 activity, improved pancreatic β-cell function, and regulated glucose transport proteins (SGLT1, GLUT2), improving glucose tolerance and insulin sensitivity in diabetic models, with efficacy comparable to metformin. Additionally, SF-ETAC addressed obesity by activating AMPK, suppressing adipogenesis via PPARγ and SREBP-1 downregulation, promoting lipolysis, and preserving brown adipose tissue (BAT) function. It reduced systemic inflammation by lowering pro-inflammatory cytokines and MAPK pathway activity. In NAFLD models, SF-ETAC improved liver function, suppressed hepatic DPP-IV activity, reduced lipogenesis, and enhanced fatty acid oxidation. Fucosterol, a bioactive compound in SF-ETAC, further amplified glucose regulation and anti-inflammatory effects. These findings position SF-ETAC as a natural, sustainable therapeutic for metabolic syndrome, addressing the multifactorial nature of T2DM, obesity, and NAFLD with a safer and more integrative approach.
Keywords: Sargassum fulvellum, DPP-IV inhibition, AMPK activation, GLP-1, metabolic syndrome, NAFLD, obesity, diabetes.
- Issued Date
- 2025
- Awarded Date
- 2025-02
- Type
- Dissertation
- Publisher
- 국립부경대학교 일반대학원
- Affiliation
- 국립부경대학교 대학원
- Department
- 대학원 식품생명과학과
- Advisor
- Jae-Young Je
- Table Of Contents
- Chapter I. Introduction 1
I.1 Overview and significance 1
I.2 Type II diabetes mellitus (T2DM) 3
I.3 T2DM and obesity 5
I.4 T2DM and NAFLD 7
I.5 DPP-IV 8
I.6 Sargassum fulvellum 9
I.7 Hypothesis and objective 12
I.8 References 14
Chapter II. Sargassum fulvellum Ethyl Acetate Extract Improves Glucose Homeostasis and Pancreatic Function in HFD/STZ-Induced Diabetic Mice via Glucose Transport and DPP-IV Inhibition 18
II.1 Introduction 19
II.2 Methodology 21
II.2.1 Materials 21
II.2.2 Enzyme inhibition assay 22
II.2.3 Compound identification of SF-ETAC 23
II.2.4 Total phenolic compound and total flavonoids compound 24
II.2.5 Caco2 cell culture 25
II.2.6 Cytotoxicity assay 25
II.2.7 α-Glucosidase and DPP-IV inhibition on Caco-2 cell 25
II.2.8 Glucose uptake in Caco2 cells 26
II.2.9 HFD/STZ induced diabetic mouse model and treatment 27
II.2.10 Glucose and insulin tolerance test 29
II.2.11 Histology and immunostaining of pancreas 29
II.2.12 Western blot analysis. 30
II.2.13 Statistical analysis 31
II.3 Result 32
II.3.1 Enzymatic inhibition evaluation from SF with various solvent. 32
II.3.2 SF-ETAC compound identification using GC/MS and LC/MS-MS 35
II.3.3 SF-ETAC suppresses carbohydrate digestion and glucose absorption via α-glucosidase and transport protein inhibition 37
II.3.4 SF-ETAC inhibit DPP-IV enzyme activity and upregulate incretin hormone production in Caco2 cell monolayer 41
II.3.5 SF-ETAC improves glucose metabolism and insulin sensitivity in HFD/STZ mouse model 43
II.3.6 Evaluation of glucose-digestion enzyme activity and glucose transport protein in mouse intestine 46
II.3.7 Evaluation of DPP-IV enzyme inhibition and GLP-1 activity in mouse intestine 48
II.3.8 SF-ETAC protect pancreas islet and function 50
II.3.9 Molecular docking against DPP-IV 52
II.4 Discussion 55
II.5 Conclusion 58
II.6 References 59
Chapter III. The Effect of DPP-IV Inhibition on Adiposity: Insights from Sargassum fulvellum Ethyl Acetate Extract Treatment in Cellular and Animal Models 63
III.1 Introduction 64
III.2 Methodology 66
III.2.1 Materials 66
III.2.2 Animals, treatment and collection 66
III.2.3 Lipid profile analysis in serum and cell medium 67
III.2.4 Histology staining 67
III.2.5 Cell culture, cytotoxicity, and adipogenesis differentiation 67
III.2.6 Adipogenesis determination by oil red o staining 68
III.2.7 Determination of intracellular ROS 68
III.2.8 Determination of antioxidant enzyme activities 69
III.2.9 Measurement of DPP-IV activities in 3T3-L1 and mouse WAT 69
III.2.10 Pro-inflammatory cytokines evaluation 70
III.2.11 Western blot analysis 70
III.2.12 Data analysis 70
III.3 Result 71
III.3.1 DPP-IV activity in 3T3-L1 pre-adipocyte, after SE-ETAC treatment 71
III.3.2 SF-ETAC reduce lipid accumulation in 3T3-L1 pre-adipocytes 73
III.3.3 SF-ETAC improve lipolysis, and improve thermogenic protein in 3T3-L1 pre- adipocytes 75
III.3.4 SF-ETAC regulate ROS and inflammation generated by adipogenesis 77
III.3.5 SF-ETAC inhibit DPP-IV and increasing incretin in mouse WAT 79
III.3.6 Effect of DPP-IV inhibition on adipose tissue enhancement and lipid accumulation in HFD/STZ-induced diabetic mice 81
III.3.7 DPP-IV inhibition prevent whitening in brown adipose tissue and in 3T3-L1 cell 84
III.3.8 SF-ETAC oral administration regulate obesity-related inflammation 86
III.4 Discussion 88
III.5 Conclusion 92
III.6 References 93
Chapter IV. Oral Administration of Sargassum fulvellum Ethyl Acetate Extract Alleviates Non-Alcoholic Fatty Liver Disease and Inflammation by Suppressing Hepatic DPP-IV in a Diabetic Mouse Model 96
IV.1 Introduction 97
IV.2 Methodology 99
IV.2.1 Materials 99
IV.2.2 Cell culture, cell viability and induction of steatosis 99
IV.2.3 Oil red o staining 100
IV.2.4 Animals, treatment and collection 100
IV.2.5 Determination of lipid and biochemical profile 101
IV.2.6 Liver histology 101
IV.2.7 Western blot analysis 101
IV.2.8 Data analysis 102
IV.3 Result 102
IV.3.1 Effect of DPP-IV inhibition and mouse liver injury 102
IV.3.2 Liver morphology and lipid accumulation analysis 105
IV.3.3 Analysis of lipid metabolism proteins in liver tissue 107
IV.3.4 In vitro validation of SE-ETAC and fucosterol effects on HepG2 cells 109
IV.3.5 Hepatoprotective effects of SE-ETAC and fucosterol in HepG2 cells 111
IV.3.6 Mechanistic insights into lipid droplet reduction in HepG2 cells 113
IV.3.7 SF-ETAC and fucosterol improve glucose uptake in diabetic mouse and insulin-resistant HepG2 cells 115
IV.4 Discussion 117
IV.5 Conclusion 120
IV.6 References 121
- Degree
- Doctor
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