臺灣博碩士論文加值系統

非營養性甜味劑 (non- nutritive sweeteners, NNS)為熱量極低的甜味劑，但甜度一般較蔗糖高，因此被健康人及肥胖者廣泛使用於控制體重及血糖。本次研究目的為探討不同NNS與蔗糖相比對於正常及以高脂飲食誘導小鼠肥胖之影響。小鼠分為給予AIN-93M飲食之健康組與60％高脂飲食 (high fat diet, HFD)，餵予八週誘導之肥胖，於介入前先進行急性暴露 (acute exposure)接著分別於健康組給予水、低高劑量的甘草酸胺 (monoammonium glycyrrhizinate, MAG)，HFD組以等甜度的劑量給予蔗糖、低劑量的MAG、醋磺內酯鉀 (acesulfame-potassium, ACE-K)與水，介入八週後收集糞便，接著進行口服葡萄糖耐受試驗 (oral glucose tolerance test, OGTT)犧牲取其血液及器官組織做分析。結果顯示，高劑量的MAG可降低健康小鼠的體重、脂肪組織重量、肝臟中脂肪堆積，並改善血脂及增加肌肉的相對重量與腓腸肌合成指標MyoG的mRNA表現量，但短時間或長期給予MAG後，不影響其OGTT之血糖的曲線下面積，且腸道菌相Firmicutes/Bacteroidetes (F/B)比例及脂肪合成與分解之mRNA表現量無顯著差異; HFD誘導肥胖後，蔗糖體重顯著增加，而蔗糖、MAG及ACE-K相比，脂肪組織含量、F/B比例無顯著差異，但MAG及ACE-K的曲線下面積顯著高於給予水的組別，此外，MAG的F/B比例顯著低於ACE-K。表示高劑量的MAG對於正常小鼠具有抗肥胖的作用，然而對於肥胖小鼠，蔗糖具有增加體重的風險，MAG及ACE-K與蔗糖相比，其體重、血糖及脂肪組織則無正面影響，而MAG的腸道菌相F/B比例低於ACE-K，表示MAG增加肥胖的風險較低，對於肥胖者來說MAG相較於蔗糖及ACE-K是比較好的選擇。
關鍵字：肥胖、non-nutritive sweeteners、monoammonium glycyrrhizinate、acesulfame-potassium

Non-nutritive sweeteners (NNS) are sweeteners that provide minimal or no calories, so they are widely used in healthy and obese population to control weight and blood glucose. This aim of this study was to study the effects of monoammonium glycyrrhizinate (MAG), acesulfame-potassium (ACE-K) and sucrose on body weight, adiposity, glucose homeostasis and gut microbiota in normal and high fat diet-induced obese C57BL/6 mice. After mice fed AIN-93 M diet (control) or 60% fat of high fat diet-induced obese mice for 8 weeks, proceed the acute exposure. Control was administered with 1.1 g/L MAG (L-MAG) and 3.3 g/L MAG (H-MAG) in water and high fat diet (HFD) were with different sweeteners (within ADI doses), including sucrose, natural MAG as well as artificial ACE-K in drinking water with equivalent sweetness then collected feces and proceed the oral glucose tolerance test (OGTT). After 8 weeks intervention, the animals were sacrificed, and blood, liver, muscle and adipose tissues were collected. H-MAG group decreased body weight, adipose tissue, fat accumulation in liver and total cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) in serum. Moreover, H-MAG group increased relative weight of muscle and synthetic factor MyoG mRNA expression in gastrocnemius muscle. But showed no effect on blood glucose AUC from OGTT, lipogenesis and lipolysis in epidydimal adipose tissue and Firmicutes/Bacteroidetes (F/B) ratio. Sucrose increased body weight in obese mice, but showed no effect on body weight, adipose tissue, F/B ratio among sucrose, MAG and ACE-K. However, MAG and ACE-K increased blood glucose AUC than water from chronic OGTT. Moreover, MAG had lower F/B ratio than ACE-K and indicated that MAG was obesity risk lower than ACE-K. In short, H-MAG had anti-obesity effect in healthy mice. MAG was better choice than ACE-K in obese mice.
Key words: obesity, non-nutritive sweeteners, monoammonium glycyrrhizinate, acesulfame-potassium

目錄
中文摘要 I
英文摘要 II
致謝 III
目錄 V
圖目次 VII
表目次 VIII
縮寫表 IX
第一章 前言 1
第二章 文獻回顧 3
第一節 肥胖 3
1.1 肥胖的定義 3
1.2 肥胖的風險 4
1.3 肥胖的成因 6
第二節 精緻糖 7
2.1 精緻糖與肥胖 7
2.2 精緻糖與血糖 10
2.3 精緻糖與腸道菌相 11
第三節 非營養性甜味劑 13
3.1非營養性甜味劑 13
3.2 天然NNS與人工NNS 14
3.3 ACE-K 15
3.4 甘草 17
3.5 甘草萃取物及其活性成分 19
3.6 甘草次酸 20
第四節 動物高脂飲食誘導肥胖模式 23
第三章 研究目的 24
第四章 材料與方法 25
第一節 實驗藥品與儀器 25
1.1 實驗藥品 25
1.2 儀器 26
第二節 實驗一之實驗架構 27
第三節 實驗二之實驗架構 28
第四節 飼料配製 29
第五節 介入物配製 29
第六節 實驗動物與分組 31
第七節 單一劑量之口服葡萄糖耐受試驗 (acute exposure during OGTT) 33
第八節 長期暴露之口服葡萄糖耐受試驗 (chronic exposure during OGTT) 33
第九節 分析項目 34
9.1 血液分析 34
9.2 肝臟三酸甘油酯(TG)含量測定 34
9.3 肝臟總膽固醇(TC)含量測定 35
9.4 脂肪組織及肌肉RNA萃取與定量 35
9.5 Real-time Quantitative Polymerase Chain Reaction (RT-PCR) 36
9.6 肝臟及脂肪組織染色分析 39
9.7 腸道菌相分析 41
第十節 統計分析 42
第五章 結果 43
第一節 實驗一健康動物組 43
5.1.1 體重變化、攝食量、飲水量及食物利用率 43
5.1.2 脂肪組織、肌肉與器官重 43
5.1.3 血液生化數值 43
5.1.4 單一劑量及長期暴露之口服葡萄糖耐受試驗 47
5.1.5 肝臟及副睪脂肪組織病理H&E染色 49
5.1.6 副睪脂肪組織脂質代謝指標及腓腸肌合成與萎縮因子mRNA表現 53
5.1.7腸道菌相分析 56
第二節 誘導肥胖期 60
5.2.1 體重變化量、攝食量及飲水量 60
第三節 實驗二肥胖動物組 61
5.3.1 體重變化、攝食量、飲水量及食物利用率 61
5.3.2 脂肪組織、肌肉與器官重 61
5.3.3 血液生化數值 61
5.3.4 單一劑量及長期暴露之口服葡萄糖耐受試驗 61
5.3.5 肝臟及副睪脂肪組織病理H&E染色 66
5.3.6 腸道菌相分析 70
第六章 討論 74
第七章 結論 82
第八章 參考文獻 83
附錄一 實驗動物照護及使用委員會審查同意書 94
圖目次
圖2.1肪肪合成機制 9
圖2.2 脂肪分解機制 10
圖2.3 血糖的恆定機制 11
圖2.4 甘草素之代謝 22
圖2.5 甘草素代謝物造成血壓上升的機制 22
圖5.1 健康動物之單一劑量與長期暴露之口服葡萄糖耐受試驗 48
圖5.2 健康動物之肝臟組織型態 50
圖5.3對健康動物之肝臟組織病理分數評估結果圖 51
圖5.4 健康動物之副睪脂肪組織型態 52
圖5.5 副睪脂肪組織脂質代謝相關指標mRNA表現 54
圖5.6 腓腸肌合成與萎縮因子 mRNA表現 55
圖5.7 健康動物之腸道菌相的組成 57
圖5.8 健康動物之alpha & beta-diversity 58
圖5.9 健康動物之線性判斷分析效應大小 59
圖5.10 肥胖動物之單一劑量及長期暴露之口服葡萄糖耐受試驗 65
圖5.11 肥胖動物之肝臟組織型態 67
圖5.12 肥胖動物之肝臟組織病理分數評估結果圖 68
圖5.13 肥胖動物之副睪脂肪組織型態 69
圖5.14 肥胖動物之腸道菌相的組成 71
圖5.15 肥胖動物之alpha & beta-diversity 72
圖5.16 肥胖動物之線性判斷分析效應大小 73
表目次
表2.1 台灣地區成人過重及肥胖定義 3
表4.1實驗飼料成分表 30
表4.2 RT-PCR primer序列 38
表4.3 肝臟病理分析之半定量評分標準 40
表4.4 脂肪組織病理分析之半定量評分標準 40
表5.1健康動物之體重變化、攝食量、飲水量及食物利用率 44
表5.2 健康動物之肌肉、脂肪組織與器官重量 45
表5.3 健康動物之血液生化數值 46
表5.4 健康動物之肝臟中總膽固醇及三酸甘油酯的含量 (mg/g) 50
表5.5 健康動物之肝臟組織病理細項總分 51
表5.6 對健康動物之副睪脂肪組織病理評估 52
表5.7 誘導肥胖期之體重變化、攝食量及飲水量 60
表5.8 肥胖動物之體重變化、攝食量、飲水量及食物利用率 62
表5.9 肥胖動物之器官、脂肪組織與肌肉重量 63
表5.10肥胖動物之血液生化數值 64
表5.11 肥胖動物之肝臟中總膽固醇及三酸甘油酯的含量 (mg/g) 67
表5.12 肥胖動物之肝臟組織病理細項總分 68
表5.13 肥胖動物之副睪脂肪組織病理評估 69

衛生福利部國民健康署 (2017) 成人肥胖防治指引
Abo El-Magd, N. F., El-Mesery, M., El-Karef, A., & El-Shishtawy, M. M. (2018). Glycyrrhizin ameliorates high fat diet-induced obesity in rats by activating NrF2 pathway. Life Sci, 193, 159-170.
Ahmad, U., Ahmad, R. S., Arshad, M. S., Mushtaq, Z., Hussain, S. M., & Hameed, A. (2018). Antihyperlipidemic efficacy of aqueous extract of Stevia rebaudiana Bertoni in albino rats. Lipids Health Dis, 17(1), 175.
Ahn, J., Lee, H., Jang, J., Kim, S., & Ha, T. (2013). Anti-obesity effects of glabridin-rich supercritical carbon dioxide extract of licorice in high-fat-fed obese mice. Food Chem Toxicol, 51, 439-445.
Almeda-Valdés, P., Cuevas-Ramos, D., & Aguilar-Salinas, C. A. (2009). Metabolic syndrome and non-alcoholic fatty liver disease. Ann Hepatol, 8 Suppl 1, S18-24.
Armanini, D., De Palo, C. B., Mattarello, M. J., Spinella, P., Zaccaria, M., Ermolao, A., Palermo, M., Fiore, C., Sartorato, P., Francini-Pesenti, F., & Karbowiak, I. (2003). Effect of licorice on the reduction of body fat mass in healthy subjects. J Endocrinol Invest, 26(7), 646-650.
Azaïs-Braesco, V., Sluik, D., Maillot, M., Kok, F., & Moreno, L. A. (2017). A review of total & added sugar intakes and dietary sources in Europe. Nutrition Journal, 16(1), 6.
Baumgardner, J. N., Shankar, K., Hennings, L., Badger, T. M., & Ronis, M. J. (2008). A new model for nonalcoholic steatohepatitis in the rat utilizing total enteral nutrition to overfeed a high-polyunsaturated fat diet. Am J Physiol Gastrointest Liver Physiol, 294(1), G27-38.
Bian, X., Chi, L., Gao, B., Tu, P., Ru, H., & Lu, K. (2017). The artificial sweetener acesulfame potassium affects the gut microbiome and body weight gain in CD-1 mice. PLoS One, 12(6), e0178426.
Buettner, R., Parhofer, K. G., Woenckhaus, M., Wrede, C. E., Kunz-Schughart, L. A., Schölmerich, J., & Bollheimer, L. C. (2006). Defining high-fat-diet rat models: metabolic and molecular effects of different fat types. J Mol Endocrinol, 36(3), 485-501.
Burchfield, J. G., Kebede, M. A., Meoli, C. C., Stöckli, J., Whitworth, P. T., Wright, A. L., Hoffman, N. J., Minard, A. Y., Ma, X., Krycer, J. R., Nelson, M. E., Tan, S. X., Yau, B., Thomas, K. C., Wee, N. K. Y., Khor, E. C., Enriquez, R. F., Vissel, B., Biden, T. J., Baldock, P. A., Hoehn, K. L., Cantley, J., Cooney, G. J., James, D. E., & Fazakerley, D. J. (2018). High dietary fat and sucrose results in an extensive and time-dependent deterioration in health of multiple physiological systems in mice. J Biol Chem, 293(15), 5731-5745.
Carroll, J. F., Zenebe, W. J., & Strange, T. B. (2006). Cardiovascular function in a rat model of diet-induced obesity. Hypertension, 48(1), 65-72.
Choi, Y. R., Shim, J., & Kim, M. J. (2020). Genistin: A novel potent anti-adipogenic and anti-lipogenic agent. Molecules, 25(9), 2042.
Chuang, W. Y., Hsieh, Y. C., Chen, L. W., & Lee, T. T. (2020). Evaluation of the relationship between adipose metabolism patterns and secretion of appetite-related endocrines on chicken. Animals (Basel), 10(8), 1282.
Chyau, C. C., Wang, H. F., Zhang, W. J., Chen, C. C., Huang, S. H., Chang, C. C., & Peng, R. Y. (2020). Antrodan alleviates high-fat and high-fructose diet-induced fatty liver disease in C57BL/6 mice model via AMPK/Sirt1/SREBP-1c/PPARγ Pathway. Int J Mol Sci, 21(1), 360.
Cong, W. N., Wang, R., Cai, H., Daimon, C. M., Scheibye-Knudsen, M., Bohr, V. A., Turkin, R., Wood, W. H., 3rd, Becker, K. G., Moaddel, R., Maudsley, S., & Martin, B. (2013). Long-term artificial sweetener acesulfame potassium treatment alters neurometabolic functions in C57BL/6J mice. PLoS One, 8(8), e70257.
Després, J. P., & Lemieux, I. (2006). Abdominal obesity and metabolic syndrome. Nature, 444(7121), 881-887.
Deutch, M. R., Grimm, D., Wehland, M., Infanger, M., & Krüger, M. (2019). Bioactive candy: effects of licorice on the cardiovascular system. Foods, 8(10), 495
Dhingra, R., Sullivan, L., Jacques, P. F., Wang, T. J., Fox, C. S., Meigs, J. B., D'Agostino, R. B., Gaziano, J. M., & Vasan, R. S. (2007). Soft drink consumption and risk of developing cardiometabolic risk factors and the metabolic syndrome in middle-aged adults in the community. Circulation, 116(5), 480-488.
Fernando, H. A., Chandramouli, C., Rosli, D., Lam, Y. L., Yong, S. T., Yaw, H. P., Ton, S. H., Kadir, K. A., & Sainsbury, A. (2014). Glycyrrhizic acid can attenuate metabolic deviations caused by a high-sucrose diet without causing water retention in male Sprague-Dawley rats. Nutrients, 6(11), 4856-4871.
Ferré, P., & Foufelle, F. (2007). SREBP-1c transcription factor and lipid homeostasis: clinical perspective. Horm Res, 68(2), 72-82.
Ferreira, P. S., Manthey, J. A., Nery, M. S., Spolidorio, L. C., & Cesar, T. B. (2020). Low doses of eriocitrin attenuate metabolic impairment of glucose and lipids in ongoing obesogenic diet in mice. J Nutr Sci, 9, e59.
Field, A. E., Coakley, E. H., Must, A., Spadano, J. L., Laird, N., Dietz, W. H., Rimm, E., & Colditz, G. A. (2001). Impact of overweight on the risk of developing common chronic diseases during a 10-year period. Arch Intern Med, 161(13), 1581-1586.
Foletto, K. C., Melo Batista, B. A., Neves, A. M., de Matos Feijó, F., Ballard, C. R., Marques Ribeiro, M. F., & Bertoluci, M. C. (2016). Sweet taste of saccharin induces weight gain without increasing caloric intake, not related to insulin-resistance in Wistar rats. Appetite, 96, 604-610.
Fowler, S. P., Williams, K., Resendez, R. G., Hunt, K. J., Hazuda, H. P., & Stern, M. P. (2008). Fueling the obesity epidemic? Artificially sweetened beverage use and long-term weight gain. Obesity (Silver Spring), 16(8), 1894-1900.
Friedewald, W. T., Levy, R. I., & Fredrickson, D. S. (1972). Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem, 18(6), 499-502.
Giron, M., Thomas, M., Dardevet, D., Chassard, C., & Savary-Auzeloux, I. (2022). Gut microbes and muscle function: can probiotics make our muscles stronger? J Cachexia Sarcopenia Muscle, 13(3), 1460-1476.
Gr¯nning-Wang, L. M., Bindesboll, C., & Nebb, H. (2013). The role of liver X receptor in hepatic de novo lipogenesis and cross-talk with insulin and glucose signaling. In(Ed.), Lipid Metabolism.
Haran, J. P., Bucci, V., Dutta, P., Ward, D., & McCormick, B. (2018). The nursing home elder microbiome stability and associations with age, frailty, nutrition and physical location. J Med Microbiol, 67(1), 40-51.
Hariri, N., & Thibault, L. (2010). High-fat diet-induced obesity in animal models. Nutr Res Rev, 23(2), 270-299.
Hasan, N., & Yang, H. (2019). Factors affecting the composition of the gut microbiota, and its modulation. PeerJ, 7, e7502.
Hautaniemi, E. J., Tahvanainen, A. M., Koskela, J. K., Tikkakoski, A. J., Kähönen, M., Uitto, M., Sipilä, K., Niemelä, O., Mustonen, J., & Pörsti, I. H. (2017). Voluntary liquorice ingestion increases blood pressure via increased volume load, elevated peripheral arterial resistance, and decreased aortic compliance. Sci Rep, 7(1), 10947.
Hedrick, V. E., Passaro, E. M., Davy, B. M., You, W., & Zoellner, J. M. (2017). Characterization of non-nutritive sweetener intake in rural southwest virginian adults living in a health-disparate region. Nutrients, 9(7), 757.
Honda, K., Kamisoyama, H., Tominaga, Y., Yokota, S., & Hasegawa, S. (2009). The molecular mechanism underlying the reduction in abdominal fat accumulation by licorice flavonoid oil in high fat diet-induced obese rats. Anim Sci J, 80(5), 562-569.
Huo, H. Z., Wang, B., Liang, Y. K., Bao, Y. Y., & Gu, Y. (2011). Hepatoprotective and antioxidant effects of licorice extract against CCl₄-induced oxidative damage in rats. Int J Mol Sci, 12(10), 6529-6543.
Isbrucker, R. A., & Burdock, G. A. (2006). Risk and safety assessment on the consumption of Licorice root (Glycyrrhiza sp.), its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyrrhizin. Regul Toxicol Pharmacol, 46(3), 167-192.
Jiang, G. Z., Zhou, M., Zhang, D. D., Li, X. F., & Liu, W. B. (2018). The mechanism of action of a fat regulator: Glycyrrhetinic acid (GA) stimulating fatty acid transmembrane and intracellular transport in blunt snout bream (Megalobrama amblycephala). Comp Biochem Physiol A Mol Integr Physiol, 226, 83-90.
Kim, J. H., Sung, P. S., Lee, E. B., Hur, W., Park, D. J., Shin, E. C., Windisch, M. P., & Yoon, S. K. (2017). GRIM-19 restricts HCV replication by attenuating intracellular lipid accumulation. Front Microbiol, 8, 576.
Kleiner, D. E., Brunt, E. M., Van Natta, M., Behling, C., Contos, M. J., Cummings, O. W., Ferrell, L. D., Liu, Y. C., Torbenson, M. S., Unalp-Arida, A., Yeh, M., McCullough, A. J., & Sanyal, A. J. (2005). Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology, 41(6), 1313-1321.
Kowalski, G. M., Kraakman, M. J., Mason, S. A., Murphy, A. J., & Bruce, C. R. (2017). Resolution of glucose intolerance in long-term high-fat, high-sucrose-fed mice. J Endocrinol, 233(3), 269-279.
Lecoultre, V., Egli, L., Carrel, G., Theytaz, F., Kreis, R., Schneiter, P., Boss, A., Zwygart, K., Lê, K. A., Bortolotti, M., Boesch, C., & Tappy, L. (2013). Effects of fructose and glucose overfeeding on hepatic insulin sensitivity and intrahepatic lipids in healthy humans. Obesity (Silver Spring), 21(4), 782-785.
Lee, C. S., Kim, Y. J., Lee, M. S., Han, E. S., & Lee, S. J. (2008). 18beta-Glycyrrhetinic acid induces apoptotic cell death in SiHa cells and exhibits a synergistic effect against antibiotic anti-cancer drug toxicity. Life Sci, 83(13-14), 481-489.
Ley, R. E., Bäckhed, F., Turnbaugh, P., Lozupone, C. A., Knight, R. D., & Gordon, J. I. (2005). Obesity alters gut microbial ecology. Proceedings of the National Academy of Sciences of the United States of America, 102(31), 11070-11075.
Li, H. H., Tyburski, J. B., Wang, Y. W., Strawn, S., Moon, B. H., Kallakury, B. V., Gonzalez, F. J., & Fornace, A. J., Jr. (2014). Modulation of fatty acid and bile acid metabolism by peroxisome proliferator-activated receptor α protects against alcoholic liver disease. Alcohol Clin Exp Res, 38(6), 1520-1531.
Li, Y., Hou, H., Wang, X., Dai, X., Zhang, W., Tang, Q., Dong, Y., Yan, C., Wang, B., Li, Z., & Cao, H. (2021). Diammonium glycyrrhizinate ameliorates obesity through modulation of gut microbiota-conjugated BAs-FXR signaling. Front Pharmacol, 12, 796590.
Li, Y., Liu, T., Yan, C., Xie, R., Guo, Z., Wang, S., Zhang, Y., Li, Z., Wang, B., & Cao, H. (2018). Diammonium glycyrrhizinate protects against nonalcoholic fatty liver disease in mice through modulation of gut microbiota and restoration of intestinal barrier. Mol Pharm, 15(9), 3860-3870.
Ludwig, D. S., Peterson, K. E., & Gortmaker, S. L. (2001). Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational analysis. Lancet, 357(9255), 505-508.
Lutsey, P. L., Steffen, L. M., & Stevens, J. (2008). Dietary intake and the development of the metabolic syndrome: the atherosclerosis risk in communities study. Circulation, 117(6), 754-761.
Mace, O. J., Affleck, J., Patel, N., & Kellett, G. L. (2007). Sweet taste receptors in rat small intestine stimulate glucose absorption through apical GLUT2. J Physiol, 582(Pt 1), 379-392.
Maersk, M., Belza, A., Stødkilde-Jørgensen, H., Ringgaard, S., Chabanova, E., Thomsen, H., Pedersen, S. B., Astrup, A., & Richelsen, B. (2012). Sucrose-sweetened beverages increase fat storage in the liver, muscle, and visceral fat depot: a 6-mo randomized intervention study. Am J Clin Nutr, 95(2), 283-289.
Magne, F., Gotteland, M., Gauthier, L., Zazueta, A., Pesoa, S., Navarrete, P., & Balamurugan, R. (2020). The Firmicutes/Bacteroidetes ratio: A relevant marker of gut dysbiosis in obese patients? Nutrients, 12(5), 1474.
Magnuson, B. A., Carakostas, M. C., Moore, N. H., Poulos, S. P., & Renwick, A. G. (2016). Biological fate of low-calorie sweeteners. Nutr Rev, 74(11), 670-689.
Malik, Z. A., & Sharma, P. l. (2011). An ethanolic extract from licorice (glycyrrhiza glabra) exhibits anti-obesity effects by decreasing dietary fat absorption in a high fat diet-induced obesity rat model. Ijpsr, 46(22), 3010-3018
Mitsutomi, K., Masaki, T., Shimasaki, T., Gotoh, K., Chiba, S., Kakuma, T., & Shibata, H. (2014). Effects of a nonnutritive sweetener on body adiposity and energy metabolism in mice with diet-induced obesity. Metabolism, 63(1), 69-78.
Moon, M. H., Jeong, J. K., Lee, Y. J., Seol, J. W., Ahn, D. C., Kim, I. S., & Park, S. Y. (2012). 18β-Glycyrrhetinic acid inhibits adipogenic differentiation and stimulates lipolysis. Biochem Biophys Res Commun, 420(4), 805-810.
Nirmalan, N., & Nirmalan, M. (2020). Hormonal control of metabolism : regulation of plasma glucose. Anaesthesia & Intensive Care Medicine, 21(11), 578-583.
Oliveira, D. T., Fernandes, I. D. C., Sousa, G. G., Santos, T., Paiva, N. C. N., Carneiro, C. M., Evangelista, E. A., Barboza, N. R., & Guerra-Sá, R. (2020). High-sugar diet leads to obesity and metabolic diseases in ad libitum -fed rats irrespective of caloric intake. Arch Endocrinol Metab, 64(1), 71-81.
Olivier-Van Stichelen, S., Rother, K. I., & Hanover, J. A. (2019). Maternal exposure to non-nutritive sweeteners impacts progeny’s metabolism and microbiome [Original Research]. Frontiers in Microbiology, 10, 1360.
Park, J. E., & Cha, Y. S. (2010). Stevia rebaudiana Bertoni extract supplementation improves lipid and carnitine profiles in C57BL/6J mice fed a high-fat diet. J Sci Food Agric, 90(7), 1099-1105.
Park, M., Lee, J. H., Choi, J. K., Hong, Y. D., Bae, I. H., Lim, K. M., Park, Y. H., & Ha, H. (2014). 18β-glycyrrhetinic acid attenuates anandamide-induced adiposity and high-fat diet induced obesity. Mol Nutr Food Res, 58(7), 1436-1446.
Pastorino, G., Cornara, L., Soares, S., Rodrigues, F., & Oliveira, M. (2018). Liquorice (Glycyrrhiza glabra): A phytochemical and pharmacological review. Phytother Res, 32(12), 2323-2339.
Peters, J. C., Beck, J., Cardel, M., Wyatt, H. R., Foster, G. D., Pan, Z., Wojtanowski, A. C., Vander Veur, S. S., Herring, S. J., Brill, C., & Hill, J. O. (2016). The effects of water and non-nutritive sweetened beverages on weight loss and weight maintenance: A randomized clinical trial. Obesity (Silver Spring, Md.), 24(2), 297-304.
Peters, J. C., Wyatt, H. R., Foster, G. D., Pan, Z., Wojtanowski, A. C., Vander Veur, S. S., Herring, S. J., Brill, C., & Hill, J. O. (2014). The effects of water and non-nutritive sweetened beverages on weight loss during a 12-week weight loss treatment program. Obesity (Silver Spring), 22(6), 1415-1421.
Plows, J. F., Morton-Jones, J., Bridge-Comer, P. E., Ponnampalam, A., Stanley, J. L., Vickers, M. H., & Reynolds, C. M. (2020). Consumption of the artificial sweetener acesulfame potassium throughout pregnancy induces glucose intolerance and adipose tissue dysfunction in mice. J Nutr, 150(7), 1773-1781.
Qian, C., Qi, Y., Feng, R., Yang, M., Zhang, M., Liu, W., Rayner, C. K., & Ma, J. (2021). Sucralose can improve glucose tolerance and upregulate expression of sweet taste receptors and glucose transporters in an obese rat model. Eur J Nutr, 60(4), 1809-1817.
Qu, Q., Zeng, F., Liu, X., Wang, Q. J., & Deng, F. (2016). Fatty acid oxidation and carnitine palmitoyltransferase I: emerging therapeutic targets in cancer. Cell Death Dis, 7(5), e2226.

Quan, H. Y., Baek, N. I., & Chung, S. H. (2012). Licochalcone a prevents adipocyte differentiation and lipogenesis via suppression of peroxisome proliferator-activated receptor γ and sterol regulatory element-binding protein pathways. J Agric Food Chem, 60(20), 5112-5120.
Ragi, M. E., El-Haber, R., El-Masri, F., & Obeid, O. A. (2021). The effect of aspartame and sucralose intake on body weight measures and blood metabolites: role of their form (solid and/or liquid) of ingestion. Br J Nutr, 1-9.
Ramne, S., Brunkwall, L., Ericson, U., Gray, N., Kuhnle, G. G. C., Nilsson, P. M., Orho-Melander, M., & Sonestedt, E. (2021). Gut microbiota composition in relation to intake of added sugar, sugar-sweetened beverages and artificially sweetened beverages in the Malmö Offspring Study. Eur J Nutr, 60(4), 2087-2097.
Reeves, P. G. (1997). Components of the AIN-93 diets as improvements in the AIN-76A diet. The Journal of Nutrition, 127(5), 838S-841S.
Rippe, J. M., & Angelopoulos, T. J. (2016). Relationship between added sugars consumption and chronic disease risk factors: current understanding. Nutrients, 8(11), 697.
Ryuk, J. A., Kang, S., Daily, J. W., Ko, B. S., & Park, S. (2019). Moderate intake of aspartame and sucralose with meals, but not fructose, does not exacerbate energy and glucose metabolism in estrogen-deficient rats. J Clin Biochem Nutr, 65(3), 223-231.
Santuré, M., Pitre, M., Marette, A., Deshaies, Y., Lemieux, C., Larivière, R., Nadeau, A., & Bachelard, H. (2002). Induction of insulin resistance by high-sucrose feeding does not raise mean arterial blood pressure but impairs haemodynamic responses to insulin in rats. Br J Pharmacol, 137(2), 185-196.
Seki, H., Tamura, K., & Muranaka, T. (2018). Plant-derived isoprenoid sweeteners: recent progress in biosynthetic gene discovery and perspectives on microbial production. Biosci Biotechnol Biochem, 82(6), 927-934.
Semova, I., Carten, J. D., Stombaugh, J., Mackey, L. C., Knight, R., Farber, S. A., & Rawls, J. F. (2012). Microbiota regulate intestinal absorption and metabolism of fatty acids in the zebrafish. Cell Host Microbe, 12(3), 277-288.
Shackelford, C., Long, G., Wolf, J., Okerberg, C., & Herbert, R. (2002). Qualitative and quantitative analysis of nonneoplastic lesions in toxicology studies. Toxicol Pathol, 30(1), 93-96.
Shi, Q., Zhu, X., & Deng, S. (2021). Sweet taste receptor expression and its activation by sucralose to regulate glucose absorption in mouse duodenum. J Food Sci, 86(2), 540-545.
Sigurjónsdóttir, H. A., Franzson, L., Manhem, K., Ragnarsson, J., Sigurdsson, G., & Wallerstedt, S. (2001). Liquorice-induced rise in blood pressure: a linear dose-response relationship. J Hum Hypertens, 15(8), 549-552.
Simon, B. R., Parlee, S. D., Learman, B. S., Mori, H., Scheller, E. L., Cawthorn, W. P., Ning, X., Gallagher, K., Tyrberg, B., Assadi-Porter, F. M., Evans, C. R., & MacDougald, O. A. (2013). Artificial sweeteners stimulate adipogenesis and suppress lipolysis independently of sweet taste receptors. J Biol Chem, 288(45), 32475-32489.
Stamataki, N. S., Crooks, B., Ahmed, A., & McLaughlin, J. T. (2020). Effects of the daily consumption of stevia on glucose homeostasis, body weight, and energy Intake: A randomised open-label 12-week trial in healthy adults. Nutrients, 12(10), 3049.
Stumvoll, M., Mitrakou, A., Pimenta, W., Jenssen, T., Yki-Järvinen, H., Van Haeften, T., Renn, W., & Gerich, J. (2000). Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity. Diabetes Care, 23(3), 295-301.
Svendsen, O. L., Haarbo, J., Hassager, C., & Christiansen, C. (1993). Accuracy of measurements of body composition by dual-energy x-ray absorptiometry in vivo. Am J Clin Nutr, 57(5), 605-608.
Sylvetsky, A. C., Sen, S., Merkel, P., Dore, F., Stern, D. B., Henry, C. J., Cai, H., Walter, P. J., Crandall, K. A., Rother, K. I., & Hubal, M. J. (2020). Consumption of diet soda sweetened with sucralose and acesulfame-potassium alters inflammatory transcriptome pathways in females with overweight and obesity. Mol Nutr Food Res, 64(11), e1901166.
Takeda, S., Ishthara, K., Wakui, Y., Amagaya, S., Maruno, M., Akao, T., & Kobashi, K. (1996). Bioavailability study of glycyrrhetic acid after oral administration of glycyrrhizin in rats; relevance to the intestinal bacterial hydrolysis. J Pharm Pharmacol, 48(9), 902-905.
Tamano, K., Bruno, K. S., Karagiosis, S. A., Culley, D. E., Deng, S., Collett, J. R., Umemura, M., Koike, H., Baker, S. E., & Machida, M. (2013). Increased production of fatty acids and triglycerides in Aspergillus oryzae by enhancing expressions of fatty acid synthesis-related genes. Appl Microbiol Biotechnol, 97(1), 269-281.
Tey, S. L., Salleh, N. B., Henry, J., & Forde, C. G. (2017). Effects of aspartame-, monk fruit-, stevia- and sucrose-sweetened beverages on postprandial glucose, insulin and energy intake. Int J Obes (Lond), 41(3), 450-457.
Tian, M., Yan, H., & Row, K. H. (2008). Extraction of glycyrrhizic acid and glabridin from licorice. International Journal of Molecular Sciences, 9(4), 571-577.
Turnbaugh, P. J., Ley, R. E., Mahowald, M. A., Magrini, V., Mardis, E. R., & Gordon, J. I. (2006). An obesity-associated gut microbiome with increased capacity for energy harvest. Nature, 444(7122), 1027-1031.
Wang, X. R., Hao, H. G., & Chu, L. (2017). Glycyrrhizin inhibits LPS-induced inflammatory mediator production in endometrial epithelial cells. Microb Pathog, 109, 110-113.
Wen, L., & Duffy, A. (2017). Factors influencing the gut microbiota, inflammation, and type 2 diabetes. J Nutr, 147(7), 1468s-1475s.
Xi, Y., Wu, M., Li, H., Dong, S., Luo, E., Gu, M., Shen, X., Jiang, Y., Liu, Y., & Liu, H. (2015). Baicalin attenuates high fat diet-induced obesity and liver dysfunction: dose-response and potential role of CaMKKβ/AMPK/ACC Pathway. Cell Physiol Biochem, 35(6), 2349-2359.
Yu, J. Y., Ha, J. Y., Kim, K. M., Jung, Y. S., Jung, J. C., & Oh, S. (2015). Anti-Inflammatory activities of licorice extract and its active compounds, glycyrrhizic acid, liquiritin and liquiritigenin, in BV2 cells and mice liver. Molecules, 20(7), 13041-13054.
Zhang, X., Song, Y., Ding, Y., Wang, W., Liao, L., Zhong, J., Sun, P., Lei, F., Zhang, Y., & Xie, W. (2018). Effects of mogrosides on high-fat-diet-induced obesity and nonalcoholic fatty liver disease in mice. Molecules, 23(8), 1894.
Zhao, X., Yan, J., Chen, K., Song, L., Sun, B., & Wei, X. (2018). Effects of saccharin supplementation on body weight, sweet receptor mRNA expression and appetite signals regulation in post-weanling rats. Peptides, 107, 32-38.