臺灣博碩士論文加值系統

橙皮中含 Nobiletin、Tangeretin 及 5-hydroxy-Nobiletin 等多種活性物質，具組 抗氧化、抗癌及抗肥胖等活性物質。若能透過發酵與萃取技術使橙皮中活性成分釋 放，可有效減少肥胖者脂肪之累積及降低肥胖者罹患第二型糖尿病、高血壓、心血 管疾病及癌症的風險。故本篇論文以廠商發酵橙皮萃取物產品為樣品餵食以高脂飲 食誘導之 SD 肥胖大鼠，探討其減重與抗肥胖活性。
將雄性 SD 大鼠分減重模式與抗肥胖模式，每種模式各 4 組(每組 6 隻)，分為 正常飲食組(ND)、高脂飼料控制組 HFD)及兩組 HFD 實驗組(高劑量樣品組，CP3 及低劑量樣品組，CP1)。減重模式為先以高脂飼料餵食 10 週誘導肥胖後，控制組 繼續以高脂飼料餵食 6 週，實驗組改以餵食添加發酵橙皮萃取物產品之高脂飼料 6 週。抗肥胖模式為高脂飼料與發酵橙皮同時餵食，其控制組為餵食高脂飼料 10 週， 實驗組為餵食添加發酵橙皮萃取物產品之高脂飼料 10 週。兩種動物模式下經發酵 橙皮萃取物產品餵食後體重增加量與 HFD 組無顯著差異，但在減重模式下可以觀 察到 CP3 腎周脂肪重量顯著下降 13%，其體脂肪率(5.71%)顯著低於 HFD 組(7.32%)。 餵食樣品組均顯著降低血液中總膽固醇、低密度脂蛋白及過氧化值含量。此外， CP3 組空腹血糖、胰島素濃度及 HOMA-IR 均顯著降低。抗肥胖模式中，CP3 組之 口服葡萄糖耐受性試驗中曲線下面積及血漿中總膽固醇量顯著低於 HFD 組，且餵 食樣品顯著降低血漿與肝臟過氧化值，以及肝臟總膽固醇量。兩種模式各組間血中 Alanine aminotransferase(ALT)及 Aspartate aminotransferase(AST)、Creatinine 及 Uric acid 含量無顯著差異。在減重模式下，餵食樣品可顯著降低大鼠肝臟中脂肪酸合成 酶(FAS)、乙醯輔酶 A 羧化酶(ACC)活性，增加脂肪組織中荷爾蒙敏感性脂解酶 (HSL)、降低脂蛋白脂肪酶(LPL)活性。此外，由 H&E 染色及 Oil red O 染色觀察到 樣品組肝臟細胞油滴減少現象。綜言之，肥胖大鼠攝食發酵橙皮可有效降低肝臟及 脂肪組織脂肪累積、調節血糖及膽固醇且不會造成肝損傷及腎損傷。

Citrus peel contains a variety of active substances such as nobiletin, tangeretin and 5-hydroxy nobiletin with anti-oxidative. anti-cancer, and anti-obesity activity. If the active ingredients in citrus peel can be released through fermentation and extraction technology, it can effectively reduce the fat accumulation in obese people and reduce the risk of type 2 diabetes, hypertension, cardiovascular disease and cancer in obese people. In this paper, the manufacturer’s fermented citrus peel extract was used as sample to feed SD obese rats induced by high-fat diet to explore its weight loss and anti-obesity activities. Male SD rats were divided into weigh-loss and anti-obesity model, each model had 4 groups (6 rats in each group), divided into normal diet group (ND), high-fat diet control group (HFD), experimental group (high-dose sample, CP3 and low-dose sample, CP1). The Weight loss model was that after 10 weeks of HFD feeding to induce obesity, the control group continued to be fed HFD for 6 weeks, and the experimental group was fed HFD supplemented with the sample for 6 weeks. The anti-obesity model was HFD fed with the samples at the same time, and the control group was fed HFD for 10 weeks, There was no significant difference in body weight gain after feeding the samples in the two animal models, compared with the HFD group. However in the weight-loss model, significant decrease of 13% in the perirenal fat weight in CP3 group could be observed and its body fat rate (5.71%) was significantly lower than that in the HFD group (7.32%). The contents of plasma total cholesterol, low-density lipoprotein and peroxide value in the sample feeding group were significantly decreased. In addition, fasting blood glucose, insulin concentration and HOMA-IR were significantly decreased in CP3 group. In the anti- obesity model, the area under the curve of the oral glucose tolerance test and the total plasma cholesterol in the CP3 group were significantly lower than those in the HFD group. In addition, feeding the sample significantly reduced the plasma and liver peroxide values, as well as the total liver cholesterol. There were no significant differences in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine and uric acid in blood among groups in the two models. In the weight loss model, feeding the sample can significantly reduce the hepatic fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) activity in liver, and increase the adipose tissue hormone-sensitive lipase (HSL) and decrease lipoprotein lipase (LPL) activity in adipose tissue. In addition, the reduction of oil droplets in the liver cells of the sample group was observed by H&E staining and Oil red O staining. In conclusion, feeding fermented citrus peel in obese rats can effectively reduce the fat accumulation in liver and adipose tissue, regulate blood sugar and cholesterol without causing liver and kidney damage.

壹、 前言 1
貳、 文獻探討 3
一、 肥胖 3
1.1. 肥胖人口 3
1.2. 肥胖成因 3
1.3. 肥胖所引起代謝異常 3
二、 人體與脂質的關係 5
2.1. 人體的脂質來源與代謝 5
2.2. 高脂飲食 5
2.3. 脂肪細胞 5
2.4. 抗肥胖藥物與抗肥胖植化素 6
三、 脂質代謝相關酵素 6
3.1. 乙醯輔酶A羧化酶(Acetyl-CoA carboxylase, ACC) 6
3.2. 脂肪酸合成酶(Fatty acid synthase, FAS) 7
3.3. 脂蛋白脂解酶(Lipoprotein lipase, LPL) 7
3.4. 荷爾蒙敏感性脂解酶(Hormone-sensitive lipase, HSL) 8
四、 柑橘皮 8
4.1. 柑橘皮來源 8
4.2. 柑橘皮 8
4.3. 柑橘皮組成 9
4.4. 酵素處理橙皮 10
4.5. 利用微生物發酵橙皮 11
參、 實驗設計 12
肆、 實驗材料與方法 13
一、 實驗材料 13
1.1. 發酵橙皮萃取物產品粉末 13
1.2. 實驗藥品 13
1.3. 實驗動物 13
1.4. 實驗動物飼料 13
1.5. 實驗動物試劑套組 14
二、 儀器設備 14
三、 實驗方法 16
3.1. 餵食樣品製備 16
3.2. 動物飼養與分組 16
3.3. 動物犧牲與樣品收集 16
3.4. 動物分析 16
3.5. 統計分析 24
伍、 結果與討論 25
一、 發酵橙皮萃取物之活性成分 25
二、 飼料中添加發酵橙皮萃取物產品之劑量 25
三、 大鼠攝食量、飲水量、體重及組織臟器重量變化 26
3.1. 大鼠犧牲前及剖腹後外型之狀況 26
3.2. 大鼠餵食發酵橙皮萃取物產品各週體重及體重增加量 26
3.3. 大鼠餵食發酵橙皮萃取物產品期間攝食量、飲水量、糞便量及尿液量 27
3.4. 大鼠犧牲時組織臟器重量變化及脂肪重量變化 27
四、 大鼠體內葡萄糖代謝之影響 28
4.1. 大鼠於口服葡萄糖耐受性之血糖變化 28
4.2. 餵食發酵橙皮萃取物產品對大鼠胰島素及空腹血糖的影響 28
五、 餵食發酵橙皮萃取物產品對大鼠血脂之影響 29
六、 大鼠肝臟中脂肪含量 30
七、 大鼠肝臟中脂質生成相關酵素活性 30
八、 大鼠脂肪組織中脂質代謝相關酵素活性 31
九、 餵食發酵橙皮萃取物產品對大鼠肝及腎功能之影響評估 32
十、 大鼠肝臟組織病理學切片 32
陸、 結論 34
柒、 參考資料 35
捌、 圖與表 46
玖、 附錄 76

臺灣藥學會. (2015). 常用中藥 (增修一版). 台北市.
潘子明. (2019). 春節特刊《保健食品研發與產業化》系列之一 ：保健食品原料之選擇與功效評估. ILIS Taiwan.
衛生福利部國民健康署. (2019a, 2019/09/25). 兩多兩少 用「油」健康吃！. Retrieved from https://www.hpa.gov.tw/Pages/Detail.aspx?nodeid=1134&pid=2771
衛生福利部國民健康署. (2019b). 國民營養健康狀況變遷調查102-105年成果報告. Retrieved from https://www.hpa.gov.tw/Pages/List.aspx?nodeid=3998
Adan, R. A. (2013). Mechanisms underlying current and future anti-obesity drugs. Trends in Neurosciences, 36(2), 133-140.
Ahmadian, M., Suh, J. M., Hah, N., Liddle, C., Atkins, A. R., Downes, M., & Evans, R. M. (2013). PPARγ signaling and metabolism: the good, the bad and the future. Nature Medicine, 19(5), 557-566.
Ahn, S.-C., Kim, M.-S., Lee, S.-H., Kang, J.-H., Kim, B.-H., Oh, W.-K., Kim, B.-Y., & Ahn, J.-S. (2005). Increase of bioactive flavonoid aglycone extractable from Korean citrus peel by carbohydrate-hydrolysing enzymes. Microbiology and Biotechnology Letters, 33(4), 288-294.
Allain, C. C., Poon, L. S., Chan, C. S., Richmond, W., & Fu, P. C. (1974). Enzymatic determination of total serum cholesterol. Clinical Chemistry, 20(4), 470-475.
Anderson, L., McTernan, P., Harte, A., Barnett, A., & Kumar, S. (2002). The regulation of HSL and LPL expression by DHT and flutamide in human subcutaneous adipose tissue. Diabetes, Obesity and Metabolism, 4(3), 209-213.
Anthonsen, M. W., Rönnstrand, L., Wernstedt, C., Degerman, E., & Holm, C. (1998). Identification of novel phosphorylation sites in hormone-sensitive lipase that are phosphorylated in response to isoproterenol and govern activation properties in vitro. Journal of Biological Chemistry, 273(1), 215-221.
Arbo, M., Larentis, E., Linck, V., Aboy, A., Pimentel, A., Henriques, A., Dallegrave, E., Garcia, S., Leal, M., & Limberger, R. (2008). Concentrations of p-synephrine in fruits and leaves of Citrus species (Rutaceae) and the acute toxicity testing of Citrus aurantium extract and p-synephrine. Food and Chemical Toxicology, 46(8), 2770-2775.
Arcaro, G., Zamboni, M., Rossi, L., Turcato, E., Covi, G., Armellini, F., Bosello, O., & Lechi, A. (1999). Body fat distribution predicts the degree of endothelial dysfunction in uncomplicated obesity. International Journal of Obesity, 23(9), 936-942.
Armstrong, D., & Browne, R. (1994). The analysis of free radicals, lipid peroxides, antioxidant enzymes and compounds related to oxidative stress as applied to the clinical chemistry laboratory. Free Radicals in Diagnostic Medicine, 43-58.
Ashakumary, L., Rouyer, I., Takahashi, Y., Ide, T., Fukuda, N., Aoyama, T., Hashimoto, T., Mizugaki, M., & Sugano, M. (1999). Sesamin, a sesame lignan, is a potent inducer of hepatic fatty acid oxidation in the rat. Metabolism, 48(10), 1303-1313.
Assini, J. M., Mulvihill, E. E., Sutherland, B. G., Telford, D. E., Sawyez, C. G., Felder, S. L., Chhoker, S., Edwards, J. Y., Gros, R., & Huff, M. W. (2013). Naringenin prevents cholesterol-induced systemic inflammation, metabolic dysregulation, and atherosclerosis in Ldlr−/− mice [S]. Journal of Lipid Research, 54(3), 711-724.
Barham, D., & Trinder, P. (1972). An improved colour reagent for the determination of blood glucose by the oxidase system. Analyst, 97(1151), 142-145.
Bartels, H., & Bohmer, M. (1972). Kinetic determination of creatinine concentration. Clinica Chimica Acta, 37, 193-197.
Beigneux, A. P., Davies, B. S., Gin, P., Weinstein, M. M., Farber, E., Qiao, X., Peale, F., Bunting, S., Walzem, R. L., & Wong, J. S. (2007). Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metabolism, 5(4), 279-291.
Bergmeyer, H., Herder, M., & Ref, R. (1986). International federation of clinical chemistry. IFCC method for aspartate aminotransferase. Clinical Chemistry and Clinical Biochemistry., 24(7), 497-510.
Bergmeyer, H., & Hørder, M. (1980). International federation of clinical chemistry. IFCC method for alanine aminotransferase. Journal of Clinical Chemistry and Clinical Biochemistry. , 18(8), 521-534.
Bézaire, V., & Langin, D. (2009). Regulation of adipose tissue lipolysis revisited: Symposium on ‘Frontiers in adipose tissue biology’. Proceedings of the Nutrition Society, 68(4), 350-360.
Blankenberg, S., Barbaux, S., & Tiret, L. (2003). Adhesion molecules and atherosclerosis. Atherosclerosis, 170(2), 191-203.
Blundell, J. E., & MacDiarmid, J. I. (1997). Fat as a risk factor for overconsumption: satiation, satiety, and patterns of eating. Journal of the American Dietetic Association, 97(7), S63-S69.
Bombardelli, E., & Morazzoni, P. (1993). The flavonoids: new perspectives in biological activities and therapeutics. Chimica Oggi, 11(7-8), 25-28.
Boren, J., & Brindle, K. (2012). Apoptosis-induced mitochondrial dysfunction causes cytoplasmic lipid droplet formation. Cell Death & Differentiation, 19(9), 1561-1570.
Brahe, L. K., Astrup, A., & Larsen, L. H. (2016). Can we prevent obesity-related metabolic diseases by dietary modulation of the gut microbiota? Advances in Nutrition, 7(1), 90-101.
Bucolo, G., & David, H. (1973). Quantitative determination of serum triglycerides by the use of enzymes. Clinical Chemistry, 19(5), 476-482.
Buettner, R., Schölmerich, J., & Bollheimer, L. C. (2007). High‐fat diets: modeling the metabolic disorders of human obesity in rodents. Obesity, 15(4), 798-808.
Burda, S., & Oleszek, W. (2001). Antioxidant and antiradical activities of flavonoids. Journal of Agricultural and Food Chemistry, 49(6), 2774-2779.
Busiello, R. A., Savarese, S., & Lombardi, A. (2015). Mitochondrial uncoupling proteins and energy metabolism. Frontiers in Physiology, 6, 36.
Calapai, G., Firenzuoli, F., Saitta, A., Squadrito, F., Arlotta, M. R., Costantino, G., & Inferrera, G. (1999). Antiobesity and cardiovascular toxic effects of Citrus aurantium extracts in the rat: a preliminary report. Fitoterapia, 70(6), 586-592.
Cani, P. D., Neyrinck, A. M., Fava, F., Knauf, C., Burcelin, R. G., Tuohy, K. M., Gibson, G., & Delzenne, N. M. (2007). Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia, 50(11), 2374-2383.
Carlson, S. E., & Goldfarb, S. (1977). A sensitive enzymatic method for the determination of free and esterified tissue cholesterol. Clinica Chimica Acta, 79(3), 575-582.
Cha, J.-Y., Cho, Y.-S., Kim, I., Anno, T., Rahman, S., & Yanagita, T. (2001). Effect of hesperetin, a citrus flavonoid, on the liver triacylglycerol content and phosphatidate phosphohydrolase activity in orotic acid-fed rats. Plant Foods for Human Nutrition, 56(4), 349-358.
Chanet, A., Milenkovic, D., Manach, C., Mazur, A., & Morand, C. (2012). Citrus flavanones: what is their role in cardiovascular protection? Journal of Agricultural and Food Chemistry, 60(36), 8809-8822.
Chaput, J.-P., St-Pierre, S., & Tremblay, A. (2007). Currently available drugs for the treatment of obesity: sibutramine and orlistat. Mini Reviews in Medicinal Chemistry, 7(1), 3-10.
Choi, J. S., Yokozawa, T., & Oura, H. (1991). Improvement of hyperglycemia and hyperlipemia in streptozotocin-diabetic rats by a methanolic extract of Prunus davidiana stems and its main component, prunin. Planta Medica, 57(03), 208-211.
Choi, Y., Kim, Y., Ham, H., Park, Y., Jeong, H.-S., & Lee, J. (2011). Nobiletin suppresses adipogenesis by regulating the expression of adipogenic transcription factors and the activation of AMP-activated protein kinase (AMPK). Journal of Agricultural and Food Chemistry, 59(24), 12843-12849.
Chung, J. H. (2012). Using PDE inhibitors to harness the benefits of calorie restriction: lessons from resveratrol. Aging (Albany NY), 4(3), 144.
Chung, J. H., Manganiello, V., & Dyck, J. R. (2012). Resveratrol as a calorie restriction mimetic: therapeutic implications. Trends in Cell Biology, 22(10), 546-554.
Cinti, S. (2009). Transdifferentiation properties of adipocytes in the adipose organ. American Journal of Physiology-Endocrinology and Metabolism, 297(5), E977-E986.
Cohen, J. C., Horton, J. D., & Hobbs, H. H. (2011). Human fatty liver disease: old questions and new insights. Science, 332(6037), 1519-1523.
Cronan Jr, J. E., & Waldrop, G. L. (2002). Multi-subunit acetyl-CoA carboxylases. Progress in Lipid Research, 41(5), 407-435.
Czech, M. P., Tencerova, M., Pedersen, D. J., & Aouadi, M. (2013). Insulin signalling mechanisms for triacylglycerol storage. Diabetologia, 56(5), 949-964.
Davies, B. S., Beigneux, A. P., Barnes II, R. H., Tu, Y., Gin, P., Weinstein, M. M., Nobumori, C., Nyrén, R., Goldberg, I., & Olivecrona, G. (2010). GPIHBP1 is responsible for the entry of lipoprotein lipase into capillaries. Cell Metabolism, 12(1), 42-52.
Després, J.-P., & Lemieux, I. (2006). Abdominal obesity and metabolic syndrome. Nature, 444(7121), 881-887.
Di Majo, D., Giammanco, M., La Guardia, M., Tripoli, E., Giammanco, S., & Finotti, E. (2005). Flavanones in Citrus fruit: Structure–antioxidant activity relationships. Food Research International, 38(10), 1161-1166.
Ducharme, N. A., & Bickel, P. E. (2008). Minireview: lipid droplets in lipogenesis and lipolysis. Endocrinology, 149(3), 942-949.
Duncan, R. E., Ahmadian, M., Jaworski, K., Sarkadi-Nagy, E., & Sul, H. S. (2007). Regulation of lipolysis in adipocytes. Annual Review Nutrition, 27, 79-101.
Duncan, R. E., Sarkadi-Nagy, E., Jaworski, K., Ahmadian, M., & Sul, H. S. (2008). Identification and functional characterization of adipose-specific phospholipase A2 (AdPLA). Journal of Biological Chemistry, 283(37), 25428-25436.
Eckle, R. (1989). Lipoprotein lipase, a multifunctional enzyme relevant to common metabolic disease. The New England Journal of Medicine, 320, 1060-1068.
Everard, A., Lazarevic, V., Gaïa, N., Johansson, M., Ståhlman, M., Backhed, F., Delzenne, N. M., Schrenzel, J., François, P., & Cani, P. D. (2014). Microbiome of prebiotic-treated mice reveals novel targets involved in host response during obesity. The ISME Journal, 8(10), 2116-2130.
Farooqi, I., & O'rahilly, S. (2007). Genetic factors in human obesity. Obesity Reviews, 8, 37.
Faxon, D. P., Fuster, V., Libby, P., Beckman, J. A., Hiatt, W. R., Thompson, R. W., Topper, J. N., Annex, B. H., Rundback, J. H., & Fabunmi, R. P. (2004). Atherosclerotic vascular disease conference: writing group III: pathophysiology. Circulation, 109(21), 2617-2625.
Flachs, P., Rossmeisl, M., Kuda, O., & Kopecky, J. (2013). Stimulation of mitochondrial oxidative capacity in white fat independent of UCP1: a key to lean phenotype. Biochimica et Biophysica Acta, 1831(5), 986-1003.
Fredrickson, D. S. (1971). An international classification of hyperlipidemias and hyperlipoproteinemias. Annals of Internal Medicine, 75(3), 471-472.
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. Clinical Chemistry, 18(6), 499-502.
Friedman, M. I. (2007). Obesity and the hepatic control of feeding behavior. Drug News & Perspectives, 20(9), 573-578.
Gangwisch, J. E., Malaspina, D., Boden-Albala, B., & Heymsfield, S. B. (2005). Inadequate sleep as a risk factor for obesity: analyses of the NHANES I. Sleep, 28(10), 1289-1296.
Gao, Z., He, Q., Peng, B., Chiao, P. J., & Ye, J. (2006). Regulation of nuclear translocation of HDAC3 by IκBα is required for tumor necrosis factor inhibition of peroxisome proliferator-activated receptor γ function. Journal of Biological Chemistry, 281(7), 4540-4547.
Gesta, S., Tseng, Y. H., & Kahn, C. R. (2007). Developmental origin of fat: tracking obesity to its source. Cell, 131(2), 242-256.
Girousse, A., & Langin, D. (2012). Adipocyte lipases and lipid droplet-associated proteins: insight from transgenic mouse models. International Journal of Obesity, 36(4), 581-594.
Goldberg, I. J., & Merkel, M. (2001). Lipoprotein lipase: physiology, biochemistry, and molecular biology. Frontiers Bioscience, 6(3), D388.
Guchhait, R. B., Polakis, S. E., Dimroth, P., Stoll, E., Moss, J., & Lane, M. D. (1974). Acetyl coenzyme A carboxylase system of Escherichia coli: purification and properties of the biotin carboxylase, carboxyltransferase, and carboxyl carrier protein components. Journal of Biological Chemistry, 249(20), 6633-6645.
Guo, J., Cao, Y., Ho, C.-T., Jin, S., & Huang, Q. (2017). Aged citrus peel (chenpi) extract reduces lipogenesis in differentiating 3T3-L1 adipocytes. Journal of Functional Foods, 34, 297-303.
Haemmerle, G., Zimmermann, R., Hayn, M., Theussl, C., Waeg, G., Wagner, E., Sattler, W., Magin, T. M., Wagner, E. F., & Zechner, R. (2002). Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis. Journal of Biological Chemistry, 277(7), 4806-4815.
Haque, M., & Sanyal, A. J. (2002). The metabolic abnormalities associated with non-alcoholic fatty liver disease. Best Practice & Research Clinical Gastroenterology, 16(5), 709-731.
Hariri, N., & Thibault, L. (2010). High-fat diet-induced obesity in animal models. Nutrition Research Reviews, 23(2), 270-299.
Harrold, J. A., Williams, G., & Widdowson, P. S. (2000). Early leptin response to a palatable diet predicts dietary obesity in rats: key role of melanocortin‐4 receptors in the ventromedial hypothalamic nucleus. Journal of Neurochemistry, 74(3), 1224-1228.
Harwood Jr, H. J. (2005). Treating the metabolic syndrome: acetyl-CoA carboxylase inhibition. Expert Opinion on Therapeutic Targets, 9(2), 267-281.
Havel, R. J. (2010). Triglyceride-rich lipoproteins and plasma lipid transport. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(1), 9-19.
He, B., Nohara, K., Park, N., Park, Y.-S., Guillory, B., Zhao, Z., Garcia, J. M., Koike, N., Lee, C. C., & Takahashi, J. S. (2016). The small molecule nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome. Cell Metabolism, 23(4), 610-621.
Hertog, M. G., Feskens, E. J., Kromhout, D., Hollman, P., & Katan, M. (1993). Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. The Lancet, 342(8878), 1007-1011.
Hill, J. O., Melanson, E. L., & Wyatt, H. T. (2000). Dietary fat intake and regulation of energy balance: implications for obesity. The Journal of Nutrition, 130(2), 284S-288S.
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002). SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. The Journal of Clinical Investigation, 109(9), 1125-1131.
Jha, P., Singh, S., Raghuram, M., Nair, G., Jobby, R., Gupta, A., & Desai, N. (2019). Valorisation of orange peel: supplement in fermentation media for ethanol production and source of limonene. Environmental Sustainability, 2(1), 33-41.
Jo, J., Gavrilova, O., Pack, S., Jou, W., Mullen, S., Sumner, A. E., Cushman, S. W., & Periwal, V. (2009). Hypertrophy and/or hyperplasia: dynamics of adipose tissue growth. PLoS Computational Biology, 5(3), e1000324.
Jonas, A., & Phillips, M. C. (2008). Lipoprotein structure. In Biochemistry of Lipids, Lipoproteins and Membranes (pp. 485-506).
Kamphuis, M. M., Mela, D. J., & Westerterp-Plantenga, M. S. (2003). Diacylglycerols affect substrate oxidation and appetite in humans. The American Journal of Clinical Nutrition, 77(5), 1133-1139.
Kang, S.-I., Shin, H.-S., Kim, H.-M., Hong, Y.-S., Yoon, S.-A., Kang, S.-W., Kim, J.-H., Kim, M.-H., Ko, H.-C., & Kim, S.-J. (2012). Immature Citrus sunki peel extract exhibits antiobesity effects by β-oxidation and lipolysis in high-fat diet-induced obese mice. Biological and Pharmaceutical Bulletin, 35(2), 223-230.
Kiess, W., Petzold, S., Töpfer, M., Garten, A., Blüher, S., Kapellen, T., Körner, A., & Kratzsch, J. (2008). Adipocytes and adipose tissue. Best Practice & Research Clinical Endocrinology & Metabolism, 22(1), 135-153.
Kimoto‐Nira, H., Moriya, N., Nogata, Y., Sekiyama, Y., & Toguchi, Y. (2019). Fermentation of Shiikuwasha (Citrus depressa Hayata) pomace by lactic acid bacteria to generate new functional materials. International Journal of Food Science & Technology, 54(3), 688-695.
Kondo, M., Goto, M., Kodama, A., & Hirose, T. (2000). Fractional extraction by supercritical carbon dioxide for the deterpenation of bergamot oil. Industrial & Engineering Chemistry Research, 39(12), 4745-4748.
Koppel, N., Maini Rekdal, V., & Balskus, E. P. (2017). Chemical transformation of xenobiotics by the human gut microbiota. Science, 356(6344), 2770.
Kou, G., Li, P., Hu, Y., Chen, H., Nyantakyiwaa Amoah, A., Seydou Traore, S., Cui, Z., & Lyu, Q. (2021). Nobiletin activates thermogenesis of brown and white adipose tissue in high‐fat diet‐fed C57BL/6 mice by shaping the gut microbiota. The FASEB Journal, 35(2), e21267.
Kruger, J., Kohl III, H., & Miles, I. (2007). Prevalence of regular physical activity among adults-United States, 2001 and 2005. Morbidity and Mortality Weekly Report, 56(46), 1209-1212.
Kuo, S.-M. (1996). Antiproliferative potency of structurally distinct dietary flavonoids on human colon cancer cells. Cancer Letters, 110(1-2), 41-48.
Kurowska, E. M., & Manthey, J. A. (2004). Hypolipidemic effects and absorption of citrus polymethoxylated flavones in hamsters with diet-induced hypercholesterolemia. Journal of Agricultural and Food Chemistry, 52(10), 2879-2886.
Lafontan, M., & Langin, D. (2009). Lipolysis and lipid mobilization in human adipose tissue. Progress in Lipid Research, 48(5), 275-297.
Lee, M.-K., Moon, S.-S., Lee, S.-E., Bok, S.-H., Jeong, T.-S., Park, Y. B., & Choi, M.-S. (2003). Naringenin 7-O-cetyl ether as inhibitor of HMG-CoA reductase and modulator of plasma and hepatic lipids in high cholesterol-fed rats. Bioorganic & Medicinal Chemistry, 11(3), 393-398.
Lee, Y.-S., Cha, B.-Y., Saito, K., Yamakawa, H., Choi, S.-S., Yamaguchi, K., Yonezawa, T., Teruya, T., Nagai, K., & Woo, J.-T. (2010). Nobiletin improves hyperglycemia and insulin resistance in obese diabetic ob/ob mice. Biochemical Pharmacology, 79(11), 1674-1683.
Li, B., Smith, B., & Hossain, M. M. (2006). Extraction of phenolics from citrus peels: II. Enzyme-assisted extraction method. Separation and Purification Technology, 48(2), 189-196.
Li, S., Wang, Z., Sang, S., Huang, M. T., & Ho, C. T. (2006). Identification of nobiletin metabolites in mouse urine. Molecular Nutrition & Food Research, 50(3), 291-299.
Li, W., Wang, X., Niu, X., Zhang, H., He, Z., Wang, Y., Zhi, W., & Liu, F. (2016). Protective effects of nobiletin against endotoxic shock in mice through inhibiting TNF-α, IL-6, and HMGB1 and regulating NF-κB pathway. Inflammation, 39(2), 786-797.
Loftus, T. M., Jaworsky, D. E., Frehywot, G. L., Townsend, C. A., Ronnett, G. V., Lane, M. D., & Kuhajda, F. P. (2000). Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science, 288(5475), 2379-2381.
Londos, C., Brasaemle, D. L., Schultz, C. J., Adler‐Wailes, D. C., Levin, D. M., Kimmel, A. R., & Rondinone, C. M. (1999). On the control of lipolysis in adipocytes. Annals of the New York Academy of Sciences, 892(1), 155-168.
Lowell, B. B., & Shulman, G. I. (2005). Mitochondrial dysfunction and type 2 diabetes. Science, 307(5708), 384-387.
Mandalari, G., Bennett, R. N., Kirby, A. R., Lo Curto, R. B., Bisignano, G., Waldron, K. W., & Faulds, C. B. (2006). Enzymatic hydrolysis of flavonoids and pectic oligosaccharides from bergamot (Citrus bergamia Risso) peel. Journal of Agricultural and Food Chemistry, 54(21), 8307-8313.
Manthey, J. A., Guthrie, N., & Grohmann, K. (2001). Biological properties of citrus flavonoids pertaining to cancer and inflammation. Current Medicinal Chemistry, 8(2), 135-153.
Marin, F., Frutos, M., Perez-Alvarez, J., Martinez-Sanchez, F., & Del Rio, J. (2002). Flavonoids as nutraceuticals: structural related antioxidant properties and their role on ascorbic acid preservation. Studies in Natural Products Chemistry, 26, 741-778.
Marín, F. R., Soler-Rivas, C., Benavente-García, O., Castillo, J., & Pérez-Alvarez, J. A. (2007). By-products from different citrus processes as a source of customized functional fibres. Food Chemistry, 100(2), 736-741.
Martínez-Hernández, A., Enríquez, L., Moreno-Moreno, M. J., & Martí, A. (2007). Genetics of Obesity. Public Health Nutrition, 10(10A), 1138-1144.
Mattson, M. P. (2010). Perspective: does brown fat protect against diseases of aging? Ageing Research Reviews, 9(1), 69-76.
Mickelsen, O., Takahashi, S., & Craig, C. (1955). Experimental obesity. 1. Production of obesity in rats by feeding high-fat diets. Journal of Nutrition, 57, 541-554.
Miller, J. A., Thompson, P. A., Hakim, I. A., Chow, H.-H. S., & Thomson, C. A. (2011). d-Limonene: a bioactive food component from citrus and evidence for a potential role in breast cancer prevention and treatment. Oncology Reviews, 5(1), 31-42.
Miyata, Y., Tanaka, H., Shimada, A., Sato, T., Ito, A., Yamanouchi, T., & Kosano, H. (2011). Regulation of adipocytokine secretion and adipocyte hypertrophy by polymethoxyflavonoids, nobiletin and tangeretin. Life Sciences, 88(13-14), 613-618.
Moreno, L. A., & Rodríguez, G. (2007). Dietary risk factors for development of childhood obesity. Current Opinion in Clinical Nutrition & Metabolic Care, 10(3), 336-341.
Morrow, N. M., Burke, A. C., Samsoondar, J. P., Seigel, K. E., Wang, A., Telford, D. E., Sutherland, B. G., O'Dwyer, C., Steinberg, G. R., & Fullerton, M. D. (2020). The citrus flavonoid nobiletin confers protection from metabolic dysregulation in high-fat-fed mice independent of AMPK [S]. Journal of Lipid Research, 61(3), 387-402.
Munday, M. (2002). Regulation of mammalian acetyl-CoA carboxylase. Biochemical Society Transactions, 30(6), 1059-1064.
Murdick, D., & Allen, D. (1960). Germicidal effect of orange peel oil and n-limonene in water and orange juice. 1. Fungitidal properties against yeast. Food Tcclznol, 14, 441.
Nagata, E., Ichi, I., Kataoka, R., Matsushima, M., Adachi, N., Kitamura, Y., Sasaki, T., & Kojo, S. (2010). Effect of nobiletin on lipid metabolism in rats. Journal of Health Science, 56(6), 705-711.
Ohsaki, Y., Cheng, J., Suzuki, M., Shinohara, Y., Fujita, A., & Fujimoto, T. (2009). Biogenesis of cytoplasmic lipid droplets: from the lipid ester globule in the membrane to the visible structure. Biochimica et Biophysica Acta, 1791(6), 399-407.
Okabe, Y., Shimada, T., Horikawa, T., Kinoshita, K., Koyama, K., Ichinose, K., Aburada, M., & Takahashi, K. (2014). Suppression of adipocyte hypertrophy by polymethoxyflavonoids isolated from Kaempferia parviflora. Phytomedicine, 21(6), 800-806.
Pagano, C., Soardo, G., Esposito, W., Fallo, F., Basan, L., Donnini, D., Federspil, G., Sechi, L. A., & Vettor, R. (2005). Plasma adiponectin is decreased in nonalcoholic fatty liver disease. European Journal of Endocrinology, 152(1), 113-118.
Parkar, N., Bhatt, L., & Addepalli, V. (2016). Efficacy of nobiletin, a citrus flavonoid, in the treatment of the cardiovascular dysfunction of diabetes in rats. Food & Function, 7(7), 3121-3129.
Parmar, H. S., & Kar, A. (2008). Medicinal values of fruit peels from Citrus sinensis, Punica granatum, and Musa paradisiaca with respect to alterations in tissue lipid peroxidation and serum concentration of glucose, insulin, and thyroid hormones. Journal of Medicinal Food, 11(2), 376-381.
Puigserver, P., Wu, Z., Park, C. W., Graves, R., Wright, M., & Spiegelman, B. M. (1998). A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell, 92(6), 829-839.
Qi, L., Heredia, J. E., Altarejos, J. Y., Screaton, R., Goebel, N., Niessen, S., MacLeod, I. X., Liew, C. W., Kulkarni, R. N., & Bain, J. (2006). TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism. Science, 312(5781), 1763-1766.
Qin, J., Li, R., Raes, J., Arumugam, M., Burgdorf, K. S., Manichanh, C., Nielsen, T., Pons, N., Levenez, F., & Yamada, T. (2010). A human gut microbial gene catalogue established by metagenomic sequencing. Nature, 464(7285), 59-65.
Rankinen, T., Zuberi, A., Chagnon, Y. C., Weisnagel, S. J., Argyropoulos, G., Walts, B., Pérusse, L., & Bouchard, C. (2006). The human obesity gene map: the 2005 update. Obesity, 14(4), 529-644.
Ravindran, R., Hassan, S. S., Williams, G. A., & Jaiswal, A. K. (2018). A review on bioconversion of agro-industrial wastes to industrially important enzymes. Bioengineering, 5(4), 93.
Rolls, B. J. (2003). The supersizing of America: portion size and the obesity epidemic. Nutrition Today, 38(2), 42-53.
Rosen, E. D., & Spiegelman, B. M. (2006). Adipocytes as regulators of energy balance and glucose homeostasis. Nature, 444(7121), 847-853.
Rupasinghe, H. V., Sekhon-Loodu, S., Mantso, T., & Panayiotidis, M. I. (2016). Phytochemicals in regulating fatty acid β-oxidation: Potential underlying mechanisms and their involvement in obesity and weight loss. Pharmacology & Therapeutics, 165, 153-163.
Saely, C. H., Geiger, K., & Drexel, H. (2012). Brown versus white adipose tissue: a mini-review. Gerontology, 58(1), 15-23.
Salunkhe, D. K., & Kadam, S. (1995). Handbook of fruit science and technology: production, composition, storage, and processing: CRC press.
Schieber, A., Stintzing, F. C., & Carle, R. (2001). By-products of plant food processing as a source of functional compounds—recent developments. Trends in Food Science & Technology, 12(11), 401-413.
Schweiger, M., Schreiber, R., Haemmerle, G., Lass, A., Fledelius, C., Jacobsen, P., Tornqvist, H., Zechner, R., & Zimmermann, R. (2006). Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism. Journal of Biological Chemistry, 281(52), 40236-40241.
Sekiya, M., Osuga, J.-i., Yahagi, N., Okazaki, H., Tamura, Y., Igarashi, M., Takase, S., Harada, K., Okazaki, S., & Iizuka, Y. (2008). Hormone-sensitive lipase is involved in hepatic cholesteryl ester hydrolysis. Journal of Lipid Research, 49(8), 1829-1838.
Sekiya, M., Osuga, J. i., Okazaki, H., Yahagi, N., Harada, K., Shen, W. J., Tamura, Y., Tomita, S., Iizuka, Y., & Ohashi, K. (2004). Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lepob/ob mice. Journal of Biological Chemistry, 279(15), 15084-15090.
Semple, R., Crowley, V., Sewter, C., Laudes, M., Christodoulides, C., Considine, R., Vidal-Puig, A., & O'rahilly, S. (2004). Expression of the thermogenic nuclear hormone receptor coactivator PGC-1 α is reduced in the adipose tissue of morbidly obese subjects. International Journal of Obesity, 28(1), 176-179.
Shabnam, J., Rauf, A., Khurram, S., Shaista, N., Salman, S., & Yasar, S. (2013). Chemical constituents, antimicrobial and antioxidant activity of essential oil of Citrus limetta var. Mitha (sweet lime) peel in Pakistan. African Journal of Microbiology Research, 7(24), 3071-3077.
Shanik, M. H., Xu, Y., Skrha, J., Dankner, R., Zick, Y., & Roth, J. (2008). Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care, 31(Supplement_2), S262-S268.
Sharma, K., Mahato, N., Cho, M. H., & Lee, Y. R. (2017). Converting citrus wastes into value-added products: Economic and environmently friendly approaches. Nutrition, 34, 29-46.
Shen, W., Xu, Y., & Lu, Y. H. (2012). Inhibitory effects of Citrus flavonoids on starch digestion and antihyperglycemic effects in HepG2 cells. Journal of Agricultural and Food Chemistry, 60(38), 9609-9619.
Smith, S. (1994). The animal fatty acid synthase: one gene, one polypeptide, seven enzymes. The FASEB Journal, 8(15), 1248-1259.
Smith, S., Witkowski, A., & Joshi, A. K. (2003). Structural and functional organization of the animal fatty acid synthase. Progress in Lipid Research, 42(4), 289-317.
Solano, M. P., & Goldberg, R. B. (2006). Management of dyslipidemia in diabetes. Cardiology in Review, 14(3), 125-135.
Spiegel, K., Tasali, E., Penev, P., & Cauter, E. V. (2004). Brief communication: sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Annals of Internal Medicine, 141(11), 846-850.
Stunkard, A. J., Harris, J. R., Pedersen, N. L., & McClearn, G. E. (1990). The body-mass index of twins who have been reared apart. New England Journal of Medicine, 322(21), 1483-1487.
Subba, M., Soumithri, T., & Rao, R. S. (1967). Antimicrobial action of citrus oils. Journal of Food Science, 32(2), 225-227.
Tanaka, T., Makita, H., Kawabata, K., Mori, H., Kakumoto, M., Satoh, K., Hara, A., Sumida, T., Tanaka, T., & Ogawa, H. (1997). Chemoprevention of azoxymethane-induced rat colon carcinogenesis by the naturally occurring flavonoids, diosmin and hesperidin. Carcinogenesis, 18(5), 957-965.
Tian, X., Liu, Y., Feng, X., Khaskheli, A. A., Xiang, Y., & Huang, W. (2018). The effects of alcohol fermentation on the extraction of antioxidant compounds and flavonoids of pomelo peel. LWT, 89, 763-769.
Trinder, P. (1969). Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Annals of Clinical Biochemistry, 6(1), 24-27.
Tripoli, E., La Guardia, M., Giammanco, S., Di Majo, D., & Giammanco, M. (2007). Citrus flavonoids: Molecular structure, biological activity and nutritional properties: A review. Food Chemistry, 104(2), 466-479.
Tung, Y.-C., Chang, W.-T., Li, S., Wu, J.-C., Badmeav, V., Ho, C.-T., & Pan, M.-H. (2018). Citrus peel extracts attenuated obesity and modulated gut microbiota in mice with high-fat diet-induced obesity. Food & Function, 9(6), 3363-3373.
U.S. Department of Agriculture (2021). Citrus: World Markets and Trade.
Uribe, S., & Pena, A. (1990). Toxicity of allelopathic monoterpene suspensions on yeast dependence on droplet size. Journal of Chemical Ecology, 16(4), 1399-1408.
Uribe, S., Ramirez, J., & Peña, A. (1985). Effects of beta-pinene on yeast membrane functions. Journal of Bacteriology, 161(3), 1195-1200.
Uribe, S., Rangel, P., Espínola, G., & Aguirre, G. (1990). Effects of cyclohexane, an industrial solvent, on the yeast Saccharomyces cerevisiae and on isolated yeast mitochondria. Applied and Environmental Microbiology, 56(7), 2114-2119.
Wang, L., Wang, J., Fang, L., Zheng, Z., Zhi, D., Wang, S., Li, S., Ho, C.-T., & Zhao, H. (2014). Anticancer activities of citrus peel polymethoxyflavones related to angiogenesis and others. BioMed Research International, 2014.
Wang, Q., Qin, X., Liang, Z., Li, S., Cai, J., Zhu, Z., & Liu, G. (2018). HPLC–DAD–ESI–MS/MS analysis of phytochemicals from Sichuan red orange peel using ultrasound-assisted extraction. Food Bioscience, 25, 15-20.
Wilkins, M. R., Widmer, W. W., & Grohmann, K. (2007). Simultaneous saccharification and fermentation of citrus peel waste by Saccharomyces cerevisiae to produce ethanol. Process Biochemistry, 42(12), 1614-1619.
Winder, W., & Hardie, D. (1996). Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. American Journal of Physiology-Endocrinology and Metabolism, 270(2), E299-E304.
World Heath Organization. Obesity. Retrieved from https://www.who.int/health-topics/obesity/#tab=tab_1
Yamaguchi, T., Omatsu, N., Matsushita, S., & Osumi, T. (2004). CGI-58 interacts with perilipin and is localized to lipid droplets: possible involvement of CGI-58 mislocalization in Chanarin-Dorfman syndrome. Journal of Biological Chemistry, 279(29), 30490-30497.
Yang, Q., Graham, T. E., Mody, N., Preitner, F., Peroni, O. D., Zabolotny, J. M., Kotani, K., Quadro, L., & Kahn, B. B. (2005). Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature, 436(7049), 356-362.
Yaqoob, P., Sherrington, E. J., Jeffery, N. M., Sanderson, P., Harvey, D. J., Newsholme, E. A., & Calder, P. C. (1995). Comparison of the effects of a range of dietary lipids upon serum and tissue lipid composition in the rat. The International Journal of Biochemistry & Cell Biology, 27(3), 297-310.
Ye, J. (2013). Mechanisms of insulin resistance in obesity. Frontiers of Medicine, 7(1), 14-24.
Young, S. G., & Zechner, R. (2013). Biochemistry and pathophysiology of intravascular and intracellular lipolysis. Genes & Development, 27(5), 459-484.
Yu, H. Y., Park, S. W., Chung, I. M., & Jung, Y. S. (2011). Anti-platelet effects of yuzu extract and its component. Food and Chemical Toxicology, 49(12), 3018-3024.
Yuk, T., Kim, Y., Yang, J., Sung, J., Jeong, H. S., & Lee, J. (2018). Nobiletin inhibits hepatic lipogenesis via activation of AMP-activated protein kinase. Evidence-Based Complementary and Alternative Medicine, 2018.
Zhang, L., Zhang, X., Zhang, C., Bai, X., Zhang, J., Zhao, X., Chen, L., Wang, L., Zhu, C., & Cui, L. (2016). Nobiletin promotes antioxidant and anti-inflammatory responses and elicits protection against ischemic stroke in vivo. Brain Research, 1636, 130-141.
Zhang, M., Xin, Y., Feng, K., Yin, B., Kan, Q., Xiao, J., Cao, Y., Ho, C.-T., & Huang, Q. (2020). Comparative analyses of bioavailability, biotransformation, and excretion of nobiletin in lean and obese rats. Journal of Agricultural and Food Chemistry, 68(39), 10709-10718.