Background: Flavonoids are multi-functional bioactive compounds that have been used as natural compounds against various diseases. Citrus fruit is an important source for bioactive flavonoids with potential anti-obesity benefits. Methods: To determine the anti-obese effects of citrus peel, a 45% high fat diet-induced obesity (DIO) model using C57BL/6 mice was prepared for 10 weeks and then treated orally for 12 weeks with ethanol extracts of citrus peel (300 mg/kg, CP). CP was compared with normal chow diet (C), high fat diet (HF), and the anti-obesity drug orlistat (30 mg/kg, O) as a positive control. HF caused increases in lipid accumulation, body weight gain, and hepatic toxicity compared with the C group. Results: CP treatment reduced body weight gain and decreased epididymal fat, mesenteric fat, and plasma and hepatic TG levels in a similar manner as O treatment. Besides, CP was comparatively more effective than O at increasing high density lipoprotein cholesterol (HDL-c) while reducing hepatic toxicity, which is caused by HF. Fat accumulation in adipose tissue was decreased by CP treatment because of up-regulation of specific lipolysis enzymes such as HSL and AMPK and down-regulation of adipogenesis related genes such as C/EBPα and ACC. The proinflammatory cytokines, TNF-α and IL-6, which are the key factors for regulation of inflammation, were significantly decreased by CP. Conclusion: CP may be a potential natural source for new anti-obesity candidate because of its inhibitory effect on fat synthesis-related inflammation and its positive effect on lipolysis activation.
Dandona, P., Aljada, A. and Bandyopadhyay, A. (2004) Inflammation: The Link between Insulin Resistance, Obesity and Diabetes. Trends in Immunology, 25, 4-7. http://dx.doi.org/10.1016/j.it.2003.10.013
Jung, U. and Choi, M.S. (2014) Obesity and Its Metabolic Complications: The Role of Adipokines and the Relationship between Obesity, Inflammation, Insulin Resistance, Dyslipidemia and Nonalcoholic Fatty Liver Disease. International Journal of Molecular Sciences, 15, 6184-6123. http://dx.doi.org/10.3390/ijms15046184
Noriyuki, O., Parker, J.L., Lugus, J.J. and Walsh, K. (2011) Adipokines in Inflammation and Metabolic Disease. Nature Reviews Immunology, 11, 85-97. http://dx.doi.org/10.1038/nri2921
Trayhurn, P. and Beattie, J.H. (2001) Physiological Role of Adipose Tissue: White Adipose Tissue as an Endocrine and Secretory Organ. Proceedings of the Nutrition Society, 60, 329-339. http://dx.doi.org/10.1079/PNS200194
Wellen, K.E. and Hotamisligil, G.S. (2003) Obesity-Induced Inflammatory Changes in Adipose Tissue. Journal of Clinical Investigation, 112, 1785-1788. http://dx.doi.org/10.1172/JCI20514
Gaidhu, M.P. and Ceddia, R.B. (2011) The Role of Adenosine Monophosphate Kinase in Remodeling White Adipose Tissue Metabolism. Exercise and Sport Sciences Reviews, 39, 102-108. http://dx.doi.org/10.1097/JES.0b013e31820ac03e
Cheigh, C.I., Chung, E.Y. and Chung, M.S. (2012) Enhanced Extraction of Flavanones Hesperidin and Narirutin from C. unshiu Peel Using Subcritical Water. Journal of Food Engineering, 110, 472-477. http://dx.doi.org/10.1016/j.jfoodeng.2011.12.019
Balasunram, N., Sundram, K. and Samman, S. (2006) Phenolic Compounds in Plants and Agri-Industrial By-Products: Antioxidant Activity, Occurrence, and Potential Uses. Food Chemistry, 99, 191-203. http://dx.doi.org/10.1016/j.foodchem.2005.07.042
Ghasemi, K., Ghasemi, Y. and Ebrahimzadeh, M.A. (2009) Antioxidant Activity, Phenol and Flavonoid Contents of 13 Citrus Species Peels and Tissues. Pakistan Journal of Pharmaceutical Sciences, 22, 277-281.
Benavente-Garcia, O. and Castillo, J. (2008) Update on Uses and Properties of Citrus Flavonoids: New Findings in Anticancer, Cardiovascular, and Anti-Inflammatory Activity. Journal of Agricultural and Food Chemistry, 15, 6185- 6205. http://dx.doi.org/10.1021/jf8006568
Oh, Y.C., Cho, W.K., Jeong, Y.H., Im, G.Y., Yang, M.C., Hwang, Y.H., et al. (2012) Anti-Inflammatory Effect of Citrus unshiu Peel in LPS-Stimulated RAW 264.7 Macrophage Cells. The American Journal of Chinese Medicine, 40, 611-629. http://dx.doi.org/10.1142/S0192415X12500462
Min, K.Y., Lee, K.A., Kim, H.J., Kim, K.T., Chung, M.S., Chang, P.S., et al. (2014) Antioxidative and Anti-Inflammatory Activities of Citrus unshiu Peel Extracts Using a Combined Process of Subcritical Water Extraction and Acid Hydrolysis. Food Science and Biotechnology, 23, 1441-1446. http://dx.doi.org/10.1007/s10068-014-0197-y
Jung, H.K., Jeong, Y.S., Park, C.D., Park, C.H. and Hong, J.H. (2011) Inhibitory Effect of Citrus Peel Extract on Lipid Accumulation of 3T3-L1 Adipocytes. Journal of the Korean Society for Applied Biological Chemistry, 54, 169-176. http://dx.doi.org/10.3839/jksabc.2011.028
Folch, J., Lees, M. and Stanley, G.H.S. (1957) A Simple Method for the Isolation and Purification of Total Lipids from Animal Tissues. Journal of Biological Chemistry, 226, 497-509.
Johnson, R., McNutt, P., MacMahon, S. and Robson, R. (1997) Use of the Friedewald Formula to Estimate LDL- Cholesterol in Patients with Chronic Renal Failure on Dialysis. Clinical Chemistry, 43, 2183-2184.
Yi, Z.B., Yu, Y., Liang, Y.Z. and Zeng, B. (2008) In Vitro Antioxidant and Antimicrobial Activities of the Extract of Pericarpium Citri Reticulatae of a New Citrus Cultivar and Its Main Flavonoids. LWT—Food Science and Technology, 41, 597-603. http://dx.doi.org/10.1016/j.lwt.2007.04.008
Asres, K., Seyoum, A., Veeresham, C., Bucar, F. and Gibbons, S. (2005) Naturally Derived Anti-HIV Agents. Phytotherapy Research, 19, 557-581. http://dx.doi.org/10.1002/ptr.1629
Cushnie, P.T. and Lamb, A.J. (2005) Antimicrobial Activity of Flavonoids. International Journal of Antimicrobial Agents, 26, 343-356. http://dx.doi.org/10.1016/j.ijantimicag.2005.09.002
Kim, H.P., Son, K.H., Chang, H.W. and Kang, S.S. (2004) Anti-Inflammatory Plant Flavonoids and Cellular Action Mechanisms. Journal of Pharmacological Sciences, 96, 229-245. http://dx.doi.org/10.1254/jphs.CRJ04003X
Karadeniz, F., Kim, J.A., Ahn, B.N., Kwon, M.S. and Kong, C.S. (2014) Effect of Salicornia herbacea on Osteoblastogenesis and Adipogenesis in Vitro. Marine Drugs, 12, 5132-5147. http://dx.doi.org/10.3390/md12105132
Lu, Y., Xi, W., Ding, X., Fan, S., Zhang, Y., Jiang, D., et al. (2013) Citrange Fruit Extracts Alleviate Obesity-Associated Metabolic Disorder in High-Fat Diet-Induced Obese C57BL/6 Mouse. International Journal of Molecular Sciences, 14, 23736-23750. http://dx.doi.org/10.3390/ijms141223736
Fukuchi, Y., Hiramitsu, M., Okada, M., Hayashi, S., Nabeno, Y., Osawa, T., et al. (2008) Polyphenols Suppress Diet-Induced Obesity by Up-Regulation of mRNA Levels of the Enzymes Involved in β-Oxidation in Mouse White Adipose Tissue. Journal of Clinical Biochemistry and Nutrition, 43, 201-209. http://dx.doi.org/10.3164/jcbn.2008066
Bent, S., Padula, A. and Neuhaus, J. (2004) Safety and Efficacy of Citrus aurantium for Weight Loss. American Journal of Cardiology, 15, 1359-1361. http://dx.doi.org/10.1016/j.amjcard.2004.07.137
Haaz, S., Fontaine, K.R., Cutter, G., Limdi, N., Perumean-Chaney, S. and Allison, D.B. (2006) Citrus aurantium and Synephrine Alkaloids in the Treatment of Overweight and Obesity: An Update. Obesity Reviews, 7, 79-88. http://dx.doi.org/10.1111/j.1467-789X.2006.00195.x
Kelleya, D.S., Adkinsa, Y.C., Zuninoa, S.J., Woodhousea, L.R., Bonnela, E.L., Breksa, A.P., et al. (2015) Citrus Limonin Glucoside Supplementation Decreased Biomarkers of Liver Disease and Inflammation in Overweight Human Adults. Journal of Functional Foods, 12, 271-281. http://dx.doi.org/10.1016/j.jff.2014.11.026
Ma, Y., Ye, X., Fang, Z., Chen, J., Xu, G. and Liu, D. (2008) Phenolic Compounds and Antioxidant Activity of Extracts from Ultrasonic Treatment of Satsuma Mandarin (Citrus unshiu Marc.) Peels. Journal of Agricultural and Food Chemistry, 56, 5682-5690. http://dx.doi.org/10.1021/jf072474o
Gattuso, G., Barreca, D., Garguilli, C., Leuzzi, U. and Coristi, C. (2007) Flavonoid Composition of Citrus Juice. Molecules, 12, 1641-1673. http://dx.doi.org/10.3390/12081641
Ma, Y., Ye, X., Hao, Y., Xu, G., Xu, G. and Liu, D. (2008) Ultrasound-Assisted Extraction of Hesperidin from Penggan (Citrus reticulata) Peel. Ultrasonics Sonochemistry, 15, 227-232. http://dx.doi.org/10.1016/j.ultsonch.2007.03.006
Svendsen, M. and Tonstad, S. (2011) Orlistat after Initial Dietary/Behavioural Treatment: Changes in Body Weight and Dietary Maintenance in Subjects with Sleep Related Breathing Disorders. Nutrition Journal, 10, 21. http://dx.doi.org/10.1186/1475-2891-10-21
Ding, X., Fan, S., Lu, Y., Zhang, Y., Gu, M., Zhang, L., et al. (2012) Citrus ichangensis Peel Extract Exhibits Anti- Metabolic Disorder Effects by the Inhibition of PPARγ and LXR Signaling in High-Fat Diet-Induced C57BL/6 Mouse. Evidence-Based Complementary and Alternative Medicine, 2012, Article ID: 678592. http://dx.doi.org/10.1155/2012/678592
Salter, A.M., Fong, B.S., Jimenez, J., Rotstein, L. and Angel, A. (1987) Regional Variation in High-Density Lipoprotein Binding to Human Adipocyte Plasma Membranes of Massively Obese Subjects. European Journal of Clinical Investigation, 17, 16-22. http://dx.doi.org/10.1111/j.1365-2362.1987.tb01220.x
Park, H.Y., Park, Y., Lee, Y., Noh, S.K., Sung, E.G. and Chou, I. (2012) Effect of Oral Administration of Water-Soluble Extract from Citrus Peel (Citrus unshiu) on Suppressing Alcohol-Induced Fatty Liver in Rats. Food Chemistry, 130, 598-604. http://dx.doi.org/10.1016/j.foodchem.2011.07.081
Vozarova, B., Stefan, N., Lindsay, R.S., Saremi, A., Pratley, R.E., Bogardus, C., et al. (2002) High Alanine Aminotransferase Is Associated with Decreased Hepatic Insulin Sensitivity and Predicts the Development of Type 2 Diabetes. Diabetes, 51, 1889-1895. http://dx.doi.org/10.2337/diabetes.51.6.1889
Wang, S. and Peng, D. (2012) Regulation of Adipocyte Autophagy—The Potential Anti-Obesity Mechanism of High Density Lipoprotein and Apolipoprotein A-I. Lipids in Health and Disease, 11, 131. http://dx.doi.org/10.1186/1476-511X-11-131
Guha, M. and Mackman, N. (2002) The Phosphatidylinositol 3-Kinase-Akt Pathway Limits Lipopolysaccharide Activation of Signaling Pathways and Expression of Inflammatory Mediators in Human Monocytic Cells. The Journal of Biological Chemistry, 277, 32124-32132. http://dx.doi.org/10.1074/jbc.M203298200
Xu, X., Wei, X., Yang, Y., Niu, W., Kou, Q., Wang, X., et al. (2015) PPARγ, FAS, HSL mRNA and Protein Expression during Tan Sheep Fat-Tail Development. Electronic Journal of Biotechnology, 18, 122-127. http://dx.doi.org/10.1016/j.ejbt.2015.01.004
Sekiya, M., Osuga, J.I., Okazaki, H., Yahagi, N., Harada, K., Shen, W.J., et al. (2004) Absence of Hormone-Sensitive Lipase Inhibits Obesity and Adipogenesis in Lepob/ob Mice. The Journal of Biological Chemistry, 279, 15084-15090. http://dx.doi.org/10.1074/jbc.M310985200
Zechner, R., Kienesberger, P.C., Haemmerle, G., Zimmermann, R. and Lass, A. (2009) Adipose Triglyceride Lipase and the Lipolytic Catabolism of Cellular Fat Stores. Journal of Lipid Research, 50, 3-21. http://dx.doi.org/10.1194/jlr.R800031-JLR200
Consolazio, A., Alò, P.L., Rivera, M., Iacopini, F., Paoluzi, O.A., Crispino, P., et al. (2006) Overexpression of Fatty Acid Synthase in Ulcerative Colitis. American Journal of Clinical Pathology, 126, 113-118. http://dx.doi.org/10.1309/PUBVQNDNVQKJVC8M
Ji, C., Chen, X., Gao, C., Jiao, L., Wang, J., Xu, G., et al. (2011) IL-6 Induces Lipolysis and Mitochondrial Dysfunction, but Does Not Affect Insulin-Mediated Glucose Transport in 3T3-L1 Adipocytes. Journal of Bioenergetics and Biomembranes, 43, 367-375. http://dx.doi.org/10.1007/s10863-011-9361-8
Pantsulaia, I., Iobadze, M., Pantsulaia, N. and Chikovani, T. (2014) The Effect of Citrus Peel Extracts on Cytokines Levels and T Regulatory Cells in Acute Liver Injury. BioMed Research International, 2014, Article ID: 127879. http://dx.doi.org/10.1155/2014/127879
Carling, D. (2004) The AMP-Activated Protein Kinase Cascade—A Unifying System for Energy Control. Trends in Biochemical Sciences, 29, 18-24. http://dx.doi.org/10.1016/j.tibs.2003.11.005
Park, T. and Kim, Y. (2011) Phytochemicals as Potential Agents for Prevention and Treatment of Obesity and Metabolic Diseases. Anti-Obesity Drug Discovery and Development, 1, 1-48.