Nobiletin Prevents Body Weight Gain and Bone Loss in Ovariectomized C57BL/6J Mice

Abstract

Obesity and osteoporosis are associated with estrogen deficiency following menopause. Therefore, it is important to prevent and treat both disorders to maintain a healthy life in postmenopausal women. Nobiletin, a polymethoxylated flavone, exhibits various pharmacologic effects, including anti-tumor and anti-inflammatory activities. Therefore, in this study, we examined the effects of nobiletin on obesity, obesity-related metabolic disorders, and bone mass in ovariectomized (OVX) mice. Mice were divided into four groups and underwent sham operation or OVX. OVX mice were treated with 50 or 100 mg/kg nobiletin, or received vehicle alone (0.3% carboxyl methyl cellulose/0.5% dimethyl sulfoxide). Nobiletin decreased body weight gain and white adipose tissue weight in OVX mice. Nobiletin also decreased triglyceride levels, and tended to reduce plasma total cholesterol and glucose levels. Additionally, nobiletin prevented the reduction in bone mineral density of the trabecular region of the femur in OVX mice. Taken together, our results suggest that nobiletin improves adiposity, dyslipidemia, hyperglycemia, and prevents bone loss in OVX mice. Therefore, nobiletin is expected to have beneficial effects for the prevention and improvement of metabolic disorders and osteoporosis in postmenopausal women.

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Lee, Y. , Asai, M. , Choi, S. , Yonezawa, T. , Teruya, T. , Nagai, K. , Woo, J. and Cha, B. (2014) Nobiletin Prevents Body Weight Gain and Bone Loss in Ovariectomized C57BL/6J Mice. Pharmacology & Pharmacy, 5, 959-965. doi: 10.4236/pp.2014.510108.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] You, T., Ryan, A.S. and Nicklas, B.J. (2004) The Metabolic Syndrome in Obese Postmenopausal Women: Relationship to Body Composition, Visceral Fat, and Inflammation. The Journal of Clinical Endocrinology Metabolism, 89, 5517-5522.
http://press.endocrine.org/doi/abs/10.1210/jc.2004-0480?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed&
http://dx.doi.org/10.1210/jc.2004-0480
[2] Kaaja, R.J. (2008) Metabolic Syndrome and the Menopause. Menopause International, 14, 21-25.
http://min.sagepub.com/content/14/1/21.abstract
http://dx.doi.org/10.1258/mi.2007.007032
[3] Cooke, P.S. and Naaz, A. (2004) Role of Estrogens in Adipocyte Development and Function. Experimental Biology and Medicine (Maywood), 229, 1127-1235.
http://ebm.sagepub.com/content/229/11/1127.abstract
[4] Lobe, R.A. (2008) Metabolic Syndrome after Menopause and the Role of Hormones. Maturitas, 60, 10-18.
http://www.maturitas.org/article/S0378-5122(08)00039-X/abstract
http://dx.doi.org/10.1016/j.maturitas.2008.02.008
[5] Anderson, J.W., Johnstone, B.M. and Cook-Newell, M.E. (1995) Meta-Analysis of the Effects of Soy Protein Intake on Serum Lipids. The New England Journal of Medicine, 333, 276-282.
http://www.nejm.org/doi/full/10.1056/NEJM199508033330502
http://dx.doi.org/10.1056/NEJM199508033330502
[6] Messina, M.J. (2002) Soy Foods and Soybean Isoflavones and Menopausal Health. Nutrition in Clinical Care, 5, 272-282.
http://onlinelibrary.wiley.com/doi/10.1046/j.1523-5408.2002.05602.x/abstract
http://dx.doi.org/10.1046/j.1523-5408.2002.05602.x
[7] Mercader, J., Wanecq, E., Chen, J. and Carpéné, C. (2011) Isopropylnorsynephrine Is a Stronger Lipolytic Agent in Human Adipocytes than Synephrine and Other Amines Present in Citrus Aurantium. Journal of Physiology and Biochemistry, 67, 443-452.
http://link.springer.com/article/10.1007%2Fs13105-011-0078-2
[8] Nagata, U., Sakamoto, K., Shiratsuchi, H., Ishi, T., Yano, M. and Ohta, H. (2006) Flavonoid Composition of Fruit Tissues of Citrus Species. Bioscience, Biotechnology, and Biochemistry, 70, 178-192.
https://www.jstage.jst.go.jp/article/bbb/70/1/70_1_178/_article
[9] Murakami, A., Nakamura, Y., Torikai, K., et al. (2000) Inhibitory Effect of Citrus Nobiletin on Phorbol Ester-Induced Skin Inflammation Oxidative Stress, and Tumor Promotion in Mice. Cancer Research, 60, 5059-5066.
http://cancerres.aacrjournals.org/content/60/18/5059.long
[10] Silalahi, J. (2002) Anticancer and Health Protective Properties of Citrus Fruit Components. Asia Pacific Journal of Clinical Nutrition, 11, 79-84.
http://onlinelibrary.wiley.com/doi/10.1046/j.1440-6047.2002.00271.x/abstract
http://dx.doi.org/10.1046/j.1440-6047.2002.00271.x
[11] Nakajima, A., Yamakuni, T., Haraguchi, M., Omae, N., Song, S.Y., Kato, C., et al. (2007) Nobilein, a Citrus Flavonoid that Improves Memory Impairment, Rescues Bulbectomy-Induced Cholinergic Neurodegeneration in Mice. Journal of Pharmacological Sciences, 105, 122-126.
https://www.jstage.jst.go.jp/article/jphs/105/1/105_1_122/_article
[12] Harada, S., Tominari, T., Matsumoto, C., Hirata, M., Takita, M., Inada, M. and Miyaura, C. (2011) Nobiletin, a Polymethoxy Flavonoid, Suppresses Bone Resorption by Inhibiting NFκB-Dependent Prostaglandin E Synthesis in Osteoblasts and Prevents Bone Loss Due to Estrogen Deficiency. Journal of Pharmacological Sciences, 115, 89-93.
https://www.jstage.jst.go.jp/article/jphs/115/1/115_10193SC/_article
http://dx.doi.org/10.1254/jphs.10193SC
[13] Saito, T., Abe, D. and Sekiya, K. (2007) Nobiletin Enhances Differentiation and Lipolysis of 3T3-L1 Adipocytes. Biochemical and Biophysical Research Communications, 357, 371-376.
http://www.sciencedirect.com/science/article/pii/S0006291X07006109
[14] Kanda, K., Nishi, K., Kadota, A., Nishimoto, S., Liu, M.C. and Sugahara, T. (2011) Nobiletin Suppresses Adipocyte Differentiation of 3T3-L1 Cells by an Insulin and IBMX Mixture Induction. Biochimica et Biophysica Acta, 1820, 461-468.
http://www.sciencedirect.com/science/article/pii/S0304416511002923
[15] Choi, Y., Kim, Y., Ham, H., Park, Y., Jeong, H.S. and 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, 12843-12849.
http://pubs.acs.org/doi/abs/10.1021/jf2033208
http://dx.doi.org/10.1021/jf2033208
[16] Lee, Y.S., Cha, B.Y., Saito, K., Yamakawa, H., Choi, S.S., Yamaguchi, K., et al. (2010) Nobiletin Improves Hyperglycemia and Insulin Resistance in Obese Diabetic ob/ob Mice. Biochemical Pharmacology, 79, 1674-1683.
http://www.sciencedirect.com/science/article/pii/S0006295210000936
http://dx.doi.org/10.1016/j.bcp.2010.01.034
[17] Roger, N.H., Perfield II, J.W., Strissel, K.J., Obin, M.S. and Greenberg, A.S. (2009) Reduced Energy Expenditure and Increased Inflammation Are Early Events in the Development of Ovariectomy-Induced Obesity. Endocrinology, 150, 2161-2168.
http://press.endocrine.org/doi/abs/10.1210/en.2008-1405?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed
http://dx.doi.org/10.1210/en.2008-1405
[18] Kolta, S., De Vernejoul, M.C., Meneton, P., Fechtenbaum, J. and Roux, C. (2003) Bone Mineral Measurements in Mice: Comparison of Two Devices. Journal of Clinical Densitometry, 6, 251-258.
http://www.sciencedirect.com/science/article/pii/S109469500660276X
http://dx.doi.org/10.1385/JCD:6:3:251
[19] Riggs, B.L. (1992) Osteoporosis. In: Wyngaarden, J.B., Ed., Textbook of Medicine, 19th Edition, Saunders, Philadelphia, 1426-1430.

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