Generic placeholder image

Current Molecular Pharmacology

Editor-in-Chief

ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Research Article

Eucommia Leaf Extract Induces BDNF Production in Rat Hypothalamus and Enhances Lipid Metabolism and Aerobic Glycolysis in Rat Liver

Author(s): Hirotaka Oikawa, Shouhei Miyazaki, Rina Kurata, Mutsumi Hattori, Noriko Hayashi, Nami Kawaguchi, Tetsuya Hirata, Taro Ueda and Takahiko Fujikawa*

Volume 14, Issue 2, 2021

Published on: 05 May, 2020

Page: [234 - 244] Pages: 11

DOI: 10.2174/1874467213666200505094631

Price: $65

Abstract

Background: Mutations in the brain-derived neurotrophic factor (BDNF) gene and its receptor, tyrosine receptor kinase B (TrkB), have been reported to cause severe obesity in rodents. Our previous study demonstrated that the oral administration of 5% Eucommia leaf extract (ELE) or ELE aroma treatment (ELE aroma) produced anti-obesity effects.

Objective: In this study, we investigated the effects of ELE on glycolysis and lipid metabolism in male Sprague–Dawley rats, as well as the effects of ELE on BDNF in rat hypothalamus.

Methods and Results: A significant reduction and a reduction tendency in the respiratory quotient were observed in association with 5% ELE and ELE aroma treatment, respectively. Furthermore, RT-qPCR results showed significant increases in Cpt2, Acad, Complex II, and Complex V mRNA levels in the liver with both treatments. In addition, in rat hypothalamus, significant elevations in BDNF, Akt, PLCγ proteins and CREB phosphorylation were observed in the 5% ELE group and the ELE aroma group. Furthermore, the Ras protein was significantly increased in the ELE aroma group. On the other hand, significant dephosphorylation of ERK1/2 was observed by the western blotting in the 5% ELE group and the ELE aroma group.

Conclusion: These findings suggest that the ELE treatment enhances the lipid metabolism and increases the aerobic glycolytic pathway, while ELE-induced BDNF may affect such energy regulation. Therefore, ELE has the possibility to control metabolic syndrome.

Keywords: Eucommia leaf extract (ELE), Brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB), central nervous system (CNS), aroma, lipid metabolism, aerobic glycolytic.

Graphical Abstract
[1]
Xu, B.; Goulding, E.H.; Zang, K.; Cepoi, D.; Cone, R.D.; Jones, K.R.; Tecott, L.H.; Reichardt, L.F. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat. Neurosci., 2003, 6(7), 736-742.
[http://dx.doi.org/10.1038/nn1073] [PMID: 12796784]
[2]
Kernie, S.G.; Liebl, D.J.; Parada, L.F. BDNF regulates eating behavior and locomotor activity in mice. EMBO J., 2000, 19(6), 1290-1300.
[http://dx.doi.org/10.1093/emboj/19.6.1290] [PMID: 10716929]
[3]
Gray, J.; Yeo, G.S.; Cox, J.J.; Morton, J.; Adlam, A.L.; Keogh, J.M.; Yanovski, J.A.; El Gharbawy, A.; Han, J.C.; Tung, Y.C.; Hodges, J.R.; Raymond, F.L.; O’rahilly, S.; Farooqi, I.S. Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes, 2006, 55(12), 3366-3371.
[http://dx.doi.org/10.2337/db06-0550] [PMID: 17130481]
[4]
Han, J.C.; Liu, Q.R.; Jones, M.; Levinn, R.L.; Menzie, C.M.; Jefferson-George, K.S.; Adler-Wailes, D.C.; Sanford, E.L.; Lacbawan, F.L.; Uhl, G.R.; Rennert, O.M.; Yanovski, J.A. Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N. Engl. J. Med., 2008, 359(9), 918-927.
[http://dx.doi.org/10.1056/NEJMoa0801119] [PMID: 18753648]
[5]
An, J.J.; Liao, G.Y.; Kinney, C.E.; Sahibzada, N.; Xu, B. Discrete BDNF Neurons in the Paraventricular Hypothalamus Control Feeding and Energy Expenditure. Cell Metab., 2015, 22(1), 175-188.
[http://dx.doi.org/10.1016/j.cmet.2015.05.008] [PMID: 26073495]
[6]
Morton, G.J.; Cummings, D.E.; Baskin, D.G.; Barsh, G.S.; Schwartz, M.W. Central nervous system control of food intake and body weight. Nature, 2006, 443(7109), 289-295.
[http://dx.doi.org/10.1038/nature05026] [PMID: 16988703]
[7]
Balthasar, N.; Dalgaard, L.T.; Lee, C.E.; Yu, J.; Funahashi, H.; Williams, T.; Ferreira, M.; Tang, V.; McGovern, R.A.; Kenny, C.D.; Christiansen, L.M.; Edelstein, E.; Choi, B.; Boss, O.; Aschkenasi, C.; Zhang, C.Y.; Mountjoy, K.; Kishi, T.; Elmquist, J.K.; Lowell, B.B. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell, 2005, 123(3), 493-505.
[http://dx.doi.org/10.1016/j.cell.2005.08.035] [PMID: 16269339]
[8]
Atasoy, D.; Betley, J.N.; Su, H.H.; Sternson, S.M. Deconstruction of a neural circuit for hunger. Nature, 2012, 488(7410), 172-177.
[http://dx.doi.org/10.1038/nature11270] [PMID: 22801496]
[9]
Garland, T., Jr; Schutz, H.; Chappell, M.A.; Keeney, B.K.; Meek, T.H.; Copes, L.E.; Acosta, W.; Drenowatz, C.; Maciel, R.C.; van Dijk, G.; Kotz, C.M.; Eisenmann, J.C. The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives. J. Exp. Biol., 2011, 214(Pt 2), 206-229.
[http://dx.doi.org/10.1242/jeb.048397] [PMID: 21177942]
[10]
Vanevski, F.; Xu, B. Molecular and neural bases underlying roles of BDNF in the control of body weight. Front. Neurosci., 2013, 7, 37.
[http://dx.doi.org/10.3389/fnins.2013.00037] [PMID: 23519010]
[11]
Rios, M.; Fan, G.; Fekete, C.; Kelly, J.; Bates, B.; Kuehn, R.; Lechan, R.M.; Jaenisch, R. Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol. Endocrinol., 2001, 15(10), 1748-1757.
[http://dx.doi.org/10.1210/mend.15.10.0706] [PMID: 11579207]
[12]
Liao, G.Y.; An, J.J.; Gharami, K.; Waterhouse, E.G.; Vanevski, F.; Jones, K.R.; Xu, B. Dendritically targeted Bdnf mRNA is essential for energy balance and response to leptin. Nat. Med., 2012, 18(4), 564-571.
[http://dx.doi.org/10.1038/nm.2687] [PMID: 22426422]
[13]
Unger, T.J.; Calderon, G.A.; Bradley, L.C.; Sena-Esteves, M.; Rios, M. Selective deletion of Bdnf in the ventromedial and dorsomedial hypothalamus of adult mice results in hyperphagic behavior and obesity. J. Neurosci., 2007, 27(52), 14265-14274.
[http://dx.doi.org/10.1523/JNEUROSCI.3308-07.2007] [PMID: 18160634]
[14]
Xu, X.; Zeng, H.; Xiao, D.; Zhou, H.; Liu, Z. Genome wide association study of obesity. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2013, 38(1), 95-100. [Med Sci].
[PMID: 23406863]
[15]
Yeo, G.S.; Connie Hung, C.C.; Rochford, J.; Keogh, J.; Gray, J.; Sivaramakrishnan, S.; O’Rahilly, S.; Farooqi, I.S. A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat. Neurosci., 2004, 7(11), 1187-1189.
[http://dx.doi.org/10.1038/nn1336] [PMID: 15494731]
[16]
Fujikawa, T.; Hirata, T.; Wada, A.; Kawamura, N.; Yamaguchi, Y.; Fujimura, K.; Ueda, T.; Yurugi, Y.; Soya, H.; Nishibe, S. Chronic administration of Eucommia leaf stimulates metabolic function of rats across several organs. Br. J. Nutr., 2010, 104(12), 1868-1877.
[http://dx.doi.org/10.1017/S0007114510002965] [PMID: 20691136]
[17]
Hirata, T.; Kobayashi, T.; Wada, A.; Ueda, T.; Fujikawa, T.; Miyashita, H.; Ikeda, T.; Tsukamoto, S.; Nohara, T. Anti-obesity compounds in green leaves of Eucommia ulmoides. Bioorg. Med. Chem. Lett., 2011, 21(6), 1786-1791.
[http://dx.doi.org/10.1016/j.bmcl.2011.01.060] [PMID: 21324693]
[18]
Fujikawa, T.; Hirata, T.; Hosoo, S.; Nakajima, K.; Wada, A.; Yurugi, Y.; Soya, H.; Matsui, T.; Yamaguchi, A.; Ogata, M.; Nishibe, S. Asperuloside stimulates metabolic function in rats across several organs under high-fat diet conditions, acting like the major ingredient of Eucommia leaves with anti-obesity activity. J. Nutr. Sci., 2012, 1e10
[http://dx.doi.org/10.1017/jns.2012.12] [PMID: 25191539]
[19]
Zhang, W.; Fujikawa, T.; Mizuno, K.; Ishida, T.; Ooi, K.; Hirata, T.; Wada, A. Eucommia leaf extract (ELE) prevents OVX-induced osteoporosis and obesity in rats. Am. J. Chin. Med., 2012, 40(4), 735-752.
[http://dx.doi.org/10.1142/S0192415X12500553] [PMID: 22809028]
[20]
Miyazaki, S.; Oikawa, H.; Hirata, T.; Ueda, T.; Zhang, W.; Nishibe, S.; Fujikawa, T. Chronic administration of Eucommia leaf extract (ELE) and asperuloside (ASP), the major component of ELE, prevents adipocyte hypertrophy in white adipose tissues. Glob Drugs Therap., 2018, 3(2), 24-26.
[21]
Oikawa, H.; Miyazaki, S.; Zhang, W.; Nishide, H.; Nakamichi, S.; Morimoto-Kawaguchi, N.; Hirata, T.; Hosoo, S.; Yamaguchi, Y.; Yamasaki, H.; Nishibe, S.; Fujikawa, T. The characteristic taste of Eucommia leaf extract as the additive of a weight-loss and the constipation improvement is not associated with suppression of the feeding behavior of the fast rats with the extract. Glob Drugs Therap., 2017, 3(2), 14-18.
[http://dx.doi.org/10.15761/GDT.1000S2003]
[22]
Oikawa, H.; Miyazaki, S.; Nishide, H.; Nakamichi, S.; Kawaguchi, N.; Hirata, T.; Ueda, T.; Nishibe, S.; Fujikawa, T. Effect of Eucommia leaf extract on water consumption in rats is mediated by the parasympathetic nervous system. Glob Drugs Therap., 2018, 3(2), 27-30.
[23]
Oikawa, H.; Miyazaki, S.; Nishida, K.; Zhang, W.; Hirata, T.; Hosoo, S.; Yamaguchi, Y.; Yamasaki, H.; Nishibe, S.; Fujikawa, T. Promotion of osteoblastic Ca2+ accumulation by Eucommia leaf extract. Glob Drugs Therap., 2017, 3(2), 8-13.
[http://dx.doi.org/10.15761/GDT.1000S2002]
[24]
Ha, H.; Ho, J.; Shin, S.; Kim, H.; Koo, S.; Kim, I.H.; Kim, C. Effects of Eucommiae Cortex on osteoblast-like cell proliferation and osteoclast inhibition. Arch. Pharm. Res., 2003, 26(11), 929-936.
[http://dx.doi.org/10.1007/BF02980202] [PMID: 14661859]
[25]
Miyazaki, S.; Oikawa, H.; Nakamichi, S.; Hirata, T.; Yamasaki, H.; Yamaguchi, Y.; Zhang, W.; Nishibe, S.; Ogata, M.; Fujikawa, T. Aroma of Eucommia leaf extract (ELE) causes reduced locomotor activity and increased NREM sleep, acting like the partially related factors of oral ELE’s effects with locomotor-activity-dependent-increase in NREM- and REM-sleep. Glob Drugs Therap., 2017, 3(2), 1-7.
[http://dx.doi.org/10.15761/GDT.1000S2001]
[26]
Hiramoto, K.; Goto, K.; Sekijima, H.; Ooi, K.; Hirata, T.; Fujikawa, T. The preventive effects of asperuloside administration on dextran sodium sulfate-induced ulcerative colitis in mice. Glob Drugs Therap., 2017, 3(2), 19-23.
[http://dx.doi.org/10.15761/GDT.1000S2004]
[27]
Kwon, S.H.; Lee, H.K.; Kim, J.A.; Hong, S.I.; Kim, S.Y.; Jo, T.H.; Park, Y.I.; Lee, C.K.; Kim, Y.B.; Lee, S.Y.; Jang, C.G. Neuroprotective effects of Eucommia ulmoides Oliv. Bark on amyloid beta(25-35)-induced learning and memory impairments in mice. Neurosci. Lett., 2011, 487(1), 123-127.
[http://dx.doi.org/10.1016/j.neulet.2010.10.042] [PMID: 20974223]
[28]
Kwon, S.H.; Ma, S.X.; Joo, H.J.; Lee, S.Y.; Jang, C.G. Inhibitory Effects of Eucommia ulmoides Oliv. Bark on Scopolamine-Induced Learning and Memory Deficits in Mice. Biomol. Ther. (Seoul), 2013, 21(6), 462-469.
[http://dx.doi.org/10.4062/biomolther.2013.074] [PMID: 24404337]
[29]
Kwon, S.H.; Ma, S.X.; Hong, S.I.; Kim, S.Y.; Lee, S.Y.; Jang, C.G. Eucommia ulmoides Oliv. bark. attenuates 6-hydroxydopamine-induced neuronal cell death through inhibition of oxidative stress in SH-SY5Y cells. J. Ethnopharmacol., 2014, 152(1), 173-182.
[http://dx.doi.org/10.1016/j.jep.2013.12.048] [PMID: 24440915]
[30]
Wu, J.; Chen, H.; Li, H.; Tang, Y.; Yang, L.; Cao, S.; Qin, D. Antidepressant potential of chlorogenic acid-enriched extract from Eucommia ulmoides Oliver bark with neuron protection and promotion of serotonin release through enhancing synapsin I expression. Molecules, 2016, 21(3), 260.
[http://dx.doi.org/10.3390/molecules21030260] [PMID: 26927040]
[31]
Zhu, Y.L.; Sun, M.F.; Jia, X.B.; Zhang, P.H.; Xu, Y.D.; Zhou, Z.L.; Xu, Z.H.; Cui, C.; Chen, X.; Yang, X.S.; Shen, Y.Q. Aucubin alleviates glial cell activation and preserves dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian mice. Neuroreport, 2018, 29(13), 1075-1083.
[http://dx.doi.org/10.1097/WNR.0000000000001075] [PMID: 29985188]
[32]
Chen, S.; Zeng, X.; Zong, W.; Wang, X.; Chen, L.; Zhou, L.; Li, C.; Huang, Q.; Huang, X.; Zeng, G.; Hu, K.; Ouyang, D.S. Aucubin alleviates seizures activity in Li-Pilocarpine-Induced epileptic mice: Involvement of inhibition of neuroinflammation and regulation of neurotransmission. Neurochem. Res., 2019, 44(2), 472-484.
[http://dx.doi.org/10.1007/s11064-018-2700-y] [PMID: 30666488]
[33]
Oikawa, H.; Nakamichi, S.; Nishide, H.; Kawaguchi, N.; Zhang, W.; Hirata, T.; Hosoo, S.; Yamaguchi, Y.; Yamasaki, H.; Wada, A.; Fujikawa, T. Engagement of the aroma in feeding suppression behavior of Eucommia leaf. Aroma Res., 2016, 17(1), 74-79. [Japanese].
[34]
Asai, Y.; Sakakibara, Y.; Kondo, M.; Nadai, M.; Katoh, M. Species and Tissue Differences in β-Estradiol 17-Glucuronidation. Biol. Pharm. Bull., 2017, 40(10), 1754-1758.
[http://dx.doi.org/10.1248/bpb.b17-00365] [PMID: 28966247]
[35]
Hirata, T.; Ikeda, T.; Fujikawa, T.; Nishibe, S. The Chemistry and Bioactivity of Eucommia ulmoides Oliver LeavesStudies in Natural Products Chemistry; Rahman, Atta-ur-, Ed.; Elsevier Science B. V: Amsterdam, 2014, 41, pp. 225-260.
[http://dx.doi.org/10.1016/B978-0-444-63294-4.00008-5]
[36]
Aydin, C.; Jarema, K.A.; Phillips, P.M.; Gordon, C.J. Caloric restriction in lean and obese strains of laboratory rat: effects on body composition, metabolism, growth and overall health. Exp. Physiol., 2015, 100(11), 1280-1297.
[http://dx.doi.org/10.1113/EP085469] [PMID: 26283239]
[37]
Greenway, F.; Liu, Z.; Yu, Y.; Gupta, A. A clinical trial testing the safety and efficacy of a standardized Eucommia ulmoides Oliver bark extract to treat hypertension. Altern. Med. Rev., 2011, 16(4), 338-347.
[PMID: 22214253]
[38]
Hosoo, S.; Koyama, M.; Kato, M.; Hirata, T.; Yamaguchi, Y.; Yamasaki, H.; Wada, A.; Wada, K.; Nishibe, S.; Nakamura, K. The Restorative Effects of Eucommia ulmoides Oliver Leaf Extract on Vascular Function in Spontaneously Hypertensive Rats. Molecules, 2015, 20(12), 21971-21981.
[http://dx.doi.org/10.3390/molecules201219826] [PMID: 26690110]
[39]
Sugawa, H.; Ohno, R.; Shirakawa, J.; Nakajima, A.; Kanagawa, A.; Hirata, T.; Ikeda, T.; Moroishi, N.; Nagai, M.; Nagai, R. Eucommia ulmoides extracts prevent the formation of advanced glycation end products. Food Funct., 2016, 7(6), 2566-2573.
[http://dx.doi.org/10.1039/C5FO01563D] [PMID: 27080730]
[40]
Hao, S.; Xiao, Y.; Lin, Y.; Mo, Z.; Chen, Y.; Peng, X.; Xiang, C.; Li, Y.; Li, W. Chlorogenic acid-enriched extract from Eucommia ulmoides leaves inhibits hepatic lipid accumulation through regulation of cholesterol metabolism in HepG2 cells. Pharm. Biol., 2016, 54(2), 251-259.
[http://dx.doi.org/10.3109/13880209.2015.1029054] [PMID: 25845641]
[41]
Hosoo, S.; Koyama, M.; Watanabe, A.; Ishida, R.; Hirata, T.; Yamaguchi, Y.; Yamasaki, H.; Wada, K.; Higashi, Y.; Nakamura, K. Preventive effect of Eucommia leaf extract on aortic media hypertrophy in Wistar-Kyoto rats fed a high-fat diet. Hypertens. Res., 2017, 40(6), 546-551.
[http://dx.doi.org/10.1038/hr.2016.189] [PMID: 28100919]
[42]
Horii, Y.; Tanida, M.; Shen, J.; Hirata, T.; Kawamura, N.; Wada, A.; Nagai, K. Effects of Eucommia leaf extracts on autonomic nerves, body temperature, lipolysis, food intake, and body weight. Neurosci. Lett., 2010, 479(3), 181-186.
[http://dx.doi.org/10.1016/j.neulet.2010.05.030] [PMID: 20580657]
[43]
He, X.; Wang, J.; Li, M.; Hao, D.; Yang, Y.; Zhang, C.; He, R.; Tao, R. Eucommia ulmoides Oliv.: ethnopharmacology, phytochemistry and pharmacology of an important traditional Chinese medicine. J. Ethnopharmacol., 2014, 151(1), 78-92.
[http://dx.doi.org/10.1016/j.jep.2013.11.023] [PMID: 24296089]
[44]
Fonseca, T.L.; Werneck-De-Castro, J.P.; Castillo, M.; Bocco, B.M.; Fernandes, G.W.; McAninch, E.A.; Ignacio, D.L.; Moises, C.C.; Ferreira, A.R.; Gereben, B.; Bianco, A.C. Tissue-specific inactivation of type 2 deiodinase reveals multilevel control of fatty acid oxidation by thyroid hormone in the mouse. Diabetes, 2014, 63(5), 1594-1604.
[http://dx.doi.org/10.2337/db13-1768] [PMID: 24487027]
[45]
Montague, C.T.; Farooqi, I.S.; Whitehead, J.P.; Soos, M.A.; Rau, H.; Wareham, N.J.; Sewter, C.P.; Digby, J.E.; Mohammed, S.N.; Hurst, J.A.; Cheetham, C.H.; Earley, A.R.; Barnett, A.H.; Prins, J.B.; O’Rahilly, S. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature, 1997, 387(6636), 903-908.
[http://dx.doi.org/10.1038/43185] [PMID: 9202122]
[46]
Farooqi, I.S.; Yeo, G.S.; Keogh, J.M.; Aminian, S.; Jebb, S.A.; Butler, G.; Cheetham, T.; O’Rahilly, S. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J. Clin. Invest., 2000, 106(2), 271-279.
[http://dx.doi.org/10.1172/JCI9397] [PMID: 10903343]
[47]
Tran, P.V.; Akana, S.F.; Malkovska, I.; Dallman, M.F.; Parada, L.F.; Ingraham, H.A. Diminished hypothalamic bdnf expression and impaired VMH function are associated with reduced SF-1 gene dosage. J. Comp. Neurol., 2006, 498(5), 637-648.
[http://dx.doi.org/10.1002/cne.21070] [PMID: 16917842]
[48]
Richard, D.; Huang, Q.; Timofeeva, E. The corticotropin-releasing hormone system in the regulation of energy balance in obesity. Int. J. Obes. Relat. Metab. Disord., 2000, 24(Suppl. 2), S36-S39.
[http://dx.doi.org/10.1038/sj.ijo.0801275] [PMID: 10997606]
[49]
Givalois, L.; Naert, G.; Rage, F.; Ixart, G.; Arancibia, S.; Tapia-Arancibia, L. A single brain-derived neurotrophic factor injection modifies hypothalamo-pituitary-adrenocortical axis activity in adult male rats. Mol. Cell. Neurosci., 2004, 27(3), 280-295.
[http://dx.doi.org/10.1016/j.mcn.2004.07.002] [PMID: 15519243]
[50]
Naert, G.; Ixart, G.; Tapia-Arancibia, L.; Givalois, L. Continuous i.c.v. infusion of brain-derived neurotrophic factor modifies hypothalamic-pituitary-adrenal axis activity, locomotor activity and body temperature rhythms in adult male rats. Neuroscience, 2006, 139(2), 779-789.
[http://dx.doi.org/10.1016/j.neuroscience.2005.12.028] [PMID: 16457953]
[51]
Cope, J.L.; Regev, L.; Chen, Y.; Korosi, A.; Rice, C.J.; Ji, S.; Rogge, G.A.; Wood, M.A.; Baram, T.Z. Differential contribution of CBP:CREB binding to corticotropin-releasing hormone expression in the infant and adult hypothalamus. Stress, 2014, 17(1), 39-50.
[http://dx.doi.org/10.3109/10253890.2013.806907] [PMID: 23768074]
[52]
Wang, B.; Parobchak, N.; Rosen, T. RelB/NF-κB2 regulates corticotropin-releasing hormone in the human placenta. Mol. Endocrinol., 2012, 26(8), 1356-1369.
[http://dx.doi.org/10.1210/me.2012-1035] [PMID: 22734038]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy