2,6-Dimethoxy-1,4-benzoquinone Inhibits 3T3-L1 Adipocyte Differentiation via Regulation of AMPK and mTORC1

Hyo Jeong Son; Young Jin Jang; Chang Hwa Jung; Jiyun Ahn; Tae Youl Ha

doi:10.1055/a-0725-8334

Planta Medica, Inhaltsverzeichnis

Planta Med 2019; 85(03): 210-216
DOI: 10.1055/a-0725-8334

Biological and Pharmacological Activity

Original Papers

Georg Thieme Verlag KG Stuttgart · New York

2,6-Dimethoxy-1,4-benzoquinone Inhibits 3T3-L1 Adipocyte Differentiation via Regulation of AMPK and mTORC1

Authors

Hyo Jeong Son^*

¹Research Group of Natural Materials and Metabolism, Korea Food Research Institute, Wanju-gun, Republic of Korea
Young Jin Jang^*

¹Research Group of Natural Materials and Metabolism, Korea Food Research Institute, Wanju-gun, Republic of Korea
Chang Hwa Jung

¹Research Group of Natural Materials and Metabolism, Korea Food Research Institute, Wanju-gun, Republic of Korea

²Division of Food Biotechnology, University of Science and Technology, Daejeon, Republic of Korea
Jiyun Ahn

¹Research Group of Natural Materials and Metabolism, Korea Food Research Institute, Wanju-gun, Republic of Korea

²Division of Food Biotechnology, University of Science and Technology, Daejeon, Republic of Korea
Tae Youl Ha

¹Research Group of Natural Materials and Metabolism, Korea Food Research Institute, Wanju-gun, Republic of Korea

²Division of Food Biotechnology, University of Science and Technology, Daejeon, Republic of Korea

Abstract

2,6-Dimethoxy-1,4-benzoquinone is a natural phytochemical present in fermented wheat germ. It has been reported to exhibit anti-inflammatory, antitumor, and antibacterial activities. However, the anti-adipogenic effects of 2,6-dimethoxy-1,4-benzoquinone and the mechanisms responsible have not previously been elucidated. Such findings may have ramifications for the treatment of obesity. 2,6-Dimethoxy-1,4-benzoquinone (5 and 7.5 µM) significantly reduced the expression of various adipogenic transcription factors, including peroxisome proliferator-activated receptor-γ and CCAAT/enhancer binding protein α as well as adipocyte protein 2 and fatty acid synthase. 2,6-Dimethoxy-1,4-benzoquinone upregulated AMP-dependent protein kinase phosphorylation and inhibited the mature form of sterol regulatory element-binding protein 1c. Notably, 2,6-dimethoxy-1,4-benzoquinone attenuated mammalian target of rapamycin complex 1 activity in 3T3-L1 and mouse embryonic fibroblast cells. These findings highlight a potential role for 2,6-dimethoxy-1,4-benzoquinone in the suppression of adipogenesis. Further studies to determine the anti-obesity effects of 2,6-dimethoxy-1,4-benzoquinone in animal models appear warranted.

Key words

2,6-dimethoxy-1,4-benzoquinone (DMBQ) - adipogenesis - AMPK - mTORC1 - obesity

Volltext

Referenzen

References
1 Drewes SE, Khan F, van Vuuren SF, Viljoen AM. Simple 1,4-benzoquinones with antibacterial activity from stems and leaves of Gunnera perpensa . Phytochemistry 2005; 66: 1812-1816
2 Koyama J. Anti-infective quinone derivatives of recent patents. Recent Pat Antiinfect Drug Discov 2006; 1: 113-125
3 Gwon SY, Ahn JY, Jung CH, Moon BK, Ha TY. Shikonin suppresses ERK 1/2 phosphorylation during the early stages of adipocyte differentiation in 3T3-L1 cells. BMC Complement Altern Med 2013; 13: 207
4 Jang YJ, Jung CH, Ahn J, Gwon SY, Ha TY. Shikonin inhibits adipogenic differentiation via regulation of mir-34a-FKBP1B. Biochem Biophys Res Commun 2015; 467: 941-947
5 Otto C, Hahlbrock T, Eich K, Karaaslan F, Jurgens C, Germer CT, Wiegering A, Kammerer U. Antiproliferative and antimetabolic effects behind the anticancer property of fermented wheat germ extract. BMC Complement Altern Med 2016; 16: 160
6 Mueller T, Jordan K, Voigt W. Promising cytotoxic activity profile of fermented wheat germ extract (Avemar^®) in human cancer cell lines. J Exp Clin Cancer Res 2011; 30: 42
7 Reddy BS, Hirose Y, Cohen LA, Simi B, Cooma I, Rao CV. Preventive potential of wheat bran fractions against experimental colon carcinogenesis: implications for human colon cancer prevention. Cancer Res 2000; 60: 4792-4797
8 Jeong HY, Choi YS, Lee JK, Lee BJ, Kim WK, Kang H. Anti-inflammatory activity of citric acid-treated wheat germ extract in lipopolysaccharide-stimulated macrophages. Nutrients 2017; 9: E730
9 Park E, Kim HO, Kim GN, Song JH. Anti-oxidant and anti-adipogenic effects of ethanol extracts from wheat germ and wheat germ fermented with Aspergillus oryzae . Prev Nutr Food Sci 2015; 20: 29-37
10 Grundy SM. Obesity, metabolic syndrome, and cardiovascular disease. J Clin Endocrinol Metab 2004; 89: 2595-2600
11 Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 2004; 4: 579-591
12 Parekh N, Chandran U, Bandera EV. Obesity in cancer survival. Annu Rev Nutr 2012; 32: 311-342
13 Guilherme A, Virbasius JV, Puri V, Czech MP. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol 2008; 9: 367-377
14 Klyde BJ, Hirsch J. Increased cellular proliferation in adipose tissue of adult rats fed a high-fat diet. J Lipid Res 1979; 20: 705-715
15 Hamdy O, Porramatikul S, Al-Ozairi E. Metabolic obesity: the paradox between visceral and subcutaneous fat. Curr Diabetes Rev 2006; 2: 367-373
16 Farmer SR. Transcriptional control of adipocyte formation. Cell Metab 2006; 4: 263-273
17 Gesta S, Bluher M, Yamamoto Y, Norris AW, Berndt J, Kralisch S, Boucher J, Lewis C, Kahn CR. Evidence for a role of developmental genes in the origin of obesity and body fat distribution. Proc Natl Acad Sci U S A 2006; 103: 6676-6681
18 Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature 2006; 444: 847-853
19 Rosen ED, Hsu CH, Wang X, Sakai S, Freeman MW, Gonzalez FJ, Spiegelman BM. C/EBPalpha induces adipogenesis through PPARgamma: a unified pathway. Genes Dev 2002; 16: 22-26
20 Kim WS, Lee YS, Cha SH, Jeong HW, Choe SS, Lee MR, Oh GT, Park HS, Lee KU, Lane MD, Kim JB. Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity. Am J Physiol Endocrinol Metab 2009; 296: E812-E819
21 Lee JW, Choe SS, Jang H, Kim J, Jeong HW, Jo H, Jeong KH, Tadi S, Park MG, Kwak TH, Man Kim J, Hyun DH, Kim JB. AMPK activation with glabridin ameliorates adiposity and lipid dysregulation in obesity. J Lipid Res 2012; 53: 1277-1286
22 Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JY, Gao B, Wierzbicki M, Verbeuren TJ, Shaw RJ, Cohen RA, Zang M. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab 2011; 13: 376-388
23 Rosen ED, Walkey CJ, Puigserver P, Spiegelman BM. Transcriptional regulation of adipogenesis. Genes Dev 2000; 14: 1293-1307
24 Habinowski SA, Witters LA. The effects of AICAR on adipocyte differentiation of 3T3-L1 cells. Biochem Biophys Res Commun 2001; 286: 852-856
25 Villena JA, Viollet B, Andreelli F, Kahn A, Vaulont S, Sul HS. Induced adiposity and adipocyte hypertrophy in mice lacking the AMP-activated protein kinase-alpha2 subunit. Diabetes 2004; 53: 2242-2249
26 Catania C, Binder E, Cota D. mTORC1 signaling in energy balance and metabolic disease. Int J Obes (Lond) 2011; 35: 751-761
27 Seo MJ, Choi HS, Jeon HJ, Woo MS, Lee BY. Baicalein inhibits lipid accumulation by regulating early adipogenesis and m-TOR signaling. Food Chem Toxicol 2014; 67: 57-64
28 Laplante M, Sabatini DM. An emerging role of mTOR in lipid biosynthesis. Curr Biol 2009; 19: R1046-R1052
29 Jung CH, Kim H, Ahn J, Jeon TI, Lee DH, Ha TY. Fisetin regulates obesity by targeting mTORC1 signaling. J Nutr Biochem 2013; 24: 1547-1554
30 Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, Guertin DA, Madden KL, Carpenter AE, Finck BN, Sabatini DM. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 2011; 146: 408-420
31 Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci 2009; 122: 3589-3594
32 Sozio MS, Lu C, Zeng Y, Liangpunsakul S, Crabb DW. Activated AMPK inhibits PPAR-{alpha} and PPAR-{gamma} transcriptional activity in hepatoma cells. Am J Physiol Gastrointest Liver Physiol 2011; 301: G739-G747
33 He Y, Li Y, Zhao T, Wang Y, Sun C. Ursolic acid inhibits adipogenesis in 3T3-L1 adipocytes through LKB1/AMPK pathway. PLoS One 2013; 8: e70135
34 Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JY, Gao B, Wierzbicki M, Verbeuren TJ, Shaw RJ, Cohen RA, Zang M. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab 2011; 13: 376-388
35 Hasty AH, Shimano H, Yahagi N, Amemiya-Kudo M, Perrey S, Yoshikawa T, Osuga J, Okazaki H, Tamura Y, Iizuka Y, Shionoiri F, Ohashi K, Harada K, Gotoda T, Nagai R, Ishibashi S, Yamada N. Sterol regulatory element-binding protein-1 is regulated by glucose at the transcriptional level. J Biol Chem 2000; 275: 31069-31077
36 Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, Griffiths JR, Chung YL, Schulze A. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 2008; 8: 224-236
37 Rayalam S, Della-Fera MA, Baile CA. Phytochemicals and regulation of the adipocyte life cycle. J Nutr Biochem 2008; 19: 717-726
38 Perez-Jimenez A, Rufino-Palomares EE, Fernandez-Gallego N, Ortuno-Costela MC, Reyes-Zurita FJ, Peragon J, Garcia-Salguero L, Mokhtari K, Medina PP, Lupianez JA. Target molecules in 3T3-L1 adipocytes differentiation are regulated by maslinic acid, a natural triterpene from Olea europaea . Phytomedicine 2016; 23: 1301-1311
39 Nakao Y, Yoshihara H, Fujimori K. Suppression of very early stage of adipogenesis by Baicalein, a plant-derived flavonoid through reduced Akt-C/EBPalpha-GLUT4 signaling-mediated glucose uptake in 3T3-L1 adipocytes. PLoS One 2016; 11: e0163640
40 Song Y, Oh GH, Kim MB, Hwang JK. Fucosterol inhibits adipogenesis through the activation of AMPK and Wnt/β-catenin signaling pathways. Food Sci Biotechnol 2017; 26: 489-494
41 Han YH, Kee JY, Park J, Kim HL, Jeong MY, Kim DS, Jeon YD, Jung Y, Youn DH, Kang J, So HS, Park R, Lee JH, Shin S, Kim SJ, Um JY, Hong SH. Arctigenin inhibits adipogenesis by inducing AMPK activation and reduces weight gain in high-fat diet-induced obese mice. J Cell Biochem 2016; 117: 2067-2077
42 Liu X, Yuan H, Niu Y, Niu W, Fu L. The role of AMPK/mTOR/S6K1 signaling axis in mediating the physiological process of exercise-induced insulin sensitization in skeletal muscle of C57BL/6 mice. Biochim Biophys Acta 2012; 1822: 1716-1726
43 Dagon Y, Avraham Y, Berry EM. AMPK activation regulates apoptosis, adipogenesis, and lipolysis by eIF2alpha in adipocytes. Biochem Biophys Res Commun 2006; 340: 43-47
44 Quinn 3rd WJ, Birnbaum MJ. Distinct mTORC1 pathways for transcription and cleavage of SREBP-1c. Proc Natl Acad Sci U S A 2012; 109: 15974-15975
45 Laplante M, Sabatini DM. Regulation of mTORC1 and its impact on gene expression at a glance. J Cell Sci 2013; 126: 1713-1719
46 McManus EJ, Alessi DR. TSC1–TSC2: a complex tale of PKB-mediated S6K regulation. Nat Cell Biol 2002; 4: E214-E216
47 Kim SG, Hoffman GR, Poulogiannis G, Buel GR, Jang YJ, Lee KW, Kim BY, Erikson RL, Cantley LC, Choo AY, Blenis J. Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT-RUVBL1/2 complex. Mol Cell 2013; 49: 172-185
48 Kaizuka T, Hara T, Oshiro N, Kikkawa U, Yonezawa K, Takehana K, Iemura S, Natsume T, Mizushima N. Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J Biol Chem 2010; 285: 20109-20116
49 Javary J, Allain-Courtois N, Saucisse N, Costet P, Heraud C, Benhamed F, Pierre R, Bure C, Pallares-Lupon N, Do Cruzeiro M, Postic C, Cota D, Dubus P, Rosenbaum J, Benhamouche-Trouillet S. Liver Reptin/RUVBL2 controls glucose and lipid metabolism with opposite actions on mTORC1 and mTORC2 signalling. Gut 2017;