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Planta Med 2017; 83(03/04): 245-253
DOI: 10.1055/s-0042-112371
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

6-Gingerol Suppresses Adipocyte-Derived Mediators of Inflammation In Vitro and in High-Fat Diet-Induced Obese Zebra Fish

Jia Choi   *
1   Department of Food Science and Biotechnology, College of Life Science, CHA University, Seongnam, Kyonggi, Republic of Korea
,
Kui-Jin Kim   *
1   Department of Food Science and Biotechnology, College of Life Science, CHA University, Seongnam, Kyonggi, Republic of Korea
,
Byung-Hak Kim
2   Department of Pharmacology & Biomedical Science, Seoul National University College of Medicine, Seoul, Republic of Korea,
,
Eun-Jeong Koh
1   Department of Food Science and Biotechnology, College of Life Science, CHA University, Seongnam, Kyonggi, Republic of Korea
,
Min-Jung Seo
1   Department of Food Science and Biotechnology, College of Life Science, CHA University, Seongnam, Kyonggi, Republic of Korea
,
Boo-Yong Lee
1   Department of Food Science and Biotechnology, College of Life Science, CHA University, Seongnam, Kyonggi, Republic of Korea
› Author Affiliations
Further Information

Publication History

received 28 March 2016
revised 04 July 2016

accepted 09 July 2016

Publication Date:
15 August 2016 (online)

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Abstract

The present study was performed to investigate the molecular mechanism of 6-gingerol on adipocyte-mediated systemic inflammation in vitro and in high-fat diet-induced obese zebra fish. 6-Gingerol decreased adipogenesis due to the suppression of adipocyte differentiation markers, including peroxisome proliferator-activated receptor gamma, CCAATT enhancer binding protein α, and adipocyte protein 2, and triglyceride synthesis enzymes, including sterol regulatory element-binding protein-1, fatty acid synthase, lysophosphatidic acid acyltransferase, and acyl-coA : diacylglycerol acyltransferase 1, in 3T3-L1. A coculture insert system using 3T3-L1 with RAW 264.7 (coculture insert system using fully differentiated 3T3-L1 cells with RAW 264.7 macrophages) revealed that 6-gingerol increased anti-inflammatory cytokine interleukin-10. The expression of TNFα, monocyte chemotactic protein-1, interleukin-1β, and interleukin-6 were decreased in the coculture insert system using fully differentiated 3T3-L1 cells with RAW 264.7 macrophages treated with 6-gingerol. Moreover, the coculture insert system using fully differentiated 3T3-L1 cells with RAW 264.7 macrophages treated with 6-gingerol inhibited the protein expression of TNFα and monocyte chemotactic protein-1 in RAW 264.7. 6-Gingerol decreased c-JUN N-terminal kinase and I kappa B kinase beta and its downstream target AP-1 expression in the coculture insert system using fully differentiated 3T3-L1 cells with RAW 264.7 macrophages. Furthermore, 6-gingerol decreased the expression of inducible nitric oxide synthase stimulated by the coculture insert system using fully differentiated 3T3-L1 cells with RAW 264.7 macrophages in RAW 264.7 and attenuated nitric oxide production in diet-induced obese zebra fish. Our results suggest that 6-gingerol suppresses inflammation through the regulation of the c-JUN N-terminal kinase-I kappa B kinase beta and its downstream targets.

Key words

6-gingerol - coculture system - high-fat diet-induced obese zebra fish - systemic inflammation - obesity - Zingiber officinale - Zingiberaceae

* These authors contributed equally to this work.


 

  • References

  • 1 Farmer SR. Regulation of PPARγ activity during adipogenesis. Int J Obes (Lond) 2005; 29 (Suppl. 01) S13-S16
    CrossrefPubMedGoogle Scholar
  • 2 Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 2004; 25: 4-7
    CrossrefPubMedGoogle Scholar
  • 3 Tzeng TF, Chang CJ, Liu IM. 6-Gingerol inhibits rosiglitazone-induced adipogenesis in 3T3-L1 adipocytes. Phytother Res 2014; 28: 187-192
    CrossrefPubMedGoogle Scholar
  • 4 Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 2001; 81: 807-869
    PubMedGoogle Scholar
  • 5 Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature 2002; 420: 333-336
    CrossrefPubMedGoogle Scholar
  • 6 Miranda PJ, DeFronzo RA, Califf RM, Guyton JR. Metabolic syndrome: definition, pathophysiology, and mechanisms. Am Heart J 2005; 149: 33-45
    CrossrefPubMedGoogle Scholar
  • 7 Overman A, Chuang CC, McIntosh M. Quercetin attenuates inflammation in human macrophages and adipocytes exposed to macrophage-conditioned media. Int J Obes (Lond) 2011; 35: 1165-1172
    CrossrefPubMedGoogle Scholar
  • 8 Lee YJ, Choi HS, Seo MJ, Jeon HJ, Kim KJ, Lee BY. Kaempferol suppresses lipid accumulation by inhibiting early adipogenesis in 3T3-L1 cells and zebrafish. Food Funct 2015; 6: 2824-2833
    CrossrefPubMedGoogle Scholar
  • 9 Subramanian S, Han CY, Chiba T, McMillen TS, Wang SA, Haw 3rd A, Kirk EA, OʼBrien KD, Chait A. Dietary cholesterol worsens adipose tissue macrophage accumulation and atherosclerosis in obese LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol 2008; 28: 685-691
    CrossrefPubMedGoogle Scholar
  • 10 Kim JB, Spiegelman BM. ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev 1996; 10: 1096-1107
    CrossrefPubMedGoogle Scholar
  • 11 Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ . Genes Dev 2000; 14: 2819-2830
    CrossrefPubMedGoogle Scholar
  • 12 Foufelle F, Ferre P. New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein-1c. Biochem J 2002; 366: 377-391
    CrossrefPubMedGoogle Scholar
  • 13 Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S, Yoshimura K, Kadowaki T, Nagai R. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 2009; 15: 914-920
    CrossrefPubMedGoogle Scholar
  • 14 Sethi JK, Hotamisligil GS. The role of TNFα in adipocyte metabolism. Semin Cell Dev Biol 1999; 10: 19-29
    CrossrefPubMedGoogle Scholar
  • 15 Chen HC, Smith SJ, Tow B, Elias PM, Farese jr. RV. Leptin modulates the effects of acyl CoA : diacylglycerol acyltransferase deficiency on murine fur and sebaceous glands. J Clin Invest 2002; 109: 175-181
    CrossrefPubMedGoogle Scholar
  • 16 Kim KY, Kim JK, Jeon JH, Yoon SR, Choi I, Yang Y. c-Jun N-terminal kinase is involved in the suppression of adiponectin expression by TNFα in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2005; 327: 460-467
    CrossrefPubMedGoogle Scholar
  • 17 Liu Y, Shepherd EG, Nelin LD. MAPK phosphatases–regulating the immune response. Nat Rev Immunol 2007; 7: 202-212
    CrossrefPubMedGoogle Scholar
  • 18 Pang HY, Liu G, Liu GT. Compound FLZ inhibits lipopolysaccharide-induced inflammatory effects via down-regulation of the TAK-IKK and TAK-JNK/p38MAPK pathways in RAW264.7 macrophages. Acta Pharmacol Sin 2009; 30: 209-218
    CrossrefPubMedGoogle Scholar
  • 19 Coleman RA, Lee DP. Enzymes of triacylglycerol synthesis and their regulation. Prog Lipid Res 2004; 43: 134-176
    CrossrefPubMedGoogle Scholar
  • 20 Poulos SP, Dodson MV, Hausman GJ. Cell line models for differentiation: preadipocytes and adipocytes. Exp Biol Med (Maywood) 2010; 235: 1185-1193
    CrossrefPubMedGoogle Scholar
  • 21 Ali BH, Blunden G, Tanira MO, Nemmar A. Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): a review of recent research. Food Chem Toxicol 2008; 46: 409-420
    CrossrefPubMedGoogle Scholar
  • 22 Hoferl M, Stoilova I, Wanner J, Schmidt E, Jirovetz L, Trifonova D, Stanchev V, Krastanov A. Composition and comprehensive antioxidant activity of ginger (Zingiber officinale) essential oil from ecuador. Nat Prod Commun 2015; 10: 1085-1090
    PubMedGoogle Scholar
  • 23 Millar JG. Rapid and Simple isolation of zingiberene from ginger essential oil. J Nat Prod 1998; 61: 1025-1026
    CrossrefPubMedGoogle Scholar
  • 24 He XG, Bernart MW, Lian LZ, Lin LZ. High-performance liquid chromatography – electrospray mass spectrometric analysis of pungent constituents of ginger. J Chromatogr 1998; 796: 327-334
    CrossrefPubMedGoogle Scholar
  • 25 Wohlmuth H, Leach DN, Smith MK, Myers SP. Gingerol content of diploid and tetraploid clones of ginger (Zingiber officinale Roscoe). J Agric Food Chem 2005; 53: 5772-5778
    CrossrefPubMedGoogle Scholar
  • 26 Bhattarai S, Tran VH, Duke CC. The stability of gingerol and shogaol in aqueous solutions. J Pharm Sci 2001; 90: 1658-1664
    CrossrefPubMedGoogle Scholar
  • 27 Jiang C, Yao N, Wang Q, Zhang J, Sun Y, Xiao N, Liu K, Huang F, Fang S, Shang X, Liu B, Ni Y, Yin Z, Zhang J. Cyclocarya paliurus extract modulates adipokine expression and improves insulin sensitivity by inhibition of inflammation in mice. J Ethnopharmacol 2014; 153: 344-351
    CrossrefPubMedGoogle Scholar
  • 28 Guh JH, Ko FN, Jong TT, Teng CM. Antiplatelet effect of gingerol isolated from Zingiber officinale . J Pharm Pharmacol 1995; 47: 329-332
    CrossrefPubMedGoogle Scholar
  • 29 Young HY, Luo YL, Cheng HY, Hsieh WC, Liao JC, Peng WH. Analgesic and anti-inflammatory activities of [6]-gingerol. J Ethnopharmacol 2005; 96: 207-210
    CrossrefPubMedGoogle Scholar
  • 30 Harris CA, Haas JT, Streeper RS, Stone SJ, Kumari M, Yang K, Han X, Brownell N, Gross RW, Zechner R, Farese jr. RV. DGAT enzymes are required for triacylglycerol synthesis and lipid droplets in adipocytes. J Lipid Res 2011; 52: 657-667
    CrossrefPubMedGoogle Scholar
  • 31 Bost F, Aouadi M, Caron L, Binetruy B. The role of MAPKs in adipocyte differentiation and obesity. Biochimie 2005; 87: 51-56
    CrossrefPubMedGoogle Scholar
  • 32 Thakur V, Pritchard MT, McMullen MR, Nagy LE. Adiponectin normalizes LPS-stimulated TNFα production by rat Kupffer cells after chronic ethanol feeding. Am J Physiol Gastrointest Liver Physiol 2006; 290: G998-G1007
    CrossrefPubMedGoogle Scholar
  • 33 Pasparakis M, Luedde T, Schmidt-Supprian M. Dissection of the NF-κB signalling cascade in transgenic and knockout mice. Cell Death Differ 2006; 13: 861-872
    CrossrefPubMedGoogle Scholar
  • 34 Kwon H, Laurent S, Tang Y, Zong H, Vemulapalli P, Pessin JE. Adipocyte-specific IKKβ signaling suppresses adipose tissue inflammation through an IL-13-dependent paracrine feedback pathway. Cell Rep 2014; 9: 1574-1583
    CrossrefPubMedGoogle Scholar
  • 35 Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu Rev Immunol 2000; 18: 621-663
    CrossrefPubMedGoogle Scholar
  • 36 Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002; 298: 1911-1912
    CrossrefPubMedGoogle Scholar
  • 37 Xie QW, Kashiwabara Y, Nathan C. Role of transcription factor NF-κB/Rel in induction of nitric oxide synthase. J Biol Chem 1994; 269: 4705-4708
    PubMedGoogle Scholar
  • 38 Marchesi C, Ebrahimian T, Angulo O, Paradis P, Schiffrin EL. Endothelial nitric oxide synthase uncoupling and perivascular adipose oxidative stress and inflammation contribute to vascular dysfunction in a rodent model of metabolic syndrome. Hypertension 2009; 54: 1384-1392
    CrossrefPubMedGoogle Scholar
  • 39 Lowe CE, OʼRahilly S, Rochford JJ. Adipogenesis at a glance. J Cell Sci 2011; 124: 2681-2686
    CrossrefPubMedGoogle Scholar
  • 40 Kim KJ, Lee BY. Fucoidan from the sporophyll of Undaria pinnatifida suppresses adipocyte differentiation by inhibition of inflammation-related cytokines in 3T3-L1 cells. Nutr Res 2012; 32: 439-447
    CrossrefPubMedGoogle Scholar
  • 41 Hsu LC, Enzler T, Seita J, Timmer AM, Lee CY, Lai TY, Yu GY, Lai LC, Temkin V, Sinzig U, Aung T, Nizet V, Weissman IL, Karin M. IL-1β-driven neutrophilia preserves antibacterial defense in the absence of the kinase IKKβ . Nat Immunol 2011; 12: 144-150
    CrossrefPubMedGoogle Scholar
  • 42 Chen LW, Egan L, Li ZW, Greten FR, Kagnoff MF, Karin M. The two faces of IKK and NF-κB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion. Nat Med 2003; 9: 575-581
    CrossrefPubMedGoogle Scholar
  • 43 Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D. Hypothalamic IKKβ/NF-κB and ER stress link overnutrition to energy imbalance and obesity. Cell 2008; 135: 61-73
    CrossrefPubMedGoogle Scholar
  • 44 Wong ML, Rettori V, al-Shekhlee A, Bongiorno PB, Canteros G, McCann SM, Gold PW, Licinio J. Inducible nitric oxide synthase gene expression in the brain during systemic inflammation. Nat Med 1996; 2: 581-584
    CrossrefPubMedGoogle Scholar
  • 45 Ashino T, Yamanaka R, Yamamoto M, Shimokawa H, Sekikawa K, Iwakura Y, Shioda S, Numazawa S, Yoshida T. Negative feedback regulation of lipopolysaccharide-induced inducible nitric oxide synthase gene expression by heme oxygenase-1 induction in macrophages. Mol Immunol 2008; 45: 2106-2115
    CrossrefPubMedGoogle Scholar
  • 46 Andrukhov O, Haririan H, Bertl K, Rausch WD, Bantleon HP, Moritz A, Rausch-Fan X. Nitric oxide production, systemic inflammation and lipid metabolism in periodontitis patients: possible gender aspect. J Clin Periodontol 2013; 40: 916-923
    CrossrefPubMedGoogle Scholar