<em>In vitro</em> anti-obesity effects of sesamol mediated by adenosine monophosphate-activated protein kinase and mitogen-activated protein kinase signaling in 3T3-L1 cells

Geon Go

Jung Sung

Seung Jee

Min Kim

Abstract

Sesamol is a phenol derivative of sesame oil and a potent anti-oxidant, anti-inflammatory, anti-hepatotoxic, and anti-aging compound. We investigated the effects of sesamol on the molecular mechanisms of adipogenesis in 3T3-L1 preadipocytes. The intracellular lipid accumulation accompanied by increased extracellular release of free glycerol was decreased during differentiation on treating 3T3-L1 with sesamol. Sesamol treatment on 3T3-L1 inhibited adipogenic differentiation by down-regulating adipogenesis-related factors (C/EBPα, PPARγ, and SREBP-1). Lipid accumulation was repressed by decreasing fatty acid synthase and by up-regulating lipolysis-response genes (HSL and LPL). The molecular mechanisms of sesamol-induced inhibition in adipogenesis were mediated by increased levels of phosphorylated adenosine monophosphate-activated protein kinase and its substrate acetyl-CoA carboxylase. Sesamol treatment, in turn, modulated the different members of the mitogenactivated protein kinase family by suppressing phosphorylation of ERK 1/2 and JNK and by increasing the phosphorylation of p38. In summary, sesamol inhibits adipogenic differentiation by reducing phosphorylation levels of ERK 1/2 and JNK while inducing lipolysis by activating p38 and AMPK. Our results demonstrate that the molecular mechanisms of in vitro anti-obesity effects of sesamol are due to the combined effects of preventing both lipid accumulation and adipogenesis.

Keywords: sesamol, adipogenesis, anti-obesity, AMPK, lipolysis, MAPK

^{Department of Life Science, Dongguk University-Seoul, Goyang, Gyeonggi, 10326 Korea}

^{Department of Biological and Environmental Science, Dongguk University-Seoul, Goyang, Gyeonggi, 10326 Korea}

^{Department of Food Science and Biotechnology, Dongguk University-Seoul, Goyang, Gyeonggi, 10326 Korea}

Han-Seung Shin, Phone: +82-31-961-5143, Fax: +82-31-961-5108, Email: ude.kuggnod@natraps.

^{Corresponding author.}

Received 2015 Dec 31; Revised 2016 Sep 25; Accepted 2016 Dec 15.

References

1. Yu YH, Ginsberg HNAdipocyte signaling and lipid homeostasis: Sequelae of insulin-resistant adipose tissue. Circ. Res. 2005;96:1042–1052. doi: 10.1161/01.RES.0000165803.47776.38.] [[PubMed][Google Scholar]
2. Furuyashiki T, Nagayasu H, Aoki Y, Bessho H, Hashimoto T, Kanazawa K, Ashida HTea catechin suppresses adipocyte differentiation accompanied by downregulation of PPARgamma2 and C/EBPalpha in 3T3-L1 cells. Biosci. Biotech. Bioch. 2004;68:2353–2359. doi: 10.1271/bbb.68.2353.] [[PubMed][Google Scholar]
3. Kopelman PGObesity as a medical problem. Nature. 2000;404:635–643.[PubMed][Google Scholar]
4. Visscher TL, Seidell JCThe public health impact of obesity. Annu. Rev. Publ. Health. 2001;22:355–375. doi: 10.1146/annurev.publhealth.22.1.355.] [[PubMed][Google Scholar]
5. Thijssen E, Van Caam A v d, Kraan PMObesity and osteoarthritis, more than just wear and tear: pivotal roles for inflamed adipose tissue and dyslipidaemia in obesity-induced osteoarthritis. Rheumatology. 2015;54:588–600. doi: 10.1093/rheumatology/keu464.] [[PubMed][Google Scholar]
6. McGill ATCauses of metabolic syndrome and obesity-related co-morbidities Part 1: A composite unifying theory review of human-specific co-adaptations to brain energy consumption. Arch. Public Health. 2014;72:30. doi: 10.1186/2049-3258-72-30.] [[Google Scholar]
7. Kim SS, Seo JY, Kim BR, Kim HJ, Lee HY, Kim JSAnti-obesity activity of peanut sprout extract. Food Sci. Biotechnol. 2014;23:601–607. doi: 10.1007/s10068-014-0082-8.[PubMed][Google Scholar]
8. Wang YW, Jones PJConjugated linoleic acid and obesity control: Efficacy and mechanisms. Int. J. Obes. Relat. Metab. Disord. 2004;28:941–955. doi: 10.1038/sj.ijo.0802641.] [[PubMed][Google Scholar]
9. Liu X, Kim JK, Li Y, Li J, Liu F, Chen XTannic acid stimulates glucose transport and inhibits adipocyte differentiation in 3T3-L1 cells. J. Nutr. 2005;135:165–171.[PubMed][Google Scholar]
10. Yin J, Zhang H, Ye JTraditional chinese medicine in treatment of metabolic syndrome. Endocr. Metab. Immune Disord. Drug Targets. 2008;8:99–111. doi: 10.2174/187153008784534330.] [[Google Scholar]
11. Ailhaud G, Grimaldi P, Negrel RCellular and molecular aspects of adipose tissue development. Annu. Rev. Nutr. 1992;12:207–233. doi: 10.1146/annurev.nu.12.070192.001231.] [[PubMed][Google Scholar]
12. Boney CM, Moats-Staats BM, Stiles AD, D'Ercole AJExpression of insulin-like growth factor-I (IGF-I) and IGF-binding proteins during adipogenesis. Endocrinology. 1994;135:1863–1868.[PubMed][Google Scholar]
13. Tontonoz P, Hu E, Spiegelman BMStimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell. 1994;79:1147–1156. doi: 10.1016/0092-8674(94)90006-X.] [[PubMed][Google Scholar]
14. MacDougald OA, Cornelius P, Liu R, Lane MDInsulin regulates transcription of the CCAAT/enhancer binding protein (C/EBP) alpha, beta, and delta genes in fully-differentiated 3T3-L1 adipocytes. J. Biol. Chem. 1995;270:647–654. doi: 10.1074/jbc.270.2.647.] [[PubMed][Google Scholar]
15. Hardie DG, Hawley SAAMP-activated protein kinase: The energy charge hypothesis revisited. Bioessays. 2001;23:1112–1119. doi: 10.1002/bies.10009.] [[PubMed][Google Scholar]
16. Prusty D, Park BH, Davis KE, Farmer SRActivation of MEK/ERK signaling promotes adipogenesis by enhancing peroxisome proliferator-activated receptor gamma (PPARgamma) and C/EBPalpha gene expression during the differentiation of 3T3-L1 preadipocytes. J. Biol. Chem. 2002;277:46226–46232. doi: 10.1074/jbc.M207776200.] [[PubMed][Google Scholar]
17. Belmonte N, Phillips BW, Massiera F, Villageois P, Wdziekonski B, Saint-Marc P, Nichols J, Aubert J, Saeki K, Yuo A, Narumiya S, Ailhaud G, Dani CActivation of extracellular signal-regulated kinases and CREB/ATF-1 mediate the expression of CCAAT/enhancer binding proteins beta and -delta in preadipocytes. Mol. Endocrinol. 2001;15:2037–2049.[PubMed][Google Scholar]
18. Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GSA central role for JNK in obesity and insulin resistance. Nature. 2002;420:333–336. doi: 10.1038/nature01137.] [[PubMed][Google Scholar]
19. Yang TT, Xiong Q, Enslen H, Davis RJ, Chow CWPhosphorylation of NFATc4 by p38 mitogen-activated protein kinases. Mol. Cell. Biol. 2002;22:3892–3904. doi: 10.1128/MCB.22.11.3892-3904.2002.] [[Google Scholar]
20. Pan J, Kim M, Kim J, Cho Y, Shin H-S, Sung J-S, Park T, Yoon H-G, Park S, Kim YInhibition of the lipogenesis in liver and adipose tissue of diet-induced obese C57BL/6 mice by feeding oleic acid-rich sesame oil. Food Sci. Biotechnol. 2015;24:1115–1121. doi: 10.1007/s10068-015-0142-8.[PubMed][Google Scholar]
21. Chu PY, Hsu DZ, Hsu PY, Liu MYSesamol down-regulates the lipopolysaccharide-induced inflammatory response by inhibiting nuclear factor-kappa B activation. Innate Immun. 2010;16:333–339. doi: 10.1177/1753425909351880.] [[PubMed][Google Scholar]
22. Kumar N, Mudgal J, Parihar VK, Nayak PG, Kutty NG, Rao CMSesamol treatment reduces plasma cholesterol and triacylglycerol levels in mouse models of acute and chronic hyperlipidemia. Lipids. 2013;48:633–638. doi: 10.1007/s11745-013-3778-2.] [[PubMed][Google Scholar]
23. Chopra K, Tiwari V, Arora V, Kuhad ASesamol suppresses neuro-inflammatory cascade in experimental model of diabetic neuropathy. J. Pain. 2010;11:950–957. doi: 10.1016/j.jpain.2010.01.006.] [[PubMed][Google Scholar]
24. Ahmadian M, Duncan RE, Jaworski K, Sarkadi-Nagy E, Sul HSTriacylglycerol metabolism in adipose tissue. Future Lipidol. 2007;2:229–237. doi: 10.2217/17460875.2.2.229.] [[Google Scholar]
25. Rayalam S, Della-Fera MA, Baile CAPhytochemicals and regulation of the adipocyte life cycle. J. Nutr. Biochem. 2008;19:717–726. doi: 10.1016/j.jnutbio.2007.12.007.] [[PubMed][Google Scholar]
26. Madsen MS, Siersbaek R, Boergesen M, Nielsen R, Mandrup SPeroxisome proliferator-activated receptor gamma and C/EBPalpha synergistically activate key metabolic adipocyte genes by assisted loading. Mol. Cell. Biol. 2014;34:939–954. doi: 10.1128/MCB.01344-13.] [[Google Scholar]
27. Bost F, Aouadi M, Caron L, Binetruy BThe role of MAPKs in adipocyte differentiation and obesity. Biochimie. 2005;87:51–56. doi: 10.1016/j.biochi.2004.10.018.] [[PubMed][Google Scholar]
28. Sakaue H, Ogawa W, Matsumoto M, Kuroda S, Takata M, Sugimoto T, Spiegelman BM, Kasuga MPosttranscriptional control of adipocyte differentiation through activation of phosphoinositide 3-kinase. J. Biol. Chem. 1998;273:28945–28952. doi: 10.1074/jbc.273.44.28945.] [[PubMed][Google Scholar]
29. Poudel B, Lim SW, Ki HH, Nepali S, Lee YM, Kim DKDioscin inhibits adipogenesis through the AMPK/MAPK pathway in 3T3-L1 cells and modulates fat accumulation in obese mice. Int. J. Mol. Med. 2014;34:1401–1408.[PubMed][Google Scholar]
30. Wang M, Wang JJ, Li J, Park K, Qian X, Ma JX, Zhang SXPigment epitheliumderived factor suppresses adipogenesis via inhibition of the MAPK/ERK pathway in 3T3-L1 preadipocytes. Am. J. Physiol.-Endoc. M. 2009;297:E1387.[Google Scholar]
31. Kimura I, Konishi M, Asaki T, Furukawa N, Ukai K, Mori M, Hirasawa A, Tsujimoto G, Ohta M, Itoh N, Fujimoto MNeudesin, an extracellular hemebinding protein, suppresses adipogenesis in 3T3-L1 cells via the MAPK cascade. Biochem Bioph. Res. Co. 2009;381:75–80. doi: 10.1016/j.bbrc.2009.02.011.] [[PubMed][Google Scholar]
32. Zhang B, Berger J, Zhou G, Elbrecht A, Biswas S, White-Carrington S, Szalkowski D, Moller DEInsulin-and mitogen-activated protein kinasemediated phosphorylation and activation of peroxisome proliferatoractivated receptor gamma. J. Biol. Chem. 1996;271:31771–31774. doi: 10.1074/jbc.271.50.31771.] [[PubMed][Google Scholar]
33. Bost F, Caron L, Marchetti I, Dani C L, Marchand-Brustel Y, Binetruy BRetinoic acid activation of the ERK pathway is required for embryonic stem cell commitment into the adipocyte lineage. Biochem. J. 2002;361:621–627. doi: 10.1042/bj3610621.] [[Google Scholar]
34. Aouadi M, Laurent K, Prot M L, Marchand-Brustel Y, Binetruy B, Bost FInhibition of p38MAPK increases adipogenesis from embryonic to adult stages. Diabetes. 2006;55:281–289. doi: 10.2337/diabetes.55.02.06.db05-0963.] [[PubMed][Google Scholar]
35. Hata K, Nishimura R, Ikeda F, Yamashita K, Matsubara T, Nokubi T, Yoneda TDifferential roles of Smad1 and p38 kinase in regulation of peroxisome proliferator-activating receptor gamma during bone morphogenetic protein 2-induced adipogenesis. Mol. Biol. Cell. 2003;14:545–555. doi: 10.1091/mbc.E02-06-0356.] [[Google Scholar]
36. 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 MAMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab. 2011;13:376–388. doi: 10.1016/j.cmet.2011.03.009.] [[Google Scholar]
37. Kahn BB, Alquier T, Carling D, Hardie DGAMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005;1:15–25. doi: 10.1016/j.cmet.2004.12.003.] [[PubMed][Google Scholar]
38. Gao Y, Zhou Y, Xu A, Wu DEffects of an AMP-activated protein kinase inhibitor, compound C, on adipogenic differentiation of 3T3-L1 cells. Biol. Pharm. Bull. 2008;31:1716–1722. doi: 10.1248/bpb.31.1716.] [[PubMed][Google Scholar]
39. Hardie DG, Scott JW, Pan DA, Hudson ERManagement of cellular energy by the AMP-activated protein kinase system. FEBS Lett. 2003;546:113–120. doi: 10.1016/S0014-5793(03)00560-X.] [[PubMed][Google Scholar]
40. Holm CMolecular mechanisms regulating hormone-sensitive lipase and lipolysis. Biochem. Soc. T. 2003;31:1120–1124. doi: 10.1042/bst0311120.] [[PubMed][Google Scholar]