Quercetin, Luteolin, and Epigallocatechin Gallate Promote Glucose Disposal in Adipocytes with Regulation of AMP-Activated Kinase and/or Sirtuin 1 Activity

Abstract

Quercetin, luteolin, and epigallocatechin gallate are flavonoids abundant in edible and medicinal plants with beneficial effects on glucose homeostasis. This study explored the action of these flavonoids on glucose disposal in adipocytes. Quercetin, luteolin, and epigallocatechin gallate enhanced glucose consumption with the positive regulation of AMP-activated kinase phosphorylation, and the AMP-activated kinase inhibitor compound C abolished their effects on glucose consumption. Luteolin and epigallocatechin gallate, but not quercetin, increased sirtuin 1 abundance, and their regulation of glucose consumption was also attenuated by co-treatment with sirtuin 1 inhibitor nicotinamide. Quercetin, luteolin, and epigallocatechin gallate suppressed nuclear factor-κB activation by inhibition of p65 phosphorylation with beneficial regulation of adipokine expression, whereas these actions were diminished by coincubation with compound C. The sirtuin 1 inhibitor nicotinamide attenuated the effects of luteolin and EGCG on p65 phosphorylation and adipokine expression without any influence on the activity of quercetin. Results of Western blot and fluorescence microscopy also showed that quercetin, luteolin, and epigallocatechin gallate increased Akt substrate of 160 kDa phosphorylation and promoted 2-deoxy-D-glucose uptake by adipocytes under basal and inflammatory conditions. These findings suggested that quercetin, luteolin, and epigallocatechin gallate inhibited inflammation and promoted glucose disposal in adipocytes with the regulation of AMP-activated kinase and/or sirtuin 1.

Key words

flavonoids - AMPK - SIRT1 - glucose disposal - adipocytes

• References

• 1 Treebak JT, Taylor EB, Witczak CA, An D, Toyoda T, Koh HJ, Xie J, Feener EP, Wojtaszewski JF, Hirshman MF, Goodyear LJ. Identification of a novel phosphorylation site on TBC1D4 regulated by AMP-activated protein kinase in skeletal muscle. Am J Physiol 2010; 298: C377-C385
• 2 Kramer HF, Witczak CA, Fujii N, Jessen N, Taylor EB, Arnolds DE, Sakamoto K, Hirshman MF, Goodyear LJ. Distinct signals regulate AS160 phosphorylation in response to insulin, AICAR, and contraction in mouse skeletal muscle. Diabetes 2006; 55: 2067-2076
• 3 Smith JJ, Kenney RD, Gagne DJ, Frushour BP, Ladd W, Galonek HL, Israelian K, Song J, Razvadauskaite G, Lynch AV, Carney DP, Johnson RJ, Lavu S, Iffland A, Elliott PJ, Lambert PD, Elliston KO, Jirousek MR, Milne JC, Boss O. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. BMC Syst Biol 2009; 3: 31
• 4 Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 2006; 127: 1109-1122
• 5 Yang Z, Kahn BB, Shi H, Xue BZ. Macrophage alpha1 AMP-activated protein kinase (alpha1AMPK) antagonizes fatty acid-induced inflammation through SIRT1. J Biol Chem 2010; 285: 19051-19059
• 6 Galic S, Fullerton MD, Schertzer JD, Sikkema S, Marcinko K, Walkley CR, Izon D, Honeyman J, Chen ZP, van Denderen BJ, Kemp BE, Steinberg GR. Hematopoietic AMPK beta1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. J Clin Invest 2011; 121: 4903-4915
• 7 Yang Z, Wang X, He Y, Qi L, Yu L, Xue B, Shi H. The full capacity of AICAR to reduce obesity-induced inflammation and insulin resistance requires myeloid SIRT1. PloS One 2012; 7: e49935
• 8 Siriwardhana N, Kalupahana NS, Cekanova M, LeMieux M, Greer B, Moustaid-Moussa N. Modulation of adipose tissue inflammation by bioactive food compounds. J Nutr Biochem 2013; 24: 613-623
• 9 Overman A, Chuang CC, McIntosh M. Quercetin attenuates inflammation in human macrophages and adipocytes exposed to macrophage-conditioned media. Int J Obes 2011; 35: 1165-1172
• 10 Ahn J, Lee H, Kim S, Park J, Ha T. The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways. Biochem Biophys Res Commun 2008; 373: 545-549
• 11 Ding L, Jin D, Chen X. Luteolin enhances insulin sensitivity via activation of PPARgamma transcriptional activity in adipocytes. J Nutr Biochem 2010; 21: 941-947
• 12 Babu PV, Liu D, Gilbert ER. Recent advances in understanding the anti-diabetic actions of dietary flavonoids. J Nutr Biochem 2013; 24: 1777-1789
• 13 de Boer VC, de Goffau MC, Arts IC, Hollman PC, Keijer J. SIRT1 stimulation by polyphenols is affected by their stability and metabolism. Mech Ageing Dev 2006; 127: 618-627
• 14 Strobel P, Allard C, Perez-Acle T, Calderon R, Aldunate R, Leighton F. Myricetin, quercetin and catechin-gallate inhibit glucose uptake in isolated rat adipocytes. Biochem J 2005; 386: 471-478
• 15 Nomura M, Takahashi T, Nagata N, Tsutsumi K, Kobayashi S, Akiba T, Yokogawa K, Moritani S, Miyamoto K. Inhibitory mechanisms of flavonoids on insulin-stimulated glucose uptake in MC3 T3-G2/PA6 adipose cells. Biol Pharm Bull 2008; 31: 1403-1409
• 16 Eid HM, Martineau LC, Saleem A, Muhammad A, Vallerand D, Benhaddou-Andaloussi A, Nistor L, Afshar A, Arnason JT, Haddad PS. Stimulation of AMP-activated protein kinase and enhancement of basal glucose uptake in muscle cells by quercetin and quercetin glycosides, active principles of the antidiabetic medicinal plant Vaccinium vitis-idaea . Mol Nutr Food Res 2010; 54: 991-1003
• 17 Murase T, Misawa K, Haramizu S, Hase T. Catechin-induced activation of the LKB1/AMP-activated protein kinase pathway. Biochem pharmacol 2009; 78: 78-84
• 18 Collins QF, Liu HY, Pi J, Liu Z, Quon MJ, Cao W. Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, suppresses hepatic gluconeogenesis through 5′-AMP-activated protein kinase. J Biol Chem 2007; 282: 30143-30149
• 19 Liu JF, Ma Y, Wang Y, Du ZY, Shen JK, Peng HL. Reduction of lipid accumulation in HepG2 cells by luteolin is associated with activation of AMPK and mitigation of oxidative stress. Phytother Res 2011; 25: 588-596
• 20 Hwang JT, Park OJ, Lee YK, Sung MJ, Hur HJ, Kim MS, Ha JH, Kwon DY. Anti-tumor effect of luteolin is accompanied by AMP-activated protein kinase and nuclear factor-kappaB modulation in HepG2 hepatocarcinoma cells. Int J Mol Med 2011; 28: 25-31
• 21 Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F, Ido Y. AMPK and SIRT1: a long-standing partnership?. Am J Physiol Endocrinol Metab 2010; 298: E751-E760
• 22 Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 2004; 23: 2369-2380
• 23 Sakamoto K, Holman GD. Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic. Am J Physiol Endocrinol Metab 2008; 295: E29-E37
• 24 Chavez JA, Roach WG, Keller SR, Lane WS, Lienhard GE. Inhibition of GLUT4 translocation by Tbc1d1, a Rab GTPase-activating protein abundant in skeletal muscle, is partially relieved by AMP-activated protein kinase activation. J Biol Chem 2008; 283: 9187-9195
• 25 Sano H, Kane S, Sano E, Miinea CP, Asara JM, Lane WS, Garner CW, Lienhard GE. Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J Biol Chem 2003; 278: 14599-14602
• 26 Eguez L, Lee A, Chavez JA, Miinea CP, Kane S, Lienhard GE, McGraw TE. Full intracellular retention of GLUT4 requires AS160 Rab GTPase activating protein. Cell Metab 2005; 2: 263-272
• 27 Thong FS, Bilan PJ, Klip A. The Rab GTPase-activating protein AS160 integrates Akt, protein kinase C, and AMP-activated protein kinase signals regulating GLUT4 traffic. Diabetes 2007; 56: 414-423
• 28 Canto C, Jiang LQ, Deshmukh AS, Mataki C, Coste A, Lagouge M, Zierath JR, Auwerx J. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab 2010; 11: 213-219
• 29 Chung S, Yao H, Caito S, Hwang JW, Arunachalam G, Rahman I. Regulation of SIRT1 in cellular functions: role of polyphenols. Arch Biochem Biophys 2010; 501: 79-90
• 30 Nomura M, Takahashi T, Nagata N, Tsutsumi K, Kobayashi S, Akiba T, Yokogawa K, Moritani S, Miyamoto K. Inhibitory mechanisms of flavonoids on insulin-stimulated glucose uptake in MC3T3-G2/PA6 adipose cells. Biol Pharm Bull 2008; 31: 1403-1409
• 31 Liu K, Luo T, Zhang Z, Wang T, Kou J, Liu B, Huang F. Modified Si-Miao-San extract inhibits inflammatory response and modulates insulin sensitivity in hepatocytes through an IKKbeta/IRS-1/Akt-dependent pathway. J Ethnopharmacol 2011; 136: 473-479