title: (-)-Epicatechin mitigates high-fructose-associated insulin resistance by modulating redox signaling and endoplasmic reticulum stress.
abstract: We investigated the capacity of dietary (-)-epicatechin (EC) to mitigate insulin resistance through the modulation of redox-regulated mechanisms in a rat model of metabolic syndrome. Adolescent rats were fed a regular chow diet without or with high fructose (HFr; 10% w/v) in drinking water for 8 weeks, and a group of HFr-fed rats was supplemented with EC in the diet. HFr-fed rats developed insulin resistance, which was mitigated by EC supplementation. Accordingly, the activation of components of the insulin signaling cascade (insulin receptor, IRS1, Akt, and ERK1/2) was impaired, whereas negative regulators (PKC, IKK, JNK, and PTP1B) were upregulated in the liver and adipose tissue of HFr rats. These alterations were partially or totally prevented by EC supplementation. In addition, EC inhibited events that contribute to insulin resistance: HFr-associated increased expression and activity of NADPH oxidase, activation of redox-sensitive signals, expression of NF-κB-regulated proinflammatory cytokines and chemokines, and some sub-arms of endoplasmic reticulum stress signaling. Collectively, these findings indicate that EC supplementation can mitigate HFr-induced insulin resistance and are relevant for defining interventions that can prevent/mitigate MetS-associated insulin resistance.
authors.affiliation: Department of Nutrition, University of California at Davis, Davis, CA 95616, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Bettaieb
authors.affiliation: Department of Pathology, School of Medicine, National University of Cuyo and Institute of Medicine and Experimental Biology-CONICET, Mendoza, Argentina.
authors.forename: Marcela A
authors.initials: MA
authors.lastname: Vazquez Prieto
authors.affiliation: Department of Pathology, School of Medicine, National University of Cuyo and Institute of Medicine and Experimental Biology-CONICET, Mendoza, Argentina.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rodriguez Lanzi
authors.affiliation: Department of Pathology, School of Medicine, National University of Cuyo and Institute of Medicine and Experimental Biology-CONICET, Mendoza, Argentina.
authors.forename: Roberto M
authors.initials: RM
authors.lastname: Miatello
authors.affiliation: Department of Nutrition, University of California at Davis, Davis, CA 95616, USA; Department of Internal Medicine, University of California at Davis, Davis, CA 95616, USA.
authors.forename: Fawaz G
authors.initials: FG
authors.lastname: Haj
authors.affiliation: Department of Nutrition, University of California at Davis, Davis, CA 95616, USA; Physical Chemistry-IBIMOL, School of Pharmacy and Biochemistry, University of Buenos Aires-CONICET, Buenos Aires, Argentina.
authors.forename: César G
authors.initials: CG
authors.lastname: Fraga
authors.affiliation: Department of Nutrition, University of California at Davis, Davis, CA 95616, USA; Department of Environmental Toxicology, University of California at Davis, Davis, CA 95616, USA. Electronic address: poteiza@ucdavis.edu.
authors.forename: Patricia I
authors.initials: PI
authors.lastname: Oteiza
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D002392:Catechin / Q000494:pharmacology*; D019587:Dietary Supplements; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005632:Fructose / Q000633:toxicity; D007333:Insulin Resistance; D008297:Male; D024821:Metabolic Syndrome / Q000139:chemically induced / Q000517:prevention & control*; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D005632:Fructose; D002392:Catechin
keywords: Endoplasmic reticulum stress; Epicatechin and flavonoids; Free radicals; Insulin resistance; Metabolic syndrome; NADPH oxidase; Redox signaling
references.citation: Circ Res. 2001 Feb 2;88(2):E14-22
references.pmid: 11157681
references.citation: Free Radic Biol Med. 2011 Aug 15;51(4):813-23
references.pmid: 21699974
references.citation: Appl Physiol Nutr Metab. 2010 Dec;35(6):816-25
references.pmid: 21164553
references.citation: Clin Dev Immunol. 2005 Mar;12(1):11-7
references.pmid: 15712594
references.citation: Science. 2004 Oct 15;306(5695):457-61
references.pmid: 15486293
references.citation: Int J Obes (Lond). 2008 Aug;32(8):1289-96
references.pmid: 18504447
references.citation: Br J Nutr. 2007 Oct;98 Suppl 1:S121-6
references.pmid: 17922949
references.citation: J Cardiovasc Pharmacol. 2007 Feb;49(2):74-80
references.pmid: 17312446
references.citation: Biochem Biophys Res Commun. 2007 Aug 3;359(3):828-33
references.pmid: 17560937
references.citation: Can J Biochem Physiol. 1959 Aug;37(8):911-7
references.pmid: 13671378
references.citation: Diabetes. 2002 May;51(5):1319-36
references.pmid: 11978627
references.citation: Endocrinology. 2004 Nov;145(11):5087-96
references.pmid: 15297438
references.citation: J Neurochem. 2007 Jun;101(6):1596-606
references.pmid: 17298385
references.citation: Endocrinol Metab Clin North Am. 2004 Jun;33(2):351-75, table of contents
references.pmid: 15158523
references.citation: Arch Biochem Biophys. 2012 Nov 15;527(2):113-8
references.pmid: 22425757
references.citation: Arch Biochem Biophys. 2008 Jan 15;469(2):209-19
references.pmid: 17996190
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: JAMA. 2002 Jan 16;287(3):356-9
references.pmid: 11790215
references.citation: Science. 2006 Aug 25;313(5790):1137-40
references.pmid: 16931765
references.citation: Diabetes. 2006 Jan;55(1):93-101
references.pmid: 16380481
references.citation: Am J Physiol Endocrinol Metab. 2013 Feb 15;304(4):E392-404
references.pmid: 23233541
references.citation: Diabetes. 2005 Feb;54(2):311-21
references.pmid: 15677487
references.citation: J Biol Chem. 2005 Apr 15;280(15):15038-46
references.pmid: 15699041
references.citation: Diabetes. 2008 Sep;57(9):2438-44
references.pmid: 18567819
references.citation: Endocrinology. 2006 Jul;147(7):3398-407
references.pmid: 16601139
references.citation: J Nutr. 2011 Nov;141(11):1982-8
references.pmid: 21956956
references.citation: Medscape J Med. 2008 Jul 09;10(7):160
references.pmid: 18769702
references.citation: Circulation. 2009 Oct 20;120(16):1640-5
references.pmid: 19805654
references.citation: Annu Rev Biochem. 2005;74:739-89
references.pmid: 15952902
references.citation: J Clin Endocrinol Metab. 2002 Jul;87(7):3023-8
references.pmid: 12107194
references.citation: Free Radic Biol Med. 2012 Jan 1;52(1):70-9
references.pmid: 22001745
references.citation: Am J Clin Nutr. 2005 Mar;81(3):611-4
references.pmid: 15755830
references.citation: Circ Res. 2010 Sep 3;107(5):579-91
references.pmid: 20814028
references.citation: J Clin Biochem Nutr. 2011 Jan;48(1):63-7
references.pmid: 21297914
references.citation: Pharmacol Rep. 2005 Sep-Oct;57(5):610-5
references.pmid: 16227644
references.citation: Obesity (Silver Spring). 2012 Apr;20(4):748-55
references.pmid: 21633399
references.citation: JAMA. 2007 Jul 4;298(1):49-60
references.pmid: 17609490
references.citation: Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H954-62
references.pmid: 17028163
references.citation: J Pathol. 2013 Nov;231(3):290-300
references.pmid: 24037780
references.citation: Cancer Res. 2006 Sep 15;66(18):9260-9
references.pmid: 16982771
references.citation: Free Radic Biol Med. 2011 Jan 15;50(2):237-44
references.pmid: 21074608
references.citation: Eur J Clin Nutr. 2011 Mar;65(3):368-77
references.pmid: 21119694
references.citation: Science. 2001 Aug 31;293(5535):1673-7
references.pmid: 11533494
references.citation: Diabetes. 2009 Mar;58(3):693-700
references.pmid: 19066313
references.citation: J Biol Chem. 2008 Aug 29;283(35):23863-71
references.pmid: 18579519
references.citation: Diabetes Care. 2012 Feb;35(2):226-32
references.pmid: 22250063
references.citation: J Nutr Biochem. 2010 Oct;21(10):961-7
references.pmid: 19962298
references.citation: Biochem Soc Trans. 2008 Oct;36(Pt 5):920-9
references.pmid: 18793162
references.citation: Int J Obes. 1985;9(6):443-9
references.pmid: 3830936
references.citation: FASEB J. 2004 Jan;18(1):167-9
references.pmid: 14630700
references.citation: Diabetologia. 2008 Jan;51(1):130-8
references.pmid: 18008059
references.citation: J Agric Food Chem. 2006 Dec 27;54(26):9966-77
references.pmid: 17177529
references.citation: Am J Clin Nutr. 2010 Dec;92(6):1511-21
references.pmid: 20943792
references.citation: J Biol Chem. 1997 Aug 15;272(33):20313-6
references.pmid: 9252331
references.citation: Am J Physiol Endocrinol Metab. 2004 Nov;287(5):E926-33
references.pmid: 15198936
references.citation: PLoS One. 2011 Jan 31;6(1):e16446
references.pmid: 21305007
references.citation: J Clin Invest. 2007 Mar;117(3):739-45
references.pmid: 17318260
references.citation: Free Radic Res. 2006 Oct;40(10):1086-94
references.pmid: 17015253
references.citation: Free Radic Biol Med. 2011 Sep 1;51(5):993-9
references.pmid: 21163347
references.citation: Nature. 2002 Nov 21;420(6913):333-6
references.pmid: 12447443
references.citation: Diabetes. 2006 Dec;55 Suppl 2:S9-S15
references.pmid: 17130651
references.citation: J Am Diet Assoc. 2007 Jun;107(6):979-87; quiz 997
references.pmid: 17524719
references.citation: J Cardiovasc Pharmacol. 2009 Dec;54(6):483-90
references.pmid: 19701098
references.citation: J Nutr. 2012 Feb;142(2):251-7
references.pmid: 22190023
references.citation: J Clin Invest. 2009 May;119(5):1322-34
references.pmid: 19381015
references.citation: Am J Clin Nutr. 2006 Dec;84(6):1489-97
references.pmid: 17158434
references.citation: Free Radic Biol Med. 2012 Nov 15;53(10):1894-902
references.pmid: 22985936
references.citation: BMJ. 2011 Aug 26;343:d4488
references.pmid: 21875885
references.citation: J Biol Chem. 2005 Jun 10;280(23):21763-72
references.pmid: 15826936
references.citation: J Nutr. 2008 Sep;138(9):1671-6
references.pmid: 18716168