The role of the Nrf2/Keap1 pathway in obesity and metabolic syndrome

Reviews in Endocrine and Metabolic Disorders

Volumn 16, Issue 1, 2015, Pages 35-45

  Zhang, Zhiguo ^a,b   Zhou, Shanshan ^a,b   Jiang, Xin ^a,b   Wang, Yue Hui ^a   Li, Fengsheng ^b,c   Wang, Yong Gang ^a,b   Zheng, Yang ^a   Cai, Lu ^b  

^a JILIN UNIVERSITY   (China)

^b University of Louisville School of Medicine   (United States)

^c Second Artillery   (China)

Author keywords

Insulin resistance; Metabolic homeostasis; Nrf2 Keap1; Obesity; Reactive oxygen species

Indexed keywords

1 [2 CYANO 3,12 DIOXOOLEANA 1,9(11) DIEN 28 OYL] IMIDAZOLE; IMIDAZOLE DERIVATIVE; KELCH LIKE ECH ASSOCIATED PROTEIN 1; OLTIPRAZ; REACTIVE OXYGEN METABOLITE; SULFORAPHANE; TRANSCRIPTION FACTOR NRF2; UNCLASSIFIED DRUG; KEAP1 PROTEIN, HUMAN; NFE2L2 PROTEIN, HUMAN; SIGNAL PEPTIDE;

ADIPOCYTE; ADIPOGENESIS; CARBOHYDRATE METABOLISM; CELL DIFFERENTIATION; CELLULAR SECRETION; CLINICAL TRIAL (TOPIC); GENE DELETION; GENE OVEREXPRESSION; GLYCOGEN SYNTHESIS; GLYCOGENOLYSIS; HOMEOSTASIS; HUMAN; HYPERTENSION; INSULIN RELEASE; INSULIN RESISTANCE; LIPOGENESIS; METABOLIC SYNDROME X; NONHUMAN; OBESITY; OXIDATIVE STRESS; PANCREAS ISLET BETA CELL; REVIEW; SKELETAL MUSCLE; WHITE ADIPOSE TISSUE; METABOLISM; PHYSIOLOGY; SIGNAL TRANSDUCTION;

HOMEOSTASIS; HUMANS; INSULIN RESISTANCE; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; METABOLIC SYNDROME X; NF-E2-RELATED FACTOR 2; OBESITY; REACTIVE OXYGEN SPECIES; SIGNAL TRANSDUCTION;

EID: 84925488647     PISSN: 13899155     EISSN: 15732606     Source Type: Journal    
DOI: 10.1007/s11154-014-9305-9     Document Type: Review

References (91)

1. Renehan AG et al. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371(9612):569–78.
2. Swinburn BA et al. The global obesity pandemic: shaped by global drivers and local environments. Lancet. 2011;378(9793):804–14.
3. Finkelstein EA et al. Obesity and severe obesity forecasts through 2030. Am J Prev Med. 2012;42(6):563–70.
4. Pischon T et al. General and abdominal adiposity and risk of death in Europe. N Engl J Med. 2008;359(20):2105–20.
5. Go AS et al. Heart disease and stroke statistics–2013 update: a report from the American heart association. Circulation. 2013;127(1):e6–245.
6. Guo S. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. J Endocrinol. 2014;220(2):T1–23.
7. Zhai L, Ballinger SW, Messina JL. Role of reactive oxygen species in injury-induced insulin resistance. Mol Endocrinol. 2011;25(3):492–502.
8. Maddux BA et al. Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells by mircomolar concentrations of alpha-lipoic acid. Diabetes. 2001;50(2):404–10.
9. Padmanabhan B et al. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell. 2006;21(5):689–700.
10. Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells. 2011;16(2):123–40.
11. McMahon M et al. Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J Biol Chem. 2003;278(24):21592–600.
12. Wakabayashi N et al. Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers. Proc Natl Acad Sci U S A. 2004;101(7):2040–5.
13. Ishii T, Itoh K, Yamamoto M. Roles of Nrf2 in activation of antioxidant enzyme genes via antioxidant responsive elements. Methods Enzymol. 2002;348:182–90.
14. de Haan JB. Nrf2 activators as attractive therapeutics for diabetic nephropathy. Diabetes. 2011;60(11):2683–4.
15. Loh K et al. Reactive oxygen species enhance insulin sensitivity. Cell Metab. 2009;10(4):260–72.
16. Tanaka Y et al. NF-E2-related factor 2 inhibits lipid accumulation and oxidative stress in mice fed a high-fat diet. J Pharmacol Exp Ther. 2008;325(2):655–64.
17. Bonnard C et al. Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. J Clin Invest. 2008;118(2):789–800.
18. Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 2006;440(7086):944–8.
19. Anderson EJ et al. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest. 2009;119(3):573–81.
20. Lee HY et al. Targeted expression of catalase to mitochondria prevents age-associated reductions in mitochondrial function and insulin resistance. Cell Metab. 2010;12(6):668–74.
21. Morino K, Petersen KF, Shulman GI. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes. 2006;55(Supplement 2):S9–15.
22. Tirosh A et al. Oxidative stress disrupts insulin-induced cellular redistribution of insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-L1 adipocytes. A putative cellular mechanism for impaired protein kinase B activation and GLUT4 translocation. J Biol Chem. 1999;274(15):10595–602.
23. Kaneto H et al. Activation of the hexosamine pathway leads to deterioration of pancreatic β-cell function through the induction of oxidative stress. J Bio Chem. 2001;276(33):31099–104.
24. Mahadev K et al. The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction. Mol Cell Biol. 2004;24(5):1844–54.
25. Veal EA, Day AM, Morgan BA. Hydrogen peroxide sensing and signaling. Mol Cell. 2007;26(1):1–14.
26. Ristow M et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A. 2009;106(21):8665–70.
27. Gliemann L et al. Resveratrol blunts the positive effects of exercise training on cardiovascular health in aged men. J Physiol. 2013;591(Pt 20):5047–59.
28. Bocci V et al. An integrated medical treatment for type-2 diabetes. Diabetes Metab Syndr. 2014;8(1):57–61.
29. Watson JD. Type 2 diabetes as a redox disease. Lancet. 2014;383(9919):841–3.
30. Li Y et al. Deficiency in the NADPH oxidase 4 predisposes towards diet-induced obesity. Int J Obes (Lond). 2012;36(12):1503–13.
31. Bjelakovic G et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention. J Am Med Assoc. 2007;297(8):842–57.
32. Kobayashi M, Yamamoto M. Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzyme Regul. 2006;46(113).
33. Gaikwad A et al. In vivo role of NAD(P)H:quinone oxidoreductase 1 (NQO1) in the regulation of intracellular redox state and accumulation of abdominal adipose tissue. J Biol Chem. 2001;276(25):22559–64.
34. Kendig EL et al. Lipid metabolism and body composition in Gclm(−/−) mice. Toxicol Appl Pharmacol. 2011;257(3):338–48.
35. McClung JP et al. Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase. Proc Natl Acad Sci U S A. 2004;101(24):8852–7.
36. Chartoumpekis DV et al. Nrf2 represses FGF21 during long-term high-fat diet-induced obesity in mice. Diabetes. 2011;60(10):2465–73.
37. Li H, Zhang J, Jia W. Fibroblast growth factor 21: a novel metabolic regulator from pharmacology to physiology. Front Med. 2013;7(1):25–30.
38. Kliewer SA, Mangelsdorf DJ. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr. 2010;91(1):254S–7.
39. Zhang YK et al. Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet. Toxicol Appl Pharmacol. 2012;264(3):305–14.
40. Pi J et al. Deficiency in the nuclear factor E2-related factor-2 transcription factor results in impaired adipogenesis and protects against diet-induced obesity. J Biol Chem. 2010;285(12):9292–300.
41. Collins AR et al. Myeloid deletion of nuclear factor erythroid 2-related factor 2 increases atherosclerosis and liver injury. Arterioscler Thromb Vasc Biol. 2012;32(12):2839–46.
42. Meher AK et al. Nrf2 deficiency in myeloid cells is not sufficient to protect mice from high-fat diet-induced adipose tissue inflammation and insulin resistance. Free Radic Biol Med. 2012;52(9):1708–15.
43. Xue P et al. Adipose deficiency of Nrf2 in ob/ob mice results in severe metabolic syndrome. Diabetes. 2013;62(3):845–54.
44. Yu Z et al. Oltipraz upregulates the nuclear factor (erythroid-derived 2)-like 2alpha subunit (NRF2) antioxidant system and prevents insulin resistance and obesity induced by a high-fat diet in C57BL/6J mice. Diabetologia. 2011;54(4):922–34.
45. Xu J et al. Enhanced Nrf2 activity worsens insulin resistance, impairs lipid accumulation in adipose tissue, and increases hepatic steatosis in leptin-deficient mice. Diabetes. 2012;61(12):3208–18.
46. Shin S et al. Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide. Eur J Pharmacol. 2009;620(1–3):138–44.
47. Gao S et al. Curcumin attenuates arsenic-induced hepatic injuries and oxidative stress in experimental mice through activation of Nrf2 pathway, promotion of arsenic methylation and urinary excretion. Food Chem Toxicol. 2013;59:739–47.
48. Bahadoran Z, Mirmiran P, Azizi F. Potential efficacy of broccoli sprouts as a unique supplement for management of type 2 diabetes and its complications. J Med Food. 2013;16(5):375–82.
49. He HJ et al. Curcumin attenuates Nrf2 signaling defect, oxidative stress in muscle and glucose intolerance in high fat diet-fed mice. World J Diabetes. 2012;3(5):94–104.
50. Hoehn KL et al. Insulin resistance is a cellular antioxidant defense mechanism. Proc Natl Acad Sci U S A. 2009;106(42):17787–92.
51. D’Apolito M et al. Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure. J Clin Invest. 2010;120(1):203–13.
52. Lee BH et al. Ankaflavin: a natural novel PPARgamma agonist upregulates Nrf2 to attenuate methylglyoxal-induced diabetes in vivo. Free Radic Biol Med. 2012;53(11):2008–16.
53. Jung UJ, Choi MS. Obesity and its metabolic complications: The role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci. 2014;15(4):6184–223.
54. Zhang W et al. ER stress potentiates insulin resistance through PERK-mediated FOXO phosphorylation. Genes Dev. 2013;27(4):441–9.
55. Choi KM et al. Sulforaphane attenuates obesity by inhibiting adipogenesis and activating the AMPK pathway in obese mice. J Nutr Biochem. 2014;25(2):201–7.
56. Kang OH et al. Curcumin decreases oleic acid-induced lipid accumulation via AMPK phosphorylation in hepatocarcinoma cells. Eur Rev Med Pharmacol Sci. 2013;17(19):2578–86.
57. Kim TH et al. An active metabolite of oltipraz (M2) increases mitochondrial fuel oxidation and inhibits lipogenesis in the liver by dually activating AMPK. Br J Pharmacol. 2013;168(7):1647–61.
58. Cheng Z et al. Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nat Med. 2009;15(11):1307–11.
59. More VR et al. Keap1 knockdown increases markers of metabolic syndrome after long-term high fat diet feeding. Free Radic Biol Med. 2013;61C:85–94.
60. Yates MS et al. Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice. Carcinogenesis. 2009;30(6):1024–31.
61. Huang X et al. The COP9 signalosome, cullin 3 and Keap1 supercomplex regulates CHOP stability and adipogenesis. Biol Open. 2012;1(8):705–10.
62. Kitteringham NR et al. Proteomic analysis of Nrf2 deficient transgenic mice reveals cellular defence and lipid metabolism as primary Nrf2-dependent pathways in the liver. J Proteomics. 2010;73(8):1612–31.
63. Wu KC, Cui JY, Klaassen CD. Beneficial role of Nrf2 in regulating NADPH generation and consumption. Toxicol Sci. 2011;123(2):590–600.
64. Kay HY et al. Nrf2 inhibits LXRalpha-dependent hepatic lipogenesis by competing with FXR for acetylase binding. Antioxid Redox Signal. 2011;15(8):2135–46.
65. Huang J et al. Transcription factor Nrf2 regulates SHP and lipogenic gene expression in hepatic lipid metabolism. Am J Physiol Gastrointest Liver Physiol. 2010;299(6):G1211–21.
66. Lin Z et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab. 2013;17(5):779–89.
67. Straczkowski M et al. Serum fibroblast growth factor 21 in human obesity: regulation by insulin infusion and relationship with glucose and lipid oxidation. Int J Obes (Lond). 2013;37(10):1386–90.
68. Yoon JC et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature. 2001;413(6852):131–8.
69. Zhang YK et al. Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet. Toxicol Appl Pharmacol. 2010;245(3):326–34.
70. Jin SH et al. Resveratrol inhibits LXRalpha-dependent hepatic lipogenesis through novel antioxidant Sestrin2 gene induction. Toxicol Appl Pharmacol. 2013;271(1):95–105.
71. Han S et al. How aluminum, an intracellular ROS generator promotes hepatic and neurological diseases: the metabolic tale. Cell Biol Toxicol. 2013;29(2):75–84.
72. Merry TL et al. High-fat-fed obese glutathione peroxidase 1-deficient mice exhibit defective insulin secretion but protection from hepatic steatosis and liver damage. Antioxid Redox Signal. 2014;20(14):2114–29.
73. Otto TC, Lane MD. Adipose development: from stem cell to adipocyte. Crit Rev Biochem Mol Biol. 2005;40(4):229–42.
74. Rosen ED. The transcriptional basis of adipocyte development. Prostaglandins Leukot Essent Fatty Acids. 2005;73(1):31–4.
75. Vigouroux C et al. Molecular mechanisms of human lipodystrophies: from adipocyte lipid droplet to oxidative stress and lipotoxicity. Int J Biochem Cell Biol. 2011;43(6):862–76.
76. Virtue S, Vidal-Puig A. Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome–an allostatic perspective. Biochim Biophys Acta. 2010;1801(3):338–49.
77. Schneider KS, Chan JY. Emerging role of Nrf2 in adipocytes and adipose biology. Adv Nutr. 2013;4(1):62–6.
78. Hou Y et al. Nuclear factor erythroid-derived factor 2-related factor 2 regulates transcription of CCAAT/enhancer-binding protein beta during adipogenesis. Free Radic Biol Med. 2012;52(2):462–72.
79. Chang YC et al. Deficiency of NPGPx, an oxidative stress sensor, leads to obesity in mice and human. EMBO Mol Med. 2013;5(8):1165–79.
80. Shin S et al. NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis. Mol Cell Biol. 2007;27(20):7188–97.
81. Chorley BN et al. Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha. Nucleic Acids Res. 2012;40(15):7416–29.
82. Uruno A et al. The Keap1-Nrf2 system prevents onset of diabetes mellitus. Mol Cell Biol. 2013;33(15):2996–3010.
83. Barazzoni R et al. Fatty acids acutely enhance insulin-induced oxidative stress and cause insulin resistance by increasing mitochondrial reactive oxygen species (ROS) generation and nuclear factor-kappaB inhibitor (IkappaB)-nuclear factor-kappaB (NFkappaB) activation in rat muscle, in the absence of mitochondrial dysfunction. Diabetologia. 2012;55(3):773–82.
84. Song MY et al. Sulforaphane protects against cytokine- and streptozotocin-induced beta-cell damage by suppressing the NF-kappaB pathway. Toxicol Appl Pharmacol. 2009;235(1):57–67.
85. Aleksunes LM et al. Nuclear factor erythroid 2-related factor 2 deletion impairs glucose tolerance and exacerbates hyperglycemia in type 1 diabetic mice. J Pharmacol Exp Ther. 2010;333(1):140–51.
86. Yagishita Y et al. Nrf2 protects pancreatic beta-cells from oxidative and nitrosative stress in diabetic model mice. Diabetes. 2014;63(2):605–18.
87. Grossman E. Does increased oxidative stress cause hypertension? Diabetes Care. 2008;31 Suppl 2:S185–9.
88. de Champlain J et al. Oxidative stress in hypertension. Clin Exp Hypertens. 2004;26(7–8):593–601.
89. Chen TM et al. Effects of heme oxygenase-1 upregulation on blood pressure and cardiac function in an animal model of hypertensive myocardial infarction. Int J Mol Sci. 2013;14(2):2684–706.
90. Gomez-Guzman M et al. Epicatechin lowers blood pressure, restores endothelial function, and decreases oxidative stress and endothelin-1 and NADPH oxidase activity in DOCA-salt hypertension. Free Radic Biol Med. 2012;52(1):70–9.
91. Li J et al. Up-regulation of p27(kip1) contributes to Nrf2-mediated protection against angiotensin II-induced cardiac hypertrophy. Cardiovasc Res. 2011;90(2):315–24.