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Anti-inflammatory γ- and δ-tocotrienols improve cardiovascular, liver and metabolic function in diet-induced obese rats

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Abstract

Purpose

This study tested the hypothesis that γ- and δ-tocotrienols are more effective than α-tocotrienol and α-tocopherol in attenuating the signs of diet-induced metabolic syndrome in rats.

Methods

Five groups of rats were fed a corn starch-rich (C) diet containing 68 % carbohydrates as polysaccharides, while the other five groups were fed a diet (H) high in simple carbohydrates (fructose and sucrose in food, 25 % fructose in drinking water, total 68 %) and fats (beef tallow, total 24 %) for 16 weeks. Separate groups from each diet were supplemented with either α-, γ-, δ-tocotrienol or α-tocopherol (85 mg/kg/day) for the final 8 of the 16 weeks.

Results

H rats developed visceral obesity, hypertension, insulin resistance, cardiovascular remodelling and fatty liver. α-Tocopherol, α-, γ- and δ-tocotrienols reduced collagen deposition and inflammatory cell infiltration in the heart. Only γ- and δ-tocotrienols improved cardiovascular function and normalised systolic blood pressure compared to H rats. Further, δ-tocotrienol improved glucose tolerance, insulin sensitivity, lipid profile and abdominal adiposity. In the liver, these interventions reduced lipid accumulation, inflammatory infiltrates and plasma liver enzyme activities. Tocotrienols were measured in heart, liver and adipose tissue showing that chronic oral dosage delivered tocotrienols to these organs despite low or no detection of tocotrienols in plasma.

Conclusion

In rats, δ-tocotrienol improved inflammation, heart structure and function, and liver structure and function, while γ-tocotrienol produced more modest improvements, with minimal changes with α-tocotrienol and α-tocopherol. The most important mechanism of action is likely to be reduction in organ inflammation.

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References

  1. Eckel RH, Grundy SM, Zimmet PZ (2005) The metabolic syndrome. Lancet 365:1415–1428

    Article  CAS  Google Scholar 

  2. Fabbrini E, Sullivan S, Klein S (2010) Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 51:679–689

    Article  CAS  Google Scholar 

  3. Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, Eckel RH (2006) Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss. Circulation 113:898–918

    Article  Google Scholar 

  4. Tesauro M, Cardillo C (2011) Obesity, blood vessels and metabolic syndrome. Acta Physiol (Oxf) 203:279–286

    Article  CAS  Google Scholar 

  5. Nikolopoulou A, Kadoglou NP (2012) Obesity and metabolic syndrome as related to cardiovascular disease. Expert Rev Cardiovasc Ther 10:933–939

    Article  CAS  Google Scholar 

  6. Guerra F, Mancinelli L, Angelini L, Fortunati M, Rappelli A, Dessì-Fulgheri P, Sarzani R (2011) The association of left ventricular hypertrophy with metabolic syndrome is dependent on body mass index in hypertensive overweight or obese patients. PLoS One 6:e16630

    Article  CAS  Google Scholar 

  7. Nestel PJ, O’Brien R, Nelson M (2008) Management of dyslipidaemia—evidence and practical recommendations. Aust Fam Physician 37:521–527

    Google Scholar 

  8. Scarpellini E, Tack J (2012) Obesity and metabolic syndrome: an inflammatory condition. Dig Dis 30:148–153

    Article  CAS  Google Scholar 

  9. Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445

    Article  CAS  Google Scholar 

  10. Marseglia L, Manti S, D’Angelo G, Nicotera A, Parisi E, Di Rosa G, Gitto E, Arrigo T (2015) Oxidative stress in obesity: a critical component in human diseases. Int J Mol Sci 16:378–400

    Article  Google Scholar 

  11. Ahima RS, Flier JS (2000) Leptin. Annu Rev Physiol 62:413–437

    Article  CAS  Google Scholar 

  12. National Heart Foundation of Australia. Factsheet: overweight and obesity statistics 2012

  13. Health Survey of England. Adult anthropometric measures, overweight and obesity 2013

  14. Khambalia AZ, Seen LS (2010) Trends in overweight and obese adults in Malaysia (1996–2009): a systematic review. Obes Rev 11:403–412

    Article  CAS  Google Scholar 

  15. Weng-Yew W, Brown L (2011) Nutrapharmacology of tocotrienols for metabolic syndrome. Curr Pharm Des 17:2206–2214

    Article  Google Scholar 

  16. Wong WY, Poudyal H, Ward LC, Brown L (2012) Tocotrienols reverse cardiovascular, metabolic and liver changes in high carbohydrate, high fat diet-fed rats. Nutrients 4:1527–1541

    Article  CAS  Google Scholar 

  17. Traber MG, Atkinson J (2007) Vitamin E, antioxidant and nothing more. Free Radic Biol Med 43:4–15

    Article  CAS  Google Scholar 

  18. Yoshida Y, Niki E, Noguchi N (2003) Comparative study on the action of tocopherols and tocotrienols as antioxidant: chemical and physical effects. Chem Phys Lipids 123:63–75

    Article  CAS  Google Scholar 

  19. Aggarwal BB, Sundaram C, Prasad S, Kannappan R (2010) Tocotrienols, the vitamin E of the 21st century: its potential against cancer and other chronic diseases. Biochem Pharmacol 80:1613–1631

    Article  CAS  Google Scholar 

  20. Panchal SK, Poudyal H, Arumugam TV, Brown L (2011) Rutin attenuates metabolic changes, nonalcoholic steatohepatitis, and cardiovascular remodeling in high-carbohydrate, high-fat diet-fed rats. J Nutr 141:1062–1069

    Article  CAS  Google Scholar 

  21. Festing MFW, Altman DG (2002) Guidelines for the design and statistical analysis of experiments using laboratory animals. ILAR J 43:244–258

    Article  CAS  Google Scholar 

  22. National Research Council (1995) Nutrient requirements of laboratory animals, fourth revised edition, 1995. The National Academies Press, Washington

    Google Scholar 

  23. Nakamura H, Furukawa F, Nishikawa A, Miyauchi M, Son HY, Imazawa T, Hirose M (2001) Oral toxicity of a tocotrienol preparation in rats. Food Chem Toxicol 39:799–805

    Article  CAS  Google Scholar 

  24. Brown L, Fenning A, Chan V, Loch D, Wilson K, Anderson B, Burstow D (2002) Echocardiographic assessment of cardiac structure and function in rats. Heart Lung Circ 11:167–173

    Article  Google Scholar 

  25. Ward LC, Battersby KJ (2009) Assessment of body composition of rats by bioimpedance spectroscopy validation against dual-energy X-ray absorptiometry. Scand J Lab Anim Sci 36:253–261

    CAS  Google Scholar 

  26. Jeyakumar SM, Vajreswari A, Giridharan NV (2006) Chronic dietary vitamin A supplementation regulates obesity in an obese mutant WNIN/Ob rat model. Obesity 14:52–59

    Article  CAS  Google Scholar 

  27. Chan V, Hoey A, Brown L (2006) Improved cardiovascular function with aminoguanidine in DOCA-salt hypertensive rats. Br J Pharmacol 148:902–908

    Article  CAS  Google Scholar 

  28. Skrzypiec-Spring M, Grotthus B, Szelag A, Schulz R (2007) Isolated heart perfusion according to Langendorff—still viable in the new millennium. J Pharmacol Toxicol Methods 55:113–126

    Article  CAS  Google Scholar 

  29. Brown L, Duce B, Miric G, Sernia C (1999) Reversal of cardiac fibrosis in deoxycorticosterone acetate-salt hypertensive rats by inhibition of the renin-angiotensin system. J Am Soc Nephrol 10(Suppl 11):S143–S148

    CAS  Google Scholar 

  30. Sundram K, Nor R (2002) Analysis of tocotrienols in different sample matrixes by HPLC. In: Amstrong D (ed) Methods in molecular biology: oxidative stress biomarkers and antioxidant protocols. Humana Press Inc, Totowa, pp 221–232

    Chapter  Google Scholar 

  31. Ueda T, Igarashi O (1987) New solvent system for extraction of tocopherols from biological specimens for HPLC determination and evaluation of 2,2,5,7,8-pentamethyl-6-chromanol as an internal standard. J Micronutr Anal 3:185–198

    CAS  Google Scholar 

  32. Traber MG, Frei B, Beckman JS (2008) Vitamin E revisited: do new data validate benefits for chronic disease prevention? Curr Opin Lipidol 19:30–38

    CAS  Google Scholar 

  33. Yang C, Suh N (2013) Cancer prevention by different forms of tocopherols. In: Pezzuto JM, Suh N (eds) Natural products in cancer prevention and therapy. Springer, Berlin, pp 21–33

    Google Scholar 

  34. Ahsan H, Ahad A, Iqbal J, Siddiqui WA (2014) Pharmacological potential of tocotrienols: a review. Nutr Metab (Lond) 11:52

    Article  Google Scholar 

  35. Kamal-Eldin A, Appelqvist L-Å (1996) The chemistry and antioxidant properties of tocopherols and tocotrienols. Lipids 31:671–701

    Article  CAS  Google Scholar 

  36. Kotsis V, Stabouli S, Papakatsika S, Rizos Z, Parati G (2010) Mechanisms of obesity-induced hypertension. Hypertens Res 33:386–393

    Article  Google Scholar 

  37. Lambert E, Sari CI, Dawood T, Nguyen J, McGrane M, Eikelis N, Chopra R, Wong C, Chatzivlastou K, Head G, Straznicky N, Esler M, Schlaich M, Lambert G (2010) Sympathetic nervous system activity is associated with obesity-induced subclinical organ damage in young adults. Hypertension 56:351–358

    Article  CAS  Google Scholar 

  38. Dendorfer A, Raasch W, Tempel K, Dominiak P (1998) Interactions between the renin-angiotensin system (RAS) and the sympathetic system. Basic Res Cardiol 93:24–29

    Article  CAS  Google Scholar 

  39. Ishii H, Niioka T, Izumi H (2009) Circulating adrenaline released by sympathoadrenal activation elicits acute vasodilatation in the rat masseter muscle. Arch Oral Biol 54:486–494

    Article  CAS  Google Scholar 

  40. Thackeray JT, Radziuk J, Harper ME, Suuronen EJ, Ascah KJ, Beanlands RS, Dasilva JN (2011) Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia. Cardiovasc Diabetol 10:75

    Article  CAS  Google Scholar 

  41. Manzella D, Barbieri M, Ragno E, Paolisso G (2001) Chronic administration of pharmacologic doses of vitamin E improves the cardiac autonomic nervous system in patients with type 2 diabetes. Am J Clin Nutr 73:1052–1057

    CAS  Google Scholar 

  42. Nur Azlina MF, Nafeeza MI (2008) Tocotrienol and a-tocopherol reduce corticosterone and noradrenalin levels in rats exposed to restraint stress. Pharmazie 63:890–892

    CAS  Google Scholar 

  43. Anderson SL, Rubin BY (2005) Tocotrienols reverse IKAP and monoamine oxidase deficiencies in familial dysautonomia. Biochem Biophys Res Commun 336:150–156

    Article  CAS  Google Scholar 

  44. Ima-Nirwana S, Suhaniza S (2004) Effects of tocopherols and tocotrienols on body composition and bone calcium content in adrenalectomized rats replaced with dexamethasone. J Med Food 7:45–51

    Article  CAS  Google Scholar 

  45. Burdeos G, Nakagawa K, Kimura F, Miyazawa T (2012) Tocotrienol attenuates triglyceride accumulation in HepG2 Cells and F344 rats. Lipids 47:471–481

    Article  CAS  Google Scholar 

  46. Uto-Kondo H, Ohmori R, Kiyose C, Kishimoto Y, Saito H, Igarashi O, Kondo K (2009) Tocotrienol suppresses adipocyte differentiation and Akt phosphorylation in 3T3-L1 preadipocytes. J Nutr 139:51–57

    Article  CAS  Google Scholar 

  47. Gee P (2010) Unleashing the untold and misunderstood observations on vitamin E. Genes Nutr 6:5–16

    Article  Google Scholar 

  48. Ikeda I, Imasato Y, Sasaki E, Sugano M (1996) Lymphatic transport of alpha-, gamma- and delta-tocotrienols and alpha-tocopherol in rats. Int J Vitam Nutr Res 66:217–221

    CAS  Google Scholar 

  49. Haffner SM (2006) The metabolic syndrome: inflammation, diabetes mellitus, and cardiovascular disease. Am J Cardiol 97:3–11

    Article  Google Scholar 

  50. Shimizu T (2009) Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation. Annu Rev Pharmacol Toxicol 49:123–150

    Article  CAS  Google Scholar 

  51. Iyer A, Fairlie DP, Prins JB, Hammock BD, Brown L (2010) Inflammatory lipid mediators in adipocyte function and obesity. Nat Rev Endocrinol 6:71–82

    Article  CAS  Google Scholar 

  52. Shulman GI (2000) Cellular mechanisms of insulin resistance. J Clin Invest 106:171–176

    Article  CAS  Google Scholar 

  53. Virkamaki A, Korsheninnikova E, Seppala-Lindroos A, Vehkavaara S, Goto T, Halavaara J, Hakkinen AM, Yki-Jarvinen H (2001) Intramyocellular lipid is associated with resistance to in vivo insulin actions on glucose uptake, antilipolysis, and early insulin signaling pathways in human skeletal muscle. Diabetes 50:2337–2343

    Article  CAS  Google Scholar 

  54. Steinberg HO, Baron AD (2002) Vascular function, insulin resistance and fatty acids. Diabetologia 45:623–634

    Article  CAS  Google Scholar 

  55. Hayden MR, Sowers KM, Pulakat L, Joginpally T, Krueger B, Whaley-Connell A, Sowers JR (2011) Possible mechanisms of local tissue renin-angiotensin system activation in the cardiorenal metabolic syndrome and type 2 diabetes mellitus. Cardiorenal Med 1:193–210

    Article  CAS  Google Scholar 

  56. Suganami T, Tanaka M, Ogawa Y (2012) Adipose tissue inflammation and ectopic lipid accumulation. Endocr J 59:849–857

    Article  CAS  Google Scholar 

  57. Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867

    Article  CAS  Google Scholar 

  58. Zhao L, Kang I, Fang X, Wang W, Lee MA, Hollins RR, Marshall MR, Chung S (2015) Gamma-tocotrienol attenuates high-fat diet-induced obesity and insulin resistance by inhibiting adipose inflammation and M1 macrophage recruitment. Int J Obes (Lond) 39:438–446

    Article  CAS  Google Scholar 

  59. Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661

    Article  CAS  Google Scholar 

  60. EFSA (2008) Opinion on mixed tocopherols, tocotrienol tocopherol and tocotrienols as sources for vitamin E added as a nutritional substance in food supplements. Scientific Opinion of the Panel on Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food (Question No EFSA Q-2005-146, Q-2005-172, Q-2006-265) EFSA J 604:1–34

  61. Tasaki M, Umemura T, Inoue T, Okamura T, Kuroiwa Y, Ishii Y, Maeda M, Hirose M, Nishikawa A (2008) Induction of characteristic hepatocyte proliferative lesion with dietary exposure of Wistar Hannover rats to tocotrienol for 1 year. Toxicology 250:143–150

    Article  CAS  Google Scholar 

  62. Springett GM, Neuger AM, Centeno BA, Hutchinson T, Jump H, Lush R, Sebti S, Malafa MP (2011) Abstract 1299: a phase I dose-escalation study of the safety, PK, and PD of vitamin E delta-tocotrienol administered to subjects with resectable pancreatic exocrine neoplasia. Cancer Res 71:1299

    Article  Google Scholar 

  63. Khosla P, Patel V, Whinter JM, Khanna S, Rakhkovskaya M, Roy S, Sen CK (2006) Postprandial levels of the natural vitamin E tocotrienol in human circulation. Antioxid Redox Signal 8:1059–1068

    Article  CAS  Google Scholar 

  64. Fairus S, Nor RM, Cheng HM, Sundram K (2006) Postprandial metabolic fate of tocotrienol-rich vitamin E differs significantly from that of alpha-tocopherol. Am J Clin Nutr 84:835–842

    CAS  Google Scholar 

  65. Fairus S, Nor RM, Cheng HM, Sundram K (2012) Alpha-tocotrienol is the most abundant tocotrienol isomer circulated in plasma and lipoproteins after postprandial tocotrienol-rich vitamin E supplementation. Nutr J 11:5

    Article  CAS  Google Scholar 

  66. Yap SP, Yuen KH, Lim AB (2003) Influence of route of administration on the absorption and disposition of alpha-, gamma- and delta-tocotrienols in rats. J Pharm Pharmacol 55:53–58

    Article  CAS  Google Scholar 

  67. Yap SP, Yuen KH, Wong JW (2001) Pharmacokinetics and bioavailability of alpha-, gamma- and delta-tocotrienols under different food status. J Pharm Pharmacol 53:67–71

    Article  CAS  Google Scholar 

  68. Shibata A, Nakagawa K, Shirakawa H, Kobayashi T, Kawakami Y, Takashima R, Ohashi A, Sato S, Ohsaki Y, Kimura F, Kimura T, Tsuduki T, Komai M, Miyazawa T (2012) Physiological effects and tissue distribution from large doses of tocotrienol in rats. Biosci Biotechnol Biochem 76:1805–1808

    Article  CAS  Google Scholar 

  69. Uchida T, Abe C, Nomura S, Ichikawa T, Ikeda S (2012) Tissue distribution of alpha- and gamma-tocotrienol and gamma-tocopherol in rats and interference with their accumulation by alpha-tocopherol. Lipids 47:129–139

    Article  CAS  Google Scholar 

  70. Yamashita K, Ikeda S, Iizuka Y, Ikeda I (2002) Effect of sesaminol on plasma and tissue alpha-tocopherol and alpha-tocotrienol concentrations in rats fed a vitamin E concentrate rich in tocotrienols. Lipids 37:351–358

    Article  CAS  Google Scholar 

  71. Frank J, Chin XW, Schrader C, Eckert GP, Rimbach G (2012) Do tocotrienols have potential as neuroprotective dietary factors? Ageing Res Rev 11:163–180

    Article  CAS  Google Scholar 

  72. Hubbell RB, Mendel LB, Wakeman AJ (1937) A new salt mixture for use in experimental diets. J Nutr 14:273–285

    CAS  Google Scholar 

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Acknowledgments

We thank Sime Darby Foods & Beverages Marketing Sdn. Bhd., Malaysia, for the supply of α-tocopherol, Davos Life Science Pte Ltd, Singapore, for the supply of α- and γ-tocotrienol, American River Nutrition, Inc., USA, for the supply of δ-tocotrienol, and The Malaysian Palm Oil Board for the supply of vitamin E-stripped palm olein. We thank Jason Brightwell, The Prince Charles Hospital, Brisbane, Australia, for the acquisition of echocardiographic images. We thank Suet Hoay Lee from Davos Life Science Pte Ltd, Singapore, and Ghazali Abdul Razak from The Malaysian Palm Oil Board for the HPLC analyses. We thank our colleagues R. Senthil Arun Kumar, Nikolas Jin Wang, Shazini Ramli, Maharshi Bhaswant, Hemant Poudyal and Sunil Panchal for technical assistance. Weng-Yew Wong and Lindsay Brown developed the original study aims; Weng-Yew Wong conducted the experiments and carried out the data analyses; data were interpreted by all authors. Leigh C. Ward assisted with dual-energy X-ray absorptiometry and provided nutritional advice. Chee Wai Fong and Wei Ney Yap assisted with detection and evaluation of vitamin E concentrations. Weng-Yew Wong and Lindsay Brown prepared manuscript drafts, with all authors contributing to the final version. Lindsay Brown has been the corresponding author throughout the writing process. This study was supported by the Strategic Research Fund of the University of Southern Queensland.

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  1. Weng-Yew Wong

    Present address: Laboratory of Cardiovascular Signalling, Centenary Institute, Sydney, NSW, 2050, Australia

Authors and Affiliations

  1. School of Biomedical Sciences, University of Queensland, Brisbane, QLD, 4072, Australia

    Weng-Yew Wong

  2. School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, 4072, Australia

    Leigh C. Ward

  3. Davos Life Science Pte Ltd, 3 Biopolis Drive, #04-19 Synapse, Singapore, 138623, Singapore

    Chee Wai Fong & Wei Ney Yap

  4. School of Health and Wellbeing, University of Southern Queensland, Toowoomba, QLD, 4350, Australia

    Lindsay Brown

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Wong, WY., Ward, L.C., Fong, C.W. et al. Anti-inflammatory γ- and δ-tocotrienols improve cardiovascular, liver and metabolic function in diet-induced obese rats. Eur J Nutr 56, 133–150 (2017). https://doi.org/10.1007/s00394-015-1064-1

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