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Honokiol exerts dual effects on browning and apoptosis of adipocytes

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Abstract

Background

Induction of brown adipocyte-like phenotype (browning) in white adipocytes and promotion of apoptosis by dietary and pharmacological compounds is considered a novel strategy against obesity. Here, we show that honokiol exerts dual modulatory effects on adipocytes via induction of browning in 3T3-L1 white adipocytes and apoptosis as well as activation of HIB1B brown adipocytes combined with inhibition of apoptosis.

Methods

Honokiol-induced browning and apoptosis were investigated by determining expression levels of brown adipocyte-specific genes and proteins by RT-PCR and immunoblot analysis, respectively. Apoptotic data were validated by immunofluorescence and ROS levels were measured by FACS analysis.

Results

Honokiol treatment induced browning by elevating expression levels of brown adipocyte-specific genes such as Cidea, Cox8, Fgf21, Pgc-1α, and Ucp1. Honokiol promoted apoptosis of 3T3-L1 white adipocytes and inhibited apoptosis of HIB1B brown adipocytes via opposite regulation of the pro-apoptotic protein BAX and anti-apoptotic protein Bcl-2. Honokiol also significantly increased protein expression levels of ACOX1, CPT1, p-HSL, and p-PLIN and reduced ROS levels, suggesting its possible role in fat oxidation and lipid catabolism. Honokiol-induced browning could be mediated by activation of ERK, as inhibition of ERK by FR180204 abolished expression of PGC-1α and UCP1.

Conclusion

Our findings suggest that honokiol exhibits a modulatory role in adipocytes via induction of browning and apoptosis in white adipocytes, promotion of catabolic lipid metabolism, as well as activation and inhibition of apoptosis in HIB1B brown adipocytes, thereby exhibiting therapeutic potential against obesity.

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Abbreviations

ACO:

peroxisomal acylcoenzyme A oxidase

AMPK:

AMP-activated protein kinase

BAT:

brown adipose tissue

BAX:

Bcl-2-associated X protein

Bcl-2:

B-cell lymphoma 2

Cidea :

gene encoding cell death-inducing DFFA-like effector a

Cited1 :

gene encoding Cbp/p300-interacting transactivator 1

COX8:

cytochrome c oxidase subunit 8

C/EBP/Cebp:

CCAAT/enhancer-binding protein/encoding gene

CPT:

carnitine palmitoyltransferase

ERK:

extracellular signal-regulated kinase

Fgf21 :

gene encoding fibroblast growth factor 21

HSL:

hormone-sensitive lipase

PGC-1α:

peroxisome proliferator-activated receptor gamma co-activator 1-alpha

PLIN:

perilipin

PPAR:

peroxisome proliferator-activated receptor

PRDM16/Prdm16:

PR domain-containing 16/encoding gene

UCP1/Ucp1:

uncoupling protein 1/encoding gene

WAT:

white adipose tissue

References

  1. Tseng YH, Cypess AM, Kahn CR. Cellular bioenergetics as a target for obesity therapy. Nat Rev Drug Discov 2010;9(6):465–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kim SH, Plutzky J. Brown fat and browning for the treatment of obesity and related metabolic disorders. Diabetes Metab J 2016;40(1):12–21.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Rosen ED, MacDougald OA. Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol 2006;7(12):885–96.

    Article  CAS  PubMed  Google Scholar 

  4. Wood RJ. Vitamin D and adipogenesis: new molecular insights. Nutr Rev 2008;66(1):40–6.

    Article  PubMed  Google Scholar 

  5. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009;360(15):1500–8.

    Article  PubMed  Google Scholar 

  6. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, et al. Functional brown adipose tissue in healthy adults. N Engl J Med 2009;360(15):1518–25.

    Article  CAS  PubMed  Google Scholar 

  7. Bonet ML, Oliver P, Palou A. Pharmacological and nutritional agents promoting browning of white adipose tissue. Biochim Biophys Acta 2013;1831(5):969–85.

    Article  CAS  PubMed  Google Scholar 

  8. Whittle A, Relat-Pardo J, Vidal-Puig A. Pharmacological strategies for targeting BAT thermogenesis. Trends Pharmacol Sci 2013;34(6):347–55.

    Article  CAS  PubMed  Google Scholar 

  9. Cypess AM, Kahn CR. Brown fat as a therapy for obesity and diabetes. Curr Opin Endocrinol Diabetes Obes 2010;17(2):143–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sanchez-Gurmaches J, Hung CM, Sparks CA, Tang Y, Li H, Guertin DA. PTEN loss in the Myf5 lineage redistributes body fat and reveals subsets of white adipocytes that arise from Myf5 precursors. Cell Metab 2012;16(3):348–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012;150(2):366–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Barbatelli G, Murano I, Madsen L, Hao Q, Jimenez M, Kristiansen K, et al. The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation. Am J Physiol Endocrinol Metab 2010;298(6):E1244–53.

    Article  CAS  PubMed  Google Scholar 

  13. Asano H, Kanamori Y, Higurashi S, Nara T, Kato K, Matsui T, et al. Induction of beige- like adipocytes in 3T3-L1 cells. J Vet Med Sci 2014;76(1):57–64.

    Article  CAS  PubMed  Google Scholar 

  14. Xiao Y, Yuan T, Yao W, Liao K. 3T3-L1 adipocyte apoptosis induced by thiazolidinediones is peroxisome proliferator-activated receptor-gamma-dependent and mediated by the caspase-3-dependent apoptotic pathway. FEBS J 2010;277(3):687–96.

    Article  CAS  PubMed  Google Scholar 

  15. Papineau D, Gagnon A, Sorisky A. Apoptosis of human abdominal preadipocytes before and after differentiation into adipocytes in culture. Metabolism 2003;52(8):987–92.

    Article  CAS  PubMed  Google Scholar 

  16. Prins JB, Walker NI, Winterford CM, Cameron DP. Apoptosis of human adipocytes in vitro. Biochem Biophys Res Commun 1994;201(2):500–7.

    Article  CAS  PubMed  Google Scholar 

  17. Della-Fera MA, Qian H, Baile CA. Adipocyte apoptosis in the regulation of body fat mass by leptin. Diabetes Obes Metab 2001;3(5):299–310.

    Article  CAS  PubMed  Google Scholar 

  18. Pajvani UB, Trujillo ME, Combs TP, Iyengar P, Jelicks L, Roth KA, et al. Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nat Med 2005;11(7):797–803.

    Article  CAS  PubMed  Google Scholar 

  19. Prins JB, Niesler CU, Winterford CM, Bright NA, Siddle K, O’Rahilly S, et al. Tumor necrosis factor-alpha induces apoptosis of human adipose cells. Diabetes 1997;46(12):1939–44.

    Article  CAS  PubMed  Google Scholar 

  20. Yang JY, Della-Fera MA, Nelson-Dooley C, Baile CA. Molecular mechanisms of apoptosis induced by ajoene in 3T3-L1 adipocytes. Obesity (Silver Spring) 2006;14(3):388–97.

    Article  CAS  Google Scholar 

  21. Yang JY, Della-Fera MA, Rayalam S, Baile CA. Effect of xanthohumol and isoxanthohumol on 3T3-L1 cell apoptosis and adipogenesis. Apoptosis 2007;12(11):1953–63.

    Article  CAS  PubMed  Google Scholar 

  22. Ambati S, Yang JY, Rayalam S, Park HJ, Della-Fera MA, Baile CA. Ajoene exerts potent effects in 3T3-L1 adipocytes by inhibiting adipogenesis and inducing apoptosis. Phytother Res 2009;23(4):513–8.

    Article  CAS  PubMed  Google Scholar 

  23. Rayalam S, Yang JY, Ambati S, Della-Fera MA, Baile CA. Resveratrol induces apoptosis and inhibits adipogenesis in 3T3-L1 adipocytes. Phytother Res 2008;22(10):1367–71.

    Article  CAS  PubMed  Google Scholar 

  24. Prasad R, Katiyar SK. Honokiol, an active compound of magnolia plant, inhibits growth, and progression of cancers of different organs. Adv Exp Med Biol 2016;928:245–65.

    Article  CAS  PubMed  Google Scholar 

  25. Eliaz I. Research Review A promising extract with multiple applications.. p. 7.

  26. Hamasaki Y, Muro E, Miyanji S, Yamamoto S, Kobayashi I, Sato R, et al. Inhibition of leukotriene synthesis byhonokiol in rat basophilic leukemia cells. Int Arch Allergy Immunol 1996;110(3):278–81.

    Article  CAS  PubMed  Google Scholar 

  27. Arora S, Bhardwaj A, Srivastava SK, Singh S, McClellan S, Wang B, et al. Honokiol arrests cell cycle, induces apoptosis, and potentiates the cytotoxic effect of gemcitabine in human pancreatic cancer cells. PLoS One 2011;6(6):e21573.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Xu HL, Tang W, Du GH, Kokudo N. Targeting apoptosis pathways in cancer with magnolol and honokiol, bioactive constituents of the bark of Magnolia officinalis. Drug Discov Ther 2011;5(5):202–10.

    Article  CAS  PubMed  Google Scholar 

  29. Choi SS, Cha BY, Iida K, Sato M, Lee YS, Teruya T, et al. Honokiol enhances adipocyte differentiation by potentiating insulin signaling in 3T3-L1 preadipocytes. J Nat Med 2011;65(3–4):424–30.

    Article  CAS  PubMed  Google Scholar 

  30. Zhu W, Fu A, Hu J, Wang T, Luo Y, Peng M, et al. 5-Formylhonokiol exerts anti-angiogenesis activity via inactivating the ERK signaling pathway. Exp Mol Med 2011;43(3):146–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liu H, Zang C, Emde A, Planas-Silva MD, Rosche M, Kuhnl A, et al. Anti-tumor effect of honokiol alone and in combination with other anti-cancer agents in breast cancer. Eur J Pharmacol 2008;591(1–3):43–51.

    Article  CAS  PubMed  Google Scholar 

  32. Liu SH, Wang KB, Lan KH, Lee WJ, Pan HC, Wu SM, et al. Calpain/SHP-1 interaction by honokiol dampening peritoneal dissemination of gastric cancer in nu/nu mice. PLoS One 2012;7(8):e43711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Oh JH, Kang LL, Ban JO, Kim YH, Kim KH, Han SB, et al. Anti-inflammatory effect of 4-O-methylhonokiol, compound isolated from Magnolia officinalis through inhibition of NF-kappaB [corrected]. Chem Biol Interact 2009;180(3):506–14.

    Article  CAS  PubMed  Google Scholar 

  34. Zhao C, Liu ZQ. Comparison of antioxidant abilities of magnolol and honokiol to scavenge radicals and to protect DNA. Biochimie 2011;93(10):1755–60.

    Article  CAS  PubMed  Google Scholar 

  35. Ho KY, Tsai CC, Chen CP, Huang JS, Lin CC. Antimicrobial activity of honokiol and magnolol isolated from Magnolia officinalis. Phytother Res 2001;15(2):139–41.

    Article  CAS  PubMed  Google Scholar 

  36. Hoi CP, Ho YP, Baum L, Chow AH. Neuroprotective effect of honokiol and magnolol, compounds from Magnolia officinalis, on beta-amyloid-induced toxicity in PC12 cells. Phytother Res 2010;24(10):1538–42.

    Article  CAS  PubMed  Google Scholar 

  37. Kuribara H, Kishi E, Hattori N, Okada M, Maruyama Y. The anxiolytic effect of two oriental herbal drugs in Japan attributed to honokiol from magnolia bark. J Pharm Pharmacol 2000;52(11):1425–9.

    Article  CAS  PubMed  Google Scholar 

  38. Pillai VB, Samant S, Sundaresan NR, Raghuraman H, Kim G, Bonner MY, et al. Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3. Nat Commun 2015;6:6656.

    Article  CAS  PubMed  Google Scholar 

  39. Zhang Z, Chen J, Jiang X, Wang J, Yan X, Zheng Y, et al. The magnolia bioactive constituent 4-O-methylhonokiol protects against high-fat diet-induced obesity and systemic insulin resistance in mice. Oxid Med Cell Longev 2014;2014:965954.

    PubMed  PubMed Central  Google Scholar 

  40. Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M, et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab 2007;6(1):38–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tiraby C, Tavernier G, Lefort C, Larrouy D, Bouillaud F, Ricquier D, et al. Acquirement of brown fat cell features by human white adipocytes. J Biol Chem 2003;278(35):33370–6.

    Article  CAS  PubMed  Google Scholar 

  42. Sharp LZ, Shinoda K, Ohno H, Scheel DW, Tomoda E, Ruiz L, et al. Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS One 2012;7(11):e49452.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. García-Ruiz E, Reynés B, Díaz-Rûa R, Ceresi E, Oliver P, Palou A. The intake of high-fat diets induces the acquisition of brown adipocyte gene expression features in white adipose tissue. Int J Obes (Lond) 2015;39(November (11)):1619–29.

    Article  CAS  Google Scholar 

  44. Karamanlidis G, Karamitri A, Docherty K, Hazlerigg DG, Lomax MA. C/EBPbeta reprograms white 3T3-L1 preadipocytes to a Brown adipocyte pattern of gene expression. J Biol Chem 2007;282(34):24660–9.

    Article  CAS  PubMed  Google Scholar 

  45. Kleiner S, Nguyen-Tran V, Bare O, Huang X, Spiegelman B, Wu Z. PPAR{delta} agonism activates fatty acid oxidation via PGC-1{alpha} but does not increase mitochondrial gene expression and function. J Biol Chem 2009;284(28):18624–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Atanasov AG, Wang JN, Gu SP, Bu J, Kramer MP, Baumgartner L, et al. Honokiol: a non-adipogenic PPARγ agonist from nature. Biochim Biophys Acta 1830;10:4813–9.

    Google Scholar 

  47. Yuan X, Wei G, You Y, Huang Y, Lee HJ, Dong M, et al. Rutin ameliorates obesity through brown fat activation. FASEB J 2016;31:333–45.

    Article  PubMed  CAS  Google Scholar 

  48. Satterfield MC, Wu G. Brown adipose tissue growth and development: significance and nutritional regulation. Front Biosci (Landmark Ed) 2011;16:1589–608.

    Article  CAS  Google Scholar 

  49. Lone J, Choi JH, Kim SW, Yun JW. Curcumin induces brown fat-like phenotype in 3T3-L1 and primary white adipocytes. J Nutr Biochem 2016;27:193–202.

    Article  CAS  PubMed  Google Scholar 

  50. Sassmann-Schweda A, Singh P, Tang C, Wietelmann A, Wettschureck N, Offermanns S. Increased apoptosis and browning of TAK1-deficient adipocytes protects against obesity. JCI Insight 2016;1(7):e81175.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Briscini L, Tonello C, Dioni L, Carruba MO, Nisoli E. Bcl-2 and Bax are involved in the sympathetic protection of brown adipocytes from obesity-linked apoptosis. FEBS Lett 1998;431(1):80–4.

    Article  CAS  PubMed  Google Scholar 

  52. Townsend KL, An D, Lynes MD, Huang TL, Zhang H, Goodyear LJ, et al. Increased mitochondrial activity in BMP7-treated brown adipocytes, due to increased CPT1- and CD36-mediated fatty acid uptake. Antioxid Redox Signal 2013;19(3):243–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Langin D, Dicker A, Tavernier G, Hoffstedt J, Mairal A, Ryden M, et al. Adipocyte lipases and defect of lipolysis in human obesity. Diabetes 2005;54(11):3190–7.

    Article  CAS  PubMed  Google Scholar 

  54. Heinonen S, Buzkova J, Muniandy M, Kaksonen R, Ollikainen M, Ismail K, et al. Impaired mitochondrial biogenesis in adipose tissue in acquired obesity. Diabetes 2015;64(9):3135–45.

    Article  CAS  PubMed  Google Scholar 

  55. Flachs P, Rossmeisl M, Bryhn M, Kopecky J. Cellular and molecular effects of n-3 polyunsaturated fatty acids on adipose tissue biology and metabolism. Clin Sci (Lond) 2009;116(1):1–16.

    Article  CAS  Google Scholar 

  56. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 2012;13(4):251–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Greenberg AS, Shen WJ, Muliro K, Patel S, Souza SC, Roth RA, et al. Stimulation of lipolysis and hormone-sensitive lipase via the extracellular signal-regulated kinase pathway. J Biol Chem 2001;276(48):45456–61.

    Article  CAS  PubMed  Google Scholar 

  58. Lass A, Zimmermann R, Oberer M, Zechner R. Lipolysis — a highly regulated multi-enzyme complex mediates the catabolism of cellular fat stores. Prog Lipid Res 2011;50(1):14–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Tansey JT, Sztalryd C, Hlavin EM, Kimmel AR, Londos C. The central role of perilipin a in lipid metabolism and adipocyte lipolysis. IUBMB Life 2004;56(7):379–85.

    Article  CAS  PubMed  Google Scholar 

  60. Sawada T, Miyoshi H, Shimada K, Suzuki A, Okamatsu-Ogura Y, Perfield 2nd JW, et al. Perilipin overexpression in white adipose tissue induces a brown fat-like phenotype. PLoS One 2010;5(11):e14006.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS. Regulation of lipolysis in adipocytes. Annu Rev Nutr 2007;27:79–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Tansey JT, Sztalryd C, Hlavin EM, Kimmel AR, Londos C. The central role of perilipin a in lipid metabolism and adipocyte lipolysis. IUBMB Life 2004 Jul;56(7):379–85.

    Article  CAS  PubMed  Google Scholar 

  63. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004;114(12):1752–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Collins S. Beta-adrenoceptor signaling networks in adipocytes for recruiting stored fat and energy expenditure. Front Endocrinol (Lausanne) 2011;2:102.

    Article  Google Scholar 

  65. Yao A, Shen Y, Wang A, Chen S, Zhang H, Chen F, et al. Sulforaphane induces apoptosis in adipocytes via Akt/p70s6k1/Bad inhibition and ERK activation. Biochem Biophys Res Commun 2015;465(4):696–701.

    Article  CAS  PubMed  Google Scholar 

  66. Zhang Y, Li R, Meng Y, Li S, Donelan W, Zhao Y, et al. Irisin stimulates browning ofwhite adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes 2014;63(2):514–25.

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Biotechnology, Daegu University, Kyungsan, Kyungbuk, 712-714, Republic of Korea

    Jameel Lone & Jong Won Yun

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Lone, J., Yun, J.W. Honokiol exerts dual effects on browning and apoptosis of adipocytes. Pharmacol. Rep 69, 1357–1365 (2017). https://doi.org/10.1016/j.pharep.2017.06.004

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