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Cannabidiol promotes browning in 3T3-L1 adipocytes

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Abstract

Recruitment of the brown-like phenotype in white adipocytes (browning) and activation of existing brown adipocytes are currently being investigated as a means to combat obesity. Thus, a wide variety of dietary agents that contribute to browning of white adipocytes have been identified. The present study was designed to investigate the effects of cannabidiol (CBD), a major nonpsychotropic phytocannabinoid of Cannabis sativa, on induction of browning in 3T3-L1 adipocytes. CBD enhanced expression of a core set of brown fat-specific marker genes (Ucp1, Cited1, Tmem26, Prdm16, Cidea, Tbx1, Fgf21, and Pgc-1α) and proteins (UCP1, PRDM16, and PGC-1α). Increased expression of UCP1 and other brown fat-specific markers contributed to the browning of 3T3-L1 adipocytes possibly via activation of PPARγ and PI3K. In addition, CBD increased protein expression levels of CPT1, ACSL, SIRT1, and PLIN while down-regulating JNK2, SREBP1, and LPL. These data suggest possible roles for CBD in browning of white adipocytes, augmentation of lipolysis, thermogenesis, and reduction of lipogenesis. In conclusion, the current data suggest that CBD plays dual modulatory roles in the form of inducing the brown-like phenotype as well as promoting lipid metabolism. Thus, CBD may be explored as a potentially promising therapeutic agent for the prevention of obesity.

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References

  1. O’Neill S, O’Driscol L (2015) Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes Rev 16:1–12

    Article  PubMed  Google Scholar 

  2. Haslam DW, James WP (2005) Obesity. Lancet 366:1197–1209

    Article  PubMed  Google Scholar 

  3. Frühbeck G, Becerril S, Sáinz N, Garrastachu P, García-Velloso MJ (2009) BAT: a new target for human obesity. Trends Pharmacol Sci 30:387–396

    Article  PubMed  Google Scholar 

  4. Tseng YH, Cypess AM, Kahn CR (2010) Cellular bioenergetics as a target for obesity therapy. Nat Rev Drug Discov 9:465–482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Vernochet C, Mourier A, Bezy O, Macotela Y, Boucher J, Rardin MJ, An D, Lee KY, Ilkayeva OR, Zingaretti CM, Emanuelli B, Smyth G, Cinti S, Newgard CB, Gibson BW, Larsson NG, Kahn CR (2012) Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance. Cell Metab 16:765–776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Rosen ED, Spiegelman BM (2014) What we talk about when we talk about fat. Cell 156:20–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lazar MA (2008) Developmental biology. How now, brown fat. Science 321:1048–1049

    Article  CAS  PubMed  Google Scholar 

  8. Gilsanz V, Hu HH, Kajimura S (2013) Relevance of brown adipose tissue in infancy and adolescence. Pediatr Res 73:3–9

    Article  PubMed  PubMed Central  Google Scholar 

  9. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, Kolodny GM, Kahn CR (2009) Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360:1509–1517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerbäck S, Nuutila P (2009) Functional brown adipose tissue in healthy adults. N Engl J Med 360:1518–1525

    Article  CAS  PubMed  Google Scholar 

  11. Harms M, Seale P (2013) Brown and beige fat: development, function and therapeutic potential. Nat Med 19:1252–1263

    Article  CAS  PubMed  Google Scholar 

  12. Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J, Cohen P, Cinti S, Spiegelman BM (2011) Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Investig 121:96–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bartelt A, Heeren J (2014) Adipose tissue browning and metabolic health. Nat Rev Endocrinol 10:24–36

    Article  CAS  PubMed  Google Scholar 

  14. Zuardi AW, Hallak JE, Dursun SM, Morais SL, Sanches RF, Musty RE, Crippa JA (2006) Cannabidiol monotherapy for treatment-resistant schizophrenia. J Psychopharmacol 20:683–686

    Article  CAS  PubMed  Google Scholar 

  15. Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimarães FS (2006) Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res 39:421–429

    Article  CAS  PubMed  Google Scholar 

  16. Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci 95:8268–8273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R, Feldmann M (2000) The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci USA 97:9561–9566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Weiss L, Zeira M, Reich S, Har-Noy M, Mechoulam R, Slavin S, Gallily R (2006) Cannabidiol lowers incidence of diabetes in non-obese diabetic mice. Autoimmunity 39:143–151

    Article  CAS  PubMed  Google Scholar 

  19. Moreira FA, Aguiar DC, Guimaraes FS (2006) Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test. Prog Neuro-psychopharmacol Biol Psychiatr 30:1466–1471

    Article  CAS  Google Scholar 

  20. Fernandez-Ruiz J, Sagredo O, Pazos MR, Garcia C, Pertwee R, Mechoulam R, Martínez-Orgado J (2012) Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid. Br J Clin Pharmacol 75:323–333

    Article  PubMed Central  Google Scholar 

  21. McAllister SD, Murase R, Christian RT, Lau D, Zielinski AJ, Allison J, Almanza C, Pakdel A, Lee J, Limbad C, Liu Y, Debs RJ, Moore DH, Desprez PY (2011) Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis. Breast Cancer Res Treat 129:37–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Thomas BF, Gilliam AF, Burch DF, Roche MJ, Seltzman HH (1998) Comparative receptor binding analyses of cannabinoid agonists and antagonists. J Pharmacol Exp Ther 285:285–292

    CAS  PubMed  Google Scholar 

  23. NIH, Clinical trials.gov. NIH Web site.http://clinicaltrials.gov/ct2/results?term=cannabidiol. Accessed 8 July 2013

  24. Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA (2011) Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf 6:237–249

    Article  CAS  PubMed  Google Scholar 

  25. Ignatowska-Jankowska B, Jankowski MM, Swiergiel AH (2011) Cannabidiol decreases body weight gain in rats: involvement of CB2 receptors. Neurosci Lett 490:82–84

    Article  CAS  PubMed  Google Scholar 

  26. Wu J, Boström P, Ye LM, Sparks L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerbäck S, Schrauwen P, Spiegelman BM (2012) Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150:366–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tiraby C, Tavernier G, Lefort C, Larrouy D, Bouillaud F, Ricquier D, Langin D (2003) Acquirement of brown fat cell features by human white adipocytes. J Biol Chem 278:33370–33376

    Article  CAS  PubMed  Google Scholar 

  28. Sharp LZ, Shinoda K, Ohno H, Scheel DW, Tomoda E, Ruiz L, Hu H, Wang L, Pavlova Z, Gilsanz V, Kajimura S (2012) Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS One 7:e49452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lee K, Kerner J, Hoppel CL (2011) Mitochondrial carnitine palmitoyltransferase 1a (CPT1a) is part of an outer membrane fatty acid transfer complex. J Biol Chem 286:25655–25662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ou X, Lee MR, Huang X, Messina-Graham S, Broxmeyer HE (2014) SIRT1 positively regulates autophagy and mitochondria function in embryonic stem cells under oxidative stress. Stem Cells 32:1183–1194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Townsend KL, An D, Lynes MD, Huang TL, Zhang H, Goodyear LJ, Tseng YH (2013) Increased mitochondrial activity in BMP7-treated brown adipocytes, due to increased CPT1- and CD36-mediated fatty acid uptake. Antioxid Redox Signal 19:243–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ito M, Nagasawa M, Omae N, Tsunoda M, Ishiyama J, Ide T, Akasaka Y, Murakami KA (2013) novel JNK2/SREBP-1c pathway involved in insulin-induced fatty acid synthesis in human adipocytes. J Lipid Res 54:1531–1540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Shimano H, Yahagi N, Amemiya-Kudo M, Hasty AH, Osuga J, Tamura Y, Shionoiri F, Iizuka Y, Ohashi K, Harada K, Gotoda T, Ishibashi S, Yamada N (1999) Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes. J Biol Chem 274:35832–35839

    Article  CAS  PubMed  Google Scholar 

  34. Bartelt A, Weigelt C, Cherradi ML, Niemeier A, Tödter K, Heeren J, Scheja L (2013) Effects of adipocyte lipoprotein lipase on de novo lipogenesis and white adipose tissue browning. Biochim Biophys Acta 1831:934–942

    Article  CAS  PubMed  Google Scholar 

  35. Zechner R, Strauss J, Frank S, Wagner E, Hofmann W, Kratky D, Hiden M, Levak-Frank S (2000) The role of lipoprotein lipase in adipose tissue development and metabolism. Int J Obes Relat Metab Disord 24:53–56

    Article  Google Scholar 

  36. Weinstock PH, Levak-Frank S, Hudgins LC, Radner H, Friedman JM, Zechner R, Breslow JL (1997) Lipoprotein lipase controls fatty acid entry into adipose tissue, but fat mass is preserved by endogenous synthesis in mice deficient in adipose tissue lipoprotein lipase. Proc Natl Acad Sci USA 94:10261–10266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ducharme NA, Bickel PE (2008) Lipid droplets in lipogenesis and lipolysis. Endocrinology 149:942–949

    Article  CAS  PubMed  Google Scholar 

  38. Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, Evans RM (2013) PPARγ signaling and metabolism: the good, the bad and the future. Nat Med 19:557–566

    Article  CAS  PubMed  Google Scholar 

  39. Collins S, Yehuda-Shnaidman E, Wang H (2010) Positive and negative control of Ucp1 gene transcription and the role of β-adrenergic signaling networks. Int J Obes 34:28–33

    Article  Google Scholar 

  40. Fernandez-Marcos PJ, Auwerx J (2011) Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr 93:884–890

    Article  Google Scholar 

  41. Mu Q, Fang X, Li X, Zhao D, Mo F, Jiang G, Yu N, Zhang Y, Guo Y, Fu M, Liu JL, Zhang D, Gao S (2015) Ginsenoside Rb1 promotes browning through regulation of PPARγ in 3T3-L1 adipocytes. Biochem Biophys Res Commun 466:530–535

    Article  CAS  PubMed  Google Scholar 

  42. Hinoi E, Iezaki T, Fujita H, Watanabe T, Odaka Y, Ozaki K, Yoneda Y (2014) PI3K/Akt is involved in brown adipogenesis mediated by growth differentiation factor-5 in association with activation of the Smad pathway. Biochem Biophys Res Commun 450:255–260

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Mid-career Researcher Program (2013R1A2A2A05004195) and SRC Program (Center for Food & Nutritional Genomics, Grant number 2015R1A5A6001906) through NRF grant funded by the Ministry of Science, ICT and Future Planning, Korea.

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

    Hilal Ahmad Parray & Jong Won Yun

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Correspondence to Jong Won Yun.

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Parray, H.A., Yun, J.W. Cannabidiol promotes browning in 3T3-L1 adipocytes. Mol Cell Biochem 416, 131–139 (2016). https://doi.org/10.1007/s11010-016-2702-5

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