Molecular and Cellular Biochemistry

, Volume 416, Issue 1–2, pp 131–139 | Cite as

Cannabidiol promotes browning in 3T3-L1 adipocytes

Article

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-) 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.

Keywords

Lipogenesis Cannabidiol Thermogenesis Browning 

Notes

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.

Compliance with ethical standards

Conflicts of interest

The authors declared no conflicts of interest.

References

  1. 1.
    O’Neill S, O’Driscol L (2015) Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes Rev 16:1–12CrossRefPubMedGoogle Scholar
  2. 2.
    Haslam DW, James WP (2005) Obesity. Lancet 366:1197–1209CrossRefPubMedGoogle Scholar
  3. 3.
    Frühbeck G, Becerril S, Sáinz N, Garrastachu P, García-Velloso MJ (2009) BAT: a new target for human obesity. Trends Pharmacol Sci 30:387–396CrossRefPubMedGoogle Scholar
  4. 4.
    Tseng YH, Cypess AM, Kahn CR (2010) Cellular bioenergetics as a target for obesity therapy. Nat Rev Drug Discov 9:465–482CrossRefPubMedPubMedCentralGoogle Scholar
  5. 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 16:765–776CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Rosen ED, Spiegelman BM (2014) What we talk about when we talk about fat. Cell 156:20–44CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Lazar MA (2008) Developmental biology. How now, brown fat. Science 321:1048–1049CrossRefPubMedGoogle Scholar
  8. 8.
    Gilsanz V, Hu HH, Kajimura S (2013) Relevance of brown adipose tissue in infancy and adolescence. Pediatr Res 73:3–9CrossRefPubMedPubMedCentralGoogle Scholar
  9. 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 360:1509–1517CrossRefPubMedPubMedCentralGoogle Scholar
  10. 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 360:1518–1525CrossRefPubMedGoogle Scholar
  11. 11.
    Harms M, Seale P (2013) Brown and beige fat: development, function and therapeutic potential. Nat Med 19:1252–1263CrossRefPubMedGoogle Scholar
  12. 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 121:96–105CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Bartelt A, Heeren J (2014) Adipose tissue browning and metabolic health. Nat Rev Endocrinol 10:24–36CrossRefPubMedGoogle Scholar
  14. 14.
    Zuardi AW, Hallak JE, Dursun SM, Morais SL, Sanches RF, Musty RE, Crippa JA (2006) Cannabidiol monotherapy for treatment-resistant schizophrenia. J Psychopharmacol 20:683–686CrossRefPubMedGoogle Scholar
  15. 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 39:421–429CrossRefPubMedGoogle Scholar
  16. 16.
    Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci 95:8268–8273CrossRefPubMedPubMedCentralGoogle Scholar
  17. 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 97:9561–9566CrossRefPubMedPubMedCentralGoogle Scholar
  18. 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 39:143–151CrossRefPubMedGoogle Scholar
  19. 19.
    Moreira FA, Aguiar DC, Guimaraes FS (2006) Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test. Prog Neuro-psychopharmacol Biol Psychiatr 30:1466–1471CrossRefGoogle Scholar
  20. 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 75:323–333CrossRefPubMedCentralGoogle Scholar
  21. 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 129:37–47CrossRefPubMedPubMedCentralGoogle Scholar
  22. 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 285:285–292PubMedGoogle Scholar
  23. 23.
    NIH, Clinical trials.gov. NIH Web site.http://clinicaltrials.gov/ct2/results?term=cannabidiol. Accessed 8 July 2013
  24. 24.
    Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA (2011) Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf 6:237–249CrossRefPubMedGoogle Scholar
  25. 25.
    Ignatowska-Jankowska B, Jankowski MM, Swiergiel AH (2011) Cannabidiol decreases body weight gain in rats: involvement of CB2 receptors. Neurosci Lett 490:82–84CrossRefPubMedGoogle Scholar
  26. 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 150:366–376CrossRefPubMedPubMedCentralGoogle Scholar
  27. 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 278:33370–33376CrossRefPubMedGoogle Scholar
  28. 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:e49452CrossRefPubMedPubMedCentralGoogle Scholar
  29. 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 286:25655–25662CrossRefPubMedPubMedCentralGoogle Scholar
  30. 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 32:1183–1194CrossRefPubMedPubMedCentralGoogle Scholar
  31. 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 19:243–257CrossRefPubMedPubMedCentralGoogle Scholar
  32. 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 54:1531–1540CrossRefPubMedPubMedCentralGoogle Scholar
  33. 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 274:35832–35839CrossRefPubMedGoogle Scholar
  34. 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 1831:934–942CrossRefPubMedGoogle Scholar
  35. 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 24:53–56CrossRefGoogle Scholar
  36. 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 94:10261–10266CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ducharme NA, Bickel PE (2008) Lipid droplets in lipogenesis and lipolysis. Endocrinology 149:942–949CrossRefPubMedGoogle Scholar
  38. 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 19:557–566CrossRefPubMedGoogle Scholar
  39. 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 34:28–33CrossRefGoogle Scholar
  40. 40.
    Fernandez-Marcos PJ, Auwerx J (2011) Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr 93:884–890CrossRefGoogle Scholar
  41. 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 466:530–535CrossRefPubMedGoogle Scholar
  42. 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 450:255–260CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of BiotechnologyDaegu UniversityKyungsanRepublic of Korea

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