Skip to main content
SpringerLink
Log in

The endocannabinoid system in the adipose organ

  • Published:
Reviews in Endocrine and Metabolic Disorders Aims and scope Submit manuscript

Abstract

The endocannabinoid system is found in most, if not all, mammalian organs and is involved in a variety of physiological functions, ranging from the control of synaptic plasticity in the brain to the modulation of smooth muscle motility in the gastrointestinal tract. This signaling complex consists of G protein-coupled cannabinoid receptors, endogenous ligands for those receptors (endocannabinoids) and enzymes/transporters responsible for the formation and deactivation of these ligands. There are two subtypes of cannabinoid receptors, CB1 and CB2, and two major endocannabinoids, arachidonoylethanolamide (anandamide) and 2-arachidonoyl-sn-glycerol (2-AG), which are produced upon demand through cleavage of distinct phospholipid precursors. All molecular components of the endocannabinoid system are represented in the adipose organ, where endocannabinoid signals are thought to regulate critical homeostatic processes, including adipogenesis, lipogenesis and thermogenesis. Importantly, obesity was found to be associated with excess endocannabinoid activity in visceral fat depots, and the therapeutic potential of normalizing such activity by blocking CB1 receptors has been the focus of substantial preclinical and clinical research. Results have been mixed thus far, mostly owing to the emergence of psychiatric side effects rooted in the protective functions served by brain endocannabinoids in mood and affect regulation. Further studies about the roles played by the endocannabinoid system in the adipose organ will offer new insights into the pathogenesis of obesity and might help identify new ways to leverage this signaling complex for therapeutic benefit.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Jung KM, Piomelli D. Cannabinoids and Endocannabinoids. In: Pfaff D, Volkow N, editors. Neuroscience in the 21st Century. New York: Springer; 2015. https://doi.org/10.1007/978-1-4614-6434-1_136-1.

  2. Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003;4(11):873–84. https://doi.org/10.1038/nrn1247.

    Article  CAS  Google Scholar 

  3. Gaoni Y, Mechoulam R. Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc. 1964;86:1646–47.

    Article  CAS  Google Scholar 

  4. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346(6284):561–4. https://doi.org/10.1038/346561a0.

    Article  CAS  PubMed  Google Scholar 

  5. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365(6441):61–5. https://doi.org/10.1038/365061a0.

    Article  CAS  PubMed  Google Scholar 

  6. Mackie K. Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol. 2006;46:101–22. https://doi.org/10.1146/annurev.pharmtox.46.120604.141254.

    Article  CAS  PubMed  Google Scholar 

  7. Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev. 2003;83(3):1017–66. https://doi.org/10.1152/physrev.00004.2003.

    Article  CAS  PubMed  Google Scholar 

  8. Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M. Endocannabinoid-mediated control of synaptic transmission. Physiol Rev. 2009;89(1):309–80. https://doi.org/10.1152/physrev.00019.2008.

    Article  CAS  PubMed  Google Scholar 

  9. Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258(5090):1946–9. https://doi.org/10.1126/science.1470919.

    Article  CAS  PubMed  Google Scholar 

  10. Sugiura T, Kondo S, Sukagawa A, et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun. 1995;215(1):89–97. https://doi.org/10.1006/bbrc.1995.2437.

    Article  CAS  PubMed  Google Scholar 

  11. Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50(1):83–90. https://doi.org/10.1016/0006-2952(95)00109-d.

    Article  CAS  PubMed  Google Scholar 

  12. Di Marzo V, Fontana A, Cadas H, et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature. 1994;372(6507):686–91. https://doi.org/10.1038/372686a0.

    Article  PubMed  Google Scholar 

  13. Stella N, Schweitzer P, Piomelli D. A second endogenous cannabinoid that modulates long-term potentiation. Nature. 1997;388(6644):773–8. https://doi.org/10.1038/42015.

    Article  CAS  PubMed  Google Scholar 

  14. Piomelli D, Astarita G, Rapaka R. A neuroscientist’s guide to lipidomics. Nat Rev Neurosci. 2007;8(10):743–54. https://doi.org/10.1038/nrn2233.

    Article  CAS  PubMed  Google Scholar 

  15. Howlett AC, Barth F, Bonner TI, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54(2):161–202. https://doi.org/10.1124/pr.54.2.161.

    Article  CAS  PubMed  Google Scholar 

  16. Mackie K, Lai Y, Westenbroek R, Mitchell R. Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. J Neurosci. 1995;15(10):6552–61. https://doi.org/10.1523/JNEUROSCI.15-10-06552.1995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Twitchell W, Brown S, Mackie K. Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons. J Neurophysiol. 1997;78(1):43–50. https://doi.org/10.1152/jn.1997.78.1.43.

    Article  CAS  PubMed  Google Scholar 

  18. Waksman Y, Olson JM, Carlisle SJ, Cabral GA. The central cannabinoid receptor (CB1) mediates inhibition of nitric oxide production by rat microglial cells. J Pharmacol Exp Ther. 1999;288(3):1357–66.

    CAS  PubMed  Google Scholar 

  19. Gómez Del Pulgar T, De Ceballos ML, Guzmán M, Velasco G. Cannabinoids protect astrocytes from ceramide-induced apoptosis through the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem. 2002;277(39):36527–33. https://doi.org/10.1074/jbc.M205797200.

    Article  CAS  PubMed  Google Scholar 

  20. Stella N. Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia. 2010;58(9):1017–30. https://doi.org/10.1002/glia.20983.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Maccarrone M, Bab I, Bíró T, et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci. 2015;36(5):277–96. https://doi.org/10.1016/j.tips.2015.02.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kunos G, Tam J. The case for peripheral CB1 receptor blockade in the treatment of visceral obesity and its cardiometabolic complications. Br J Pharmacol. 2011;163(7):1423–31. https://doi.org/10.1111/j.1476-5381.2011.01352.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. DiPatrizio NV, Piomelli D. Intestinal lipid-derived signals that sense dietary fat. J Clin Invest. 2015;125(3):891–8. https://doi.org/10.1172/JCI76302.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kunos G, Osei-Hyiaman D. Endocannabinoids and liver disease. IV. Endocannabinoid involvement in obesity and hepatic steatosis. Am J Physiol Gastrointest Liver Physiol. 2008;294(5):G1101–4. https://doi.org/10.1152/ajpgi.00057.2008.

    Article  CAS  PubMed  Google Scholar 

  25. Tam J, Liu J, Mukhopadhyay B, Cinar R, Godlewski G, Kunos G. Endocannabinoids in liver disease. Hepatology. 2011;53(1):346–55. https://doi.org/10.1002/hep.24077.

    Article  CAS  PubMed  Google Scholar 

  26. Cota D, Marsicano G, Tschöp M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest. 2003;112(3):423–31. https://doi.org/10.1172/JCI17725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Eriksson O, Mikkola K, Espes D, et al. The Cannabinoid Receptor-1 Is an Imaging Biomarker of Brown Adipose Tissue. J Nucl Med. 2015;56(12):1937–41. https://doi.org/10.2967/jnumed.115.156422.

    Article  CAS  PubMed  Google Scholar 

  28. Starowicz KM, Cristino L, Matias I, et al. Endocannabinoid dysregulation in the pancreas and adipose tissue of mice fed with a high-fat diet. Obesity (Silver Spring). 2008;16(3):553–65. https://doi.org/10.1038/oby.2007.106.

    Article  CAS  Google Scholar 

  29. Bensaid M, Gary-Bobo M, Esclangon A, et al. The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol. 2003;63(4):908–14. https://doi.org/10.1124/mol.63.4.908.

    Article  CAS  PubMed  Google Scholar 

  30. Matias I, Gonthier MP, Orlando P, et al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab. 2006;91(8):3171–80. https://doi.org/10.1210/jc.2005-2679.

    Article  CAS  PubMed  Google Scholar 

  31. Mehrpouya-Bahrami P, Miranda K, Singh NP, Zumbrun EE, Nagarkatti M, Nagarkatti PS. Role of microRNA in CB1 antagonist-mediated regulation of adipose tissue macrophage polarization and chemotaxis during diet-induced obesity. J Biol Chem. 2019;294(19):7669–81. https://doi.org/10.1074/jbc.RA118.005094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ishac EJ, Jiang L, Lake KD, Varga K, Abood ME, Kunos G. Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB1 receptors on peripheral sympathetic nerves. Br J Pharmacol. 1996;118(8):2023–8. https://doi.org/10.1111/j.1476-5381.1996.tb15639.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Miller AM, Stella N. CB2 receptor-mediated migration of immune cells: It can go either way. Br J Pharmacol. 2008;153(2):299–308. https://doi.org/10.1038/sj.bjp.0707523.

    Article  CAS  PubMed  Google Scholar 

  34. Pagano C, Pilon C, Calcagno A, et al. The endogenous cannabinoid system stimulates glucose uptake in human fat cells via phosphatidylinositol 3-kinase and calcium-dependent mechanisms. J Clin Endocrinol Metab. 2007;92(12):4810–9. https://doi.org/10.1210/jc.2007-0768.

    Article  CAS  PubMed  Google Scholar 

  35. Roche R, Hoareau L, Bes-Houtmann S, et al. Presence of the cannabinoid receptors, CB1 and CB2, in human omental and subcutaneous adipocytes. Histochem Cell Biol. 2006;126(2):177–87. https://doi.org/10.1007/s00418-005-0127-4.

    Article  CAS  PubMed  Google Scholar 

  36. Spoto B, Fezza F, Parlongo G, et al. Human adipose tissue binds and metabolizes the endocannabinoids anandamide and 2-arachidonoylglycerol. Biochimie. 2006;88(12):1889–97. https://doi.org/10.1016/j.biochi.2006.07.019.

    Article  CAS  PubMed  Google Scholar 

  37. Pagano C, Rossato M, Vettor R. Endocannabinoids, adipose tissue and lipid metabolism. J Neuroendocrinol. 2008;20(Suppl 1):124–9. https://doi.org/10.1111/j.1365-2826.2008.01690.x.

    Article  CAS  PubMed  Google Scholar 

  38. Rossi F, Bellini G, Luongo L, et al. Cannabinoid Receptor 2 as Antiobesity Target: Inflammation, Fat Storage, and Browning Modulation. J Clin Endocrinol Metab. 2016;101(9):3469–78. https://doi.org/10.1210/jc.2015-4381.

    Article  CAS  PubMed  Google Scholar 

  39. Cadas H, di Tomaso E, Piomelli D. Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J Neurosci. 1997;17(4):1226–42. https://doi.org/10.1523/JNEUROSCI.17-04-01226.1997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Giuffrida A, Parsons LH, Kerr TM, Rodríguez de Fonseca F, Navarro M, Piomelli D. Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nat Neurosci. 1999;2(4):358–63. https://doi.org/10.1038/7268.

    Article  CAS  PubMed  Google Scholar 

  41. Wei D, Lee D, Cox CD, et al. Endocannabinoid signaling mediates oxytocin-driven social reward. Proc Natl Acad Sci U S A. 2015;112(45):14084–9. https://doi.org/10.1073/pnas.1509795112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ogura Y, Parsons WH, Kamat SS, Cravatt BF. A calcium-dependent acyltransferase that produces N-acyl phosphatidylethanolamines. Nat Chem Biol. 2016;12(9):669–71. https://doi.org/10.1038/nchembio.2127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N. Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem. 2004;279(7):5298–305. https://doi.org/10.1074/jbc.M306642200.

    Article  CAS  PubMed  Google Scholar 

  44. Tsuboi K, Ikematsu N, Uyama T, Deutsch DG, Tokumura A, Ueda N. Biosynthetic pathways of bioactive N-acylethanolamines in brain. CNS Neurol Disord Drug Targets. 2013;12(1):7–16. https://doi.org/10.2174/1871527311312010005.

    Article  CAS  PubMed  Google Scholar 

  45. Serrano A, Pavon FJ, Buczynski MW, et al. Deficient endocannabinoid signaling in the central amygdala contributes to alcohol dependence-related anxiety-like behavior and excessive alcohol intake. Neuropsychopharmacology. 2018;43(9):1840–50. https://doi.org/10.1038/s41386-018-0055-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science. 1997;277(5329):1094–7. https://doi.org/10.1126/science.277.5329.1094.

    Article  CAS  PubMed  Google Scholar 

  47. Nicolussi S, Gertsch J. Endocannabinoid transport revisited. Vitam Horm. 2015;98:441–85. https://doi.org/10.1016/bs.vh.2014.12.011.

    Article  CAS  PubMed  Google Scholar 

  48. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature. 1996;384(6604):83–7. https://doi.org/10.1038/384083a0.

    Article  CAS  PubMed  Google Scholar 

  49. McKinney MK, Cravatt BF. Structure and function of fatty acid amide hydrolase. Annu Rev Biochem. 2005;74:411–32.

    Article  CAS  Google Scholar 

  50. Seal SN, Rose ZB. Characterization of a phosphoenzyme intermediate in the reaction of phosphoglycolate phosphatase. J Biol Chem. 1987;262(28):13496–500.

    Article  CAS  Google Scholar 

  51. Bennett CF, Balcarek JM, Varrichio A, Crooke ST. Molecular cloning and complete amino-acid sequence of form-I phosphoinositide-specific phospholipase C. Nature. 1988;334(6179):268–70. https://doi.org/10.1038/334268a0.

    Article  CAS  PubMed  Google Scholar 

  52. Bisogno T, Howell F, Williams G, et al. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol. 2003;163(3):463–8. https://doi.org/10.1083/jcb.200305129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Jung KM, Sepers M, Henstridge CM, et al. Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nat Commun. 2012;3:1080. https://doi.org/10.1038/ncomms2045.

    Article  CAS  PubMed  Google Scholar 

  54. Dinh TP, Carpenter D, Leslie FM, et al. Brain monoglyceride lipase participating in endocannabinoid inactivation [published correction appears in Proc Natl Acad Sci U S A 2002 Oct 15;99(21):13961]. Proc Natl Acad Sci U S A. 2002;99(16):10819–24. https://doi.org/10.1073/pnas.152334899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Blankman JL, Simon GM, Cravatt BF. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol. 2007;14(12):1347–56. https://doi.org/10.1016/j.chembiol.2007.11.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Krott LM, Piscitelli F, Heine M, et al. Endocannabinoid regulation in white and brown adipose tissue following thermogenic activation. J Lipid Res. 2016;57(3):464–73. https://doi.org/10.1194/jlr.M065227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. van Eenige R, van der Stelt M, Rensen PCN, Kooijman S. Regulation of adipose tissue metabolism by the endocannabinoid system. Trends Endocrinol Metab. 2018;29(5):326–37. https://doi.org/10.1016/j.tem.2018.03.001.

    Article  CAS  PubMed  Google Scholar 

  58. Karlsson M, Contreras JA, Hellman U, Tornqvist H, Holm C. cDNA cloning, tissue distribution, and identification of the catalytic triad of monoglyceride lipase. Evolutionary relationship to esterases, lysophospholipases, and haloperoxidases. J Biol Chem. 1997;272(43):27218–23. https://doi.org/10.1074/jbc.272.43.27218.

    Article  CAS  PubMed  Google Scholar 

  59. Nahon KJ, Kantae V, den Haan R, et al. Gene expression of endocannabinoid system components in skeletal muscle and adipose tissue of South Asians and white caucasians with overweight. Obesity (Silver Spring). 2018;26(8):1332–7. https://doi.org/10.1002/oby.22245.

    Article  CAS  Google Scholar 

  60. You T, Disanzo BL, Wang X, Yang R, Gong D. Adipose tissue endocannabinoid system gene expression: Depot differences and effects of diet and exercise. Lipids Health Dis. 2011;10:194. https://doi.org/10.1186/1476-511X-10-194. Published 2011 Oct 28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zoerner AA, Rakers C, Engeli S, et al. Peripheral endocannabinoid microdialysis: In vitro characterization and proof-of-concept in human subjects. Anal Bioanal Chem. 2012;402(9):2727–35. https://doi.org/10.1007/s00216-012-5729-9.

    Article  CAS  PubMed  Google Scholar 

  62. Mulawa EA, Kirkwood JS, Wolfe LM, et al. Seasonal changes in endocannabinoid concentrations between active and hibernating marmots (Marmota flaviventris). J Biol Rhythms. 2018;33(4):388–401. https://doi.org/10.1177/0748730418777660.

    Article  CAS  PubMed  Google Scholar 

  63. Gasperi V, Fezza F, Pasquariello N, et al. Endocannabinoids in adipocytes during differentiation and their role in glucose uptake. Cell Mol Life Sci. 2007;64(2):219–29. https://doi.org/10.1007/s00018-006-6445-4.

    Article  CAS  PubMed  Google Scholar 

  64. Ruiz de Azua I, Mancini G, Srivastava RK, et al. Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages. J Clin Invest. 2017;127(11):4148–62. https://doi.org/10.1172/JCI83626.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Quarta C, Bellocchio L, Mancini G, et al. CB(1) signaling in forebrain and sympathetic neurons is a key determinant of endocannabinoid actions on energy balance. Cell Metab. 2010;11(4):273–85. https://doi.org/10.1016/j.cmet.2010.02.015.

    Article  CAS  PubMed  Google Scholar 

  66. DiPatrizio NV, Piomelli D. The thrifty lipids: Endocannabinoids and the neural control of energy conservation. Trends Neurosci. 2012;35(7):403–11. https://doi.org/10.1016/j.tins.2012.04.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Suárez J, Rivera P, Aparisi Rey A, et al. Adipocyte cannabinoid CB1 receptor deficiency alleviates high fat diet-induced memory deficit, depressive-like behavior, neuroinflammation and impairment in adult neurogenesis. Psychoneuroendocrinology. 2019;110:104418. https://doi.org/10.1016/j.psyneuen.2019.104418.

    Article  CAS  PubMed  Google Scholar 

  68. Cristancho AG, Lazar MA. Forming functional fat: A growing understanding of adipocyte differentiation. Nat Rev Mol Cell Biol. 2011;12(11):722–34. https://doi.org/10.1038/nrm3198. Published 2011 Sep 28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Bellocchio L, Cervino C, Vicennati V, Pasquali R, Pagotto U. Cannabinoid type 1 receptor: Another arrow in the adipocytes’ bow. J Neuroendocrinol. 2008;20(Suppl 1):130–8. https://doi.org/10.1111/j.1365-2826.2008.01682.x.

    Article  CAS  PubMed  Google Scholar 

  70. Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nat Neurosci. 2005;8(5):585–9. https://doi.org/10.1038/nn1457.

    Article  CAS  PubMed  Google Scholar 

  71. Giordano A, Frontini A, Cinti S. Convertible visceral fat as a therapeutic target to curb obesity. Nat Rev Drug Discov. 2016;15(6):405–24. https://doi.org/10.1038/nrd.2016.31.

    Article  CAS  PubMed  Google Scholar 

  72. Shapira SN, Seale P. Transcriptional control of brown and beige fat development and function. Obesity (Silver Spring). 2019;27(1):13–21. https://doi.org/10.1002/oby.22334.

    Article  CAS  Google Scholar 

  73. Maurer S, Harms M, Boucher J. The colorful versatility of adipocytes: white-to-brown transdifferentiation and its therapeutic potential in humans. FEBS J. 2020 Jul 3. doi: https://doi.org/10.1111/febs.15470.

  74. Hardie DG, Schaffer BE, Brunet A. AMPK: An energy-sensing pathway with multiple inputs and outputs. Trends Cell Biol. 2016;26(3):190–201. https://doi.org/10.1016/j.tcb.2015.10.013.

    Article  CAS  PubMed  Google Scholar 

  75. Tedesco L, Valerio A, Dossena M, et al. Cannabinoid receptor stimulation impairs mitochondrial biogenesis in mouse white adipose tissue, muscle, and liver: The role of eNOS, p38 MAPK, and AMPK pathways. Diabetes. 2010;59(11):2826–36. https://doi.org/10.2337/db09-1881.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Cheng CF, Ku HC, Lin H. PGC-1α as a pivotal factor in lipid and metabolic regulation. Int J Mol Sci. 2018;19(11):3447. Published 2018 Nov 2. https://doi.org/10.3390/ijms19113447.

  77. Perwitz N, Wenzel J, Wagner I, et al. Cannabinoid type 1 receptor blockade induces transdifferentiation towards a brown fat phenotype in white adipocytes. Diabetes Obes Metab. 2010;12(2):158–66. https://doi.org/10.1111/j.1463-1326.2009.01133.x.

    Article  CAS  PubMed  Google Scholar 

  78. Deveaux V, Cadoudal T, Ichigotani Y, et al. Cannabinoid CB2 receptor potentiates obesity-associated inflammation, insulin resistance and hepatic steatosis. PLoS One. 2009;4(6):e5844. https://doi.org/10.1371/journal.pone.0005844. Published 2009 Jun 9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Verty AN, Stefanidis A, McAinch AJ, Hryciw DH, Oldfield B. Anti-obesity effect of the CB2 receptor agonist JWH-015 in diet-induced obese mice. PLoS One. 2015;10(11):e0140592. https://doi.org/10.1371/journal.pone.0140592 Published 2015 Nov 20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Silva JE. Physiological importance and control of non-shivering facultative thermogenesis. Front Biosci (Schol Ed). 2011;3:352–71. https://doi.org/10.2741/s156. Published 2011 Jan 1.

    Article  Google Scholar 

  81. Verty AN, Evetts MJ, Crouch GJ, McGregor IS, Stefanidis A, Oldfield BJ. The cannabinoid receptor agonist THC attenuates weight loss in a rodent model of activity-based anorexia. Neuropsychopharmacology. 2011;36(7):1349–58. https://doi.org/10.1038/npp.2011.19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Krauss S, Zhang CY, Lowell BB. The mitochondrial uncoupling-protein homologues. Nat Rev Mol Cell Biol. 2005;6(3):248–61. https://doi.org/10.1038/nrm1592.

    Article  CAS  PubMed  Google Scholar 

  83. Boon MR, Kooijman S, van Dam AD, et al. Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity. FASEB J. 2014;28(12):5361–75. https://doi.org/10.1096/fj.13-247643.

    Article  CAS  PubMed  Google Scholar 

  84. Matias I, Di Marzo V. Endocannabinoids and the control of energy balance. Trends Endocrinol Metab. 2007;18(1):27–37. https://doi.org/10.1016/j.tem.2006.11.006.

    Article  CAS  PubMed  Google Scholar 

  85. Jung KM, Clapper JR, Fu J, et al. 2-arachidonoylglycerol signaling in forebrain regulates systemic energy metabolism. Cell Metab. 2012;15(3):299–310. https://doi.org/10.1016/j.cmet.2012.01.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Cinar R, Iyer MR, Kunos G. The therapeutic potential of second and third generation CB1R antagonists. Pharmacol Ther. 2020;208:107477. https://doi.org/10.1016/j.pharmthera.2020.107477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hirsch S, Tam J. Cannabis: from a plant that modulates feeding behaviors toward developing selective inhibitors of the peripheral endocannabinoid system for the treatment of obesity and metabolic syndrome. Toxins (Basel). 2019;11(5):275. Published 2019 May 15. https://doi.org/10.3390/toxins11050275.

  88. Tam J, Hinden L, Drori A, Udi S, Azar S, Baraghithy S. The therapeutic potential of targeting the peripheral endocannabinoid/CB1 receptor system. Eur J Intern Med. 2018;49:23–9. https://doi.org/10.1016/j.ejim.2018.01.009.

    Article  CAS  PubMed  Google Scholar 

  89. Jourdan T, Godlewski G, Kunos G. Endocannabinoid regulation of β-cell functions: Implications for glycaemic control and diabetes. Diabetes Obes Metab. 2016;18(6):549–57. https://doi.org/10.1111/dom.12646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Silvestri C, Di Marzo V. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab. 2013;17(4):475–90. https://doi.org/10.1016/j.cmet.2013.03.001.

    Article  CAS  PubMed  Google Scholar 

  91. Blüher M, Engeli S, Klöting N, et al. Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes. 2006;55(11):3053–60. https://doi.org/10.2337/db06-0812.

    Article  CAS  PubMed  Google Scholar 

  92. Côté M, Matias I, Lemieux I, et al. Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes (Lond). 2007;31(4):692–9. https://doi.org/10.1038/sj.ijo.0803539.

    Article  CAS  Google Scholar 

  93. Di Marzo V, Côté M, Matias I, Lemieux I, Arsenault BJ, Cartier A, Piscitelli F, Petrosino S, Alméras N, Després JP. Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: associations with changes in metabolic risk factors. Diabetologia. 2009;52(2):213-7. https://doi.org/10.1007/s00125-008-1178-6.

  94. Sarzani R, Bordicchia M, Marcucci P, et al. Altered pattern of cannabinoid type 1 receptor expression in adipose tissue of dysmetabolic and overweight patients. Metabolism. 2009;58(3):361–7. https://doi.org/10.1016/j.metabol.2008.10.009.

    Article  CAS  PubMed  Google Scholar 

  95. Bordicchia M, Battistoni I, Mancinelli L, et al. Cannabinoid CB1 receptor expression in relation to visceral adipose depots, endocannabinoid levels, microvascular damage, and the presence of the Cnr1 A3813G variant in humans. Metabolism. 2010;59(5):734–41. https://doi.org/10.1016/j.metabol.2009.09.018.

    Article  CAS  PubMed  Google Scholar 

  96. Bennetzen MF. Investigations of the endocannabinoid system in adipose tissue: effects of obesity/ weight loss and treatment options. Dan Med Bull. 2011;58(4):B4269.

    PubMed  Google Scholar 

  97. Engeli S. Central and peripheral cannabinoid receptors as therapeutic targets in the control of food intake and body weight. Handb Exp Pharmacol. 2012;209:357–81. https://doi.org/10.1007/978-3-642-24716-3_17.

    Article  CAS  Google Scholar 

  98. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rössner S. RIO-Europe Study Group. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study [published correction appears in Lancet. 2005 Jul 30-Aug 5;366(9483):370]. Lancet. 2005;365(9468):1389–1397. https://doi.org/10.1016/S0140-6736(05)66374-X.

  99. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. RIO-North America Study Group. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial [published correction appears in JAMA. 2006 Mar 15;295(11):1252]. JAMA. 2006;295(7):761–775. https://doi.org/10.1001/jama.295.7.761.

  100. Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF. RIO-Diabetes Study Group. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study [published correction appears in Lancet. 2006 Nov 11;368(9548):1650]. Lancet. 2006;368(9548):1660–1672. https://doi.org/10.1016/S0140-6736(06)69571-8.

  101. Després JP, Golay A, Sjöström L, Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353(20):2121–34. https://doi.org/10.1056/NEJMoa044537.

    Article  PubMed  Google Scholar 

  102. Clapper JR, Mangieri RA, Piomelli D. The endocannabinoid system as a target for the treatment of cannabis dependence. Neuropharmacology. 2009;56(Suppl 1):235–43. https://doi.org/10.1016/j.neuropharm.2008.07.018.

    Article  CAS  PubMed  Google Scholar 

  103. Tam J, Vemuri VK, Liu J, et al. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity [published correction appears in J Clin Invest. 2010 Oct 1;120(10):3735]. J Clin Invest. 2010;120(8):2953–2966. https://doi.org/10.1172/JCI42551.

  104. DiPatrizio NV, Joslin A, Jung KM, Piomelli D. Endocannabinoid signaling in the gut mediates preference for dietary unsaturated fats. FASEB J. 2013;27(6):2513–20. https://doi.org/10.1096/fj.13-227587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Tam J, Cinar R, Liu J, et al. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab. 2012;16(2):167–79. https://doi.org/10.1016/j.cmet.2012.07.002.

    Article  CAS  PubMed  Google Scholar 

  106. Cinar R, Godlewski G, Liu J, et al. Hepatic cannabinoid-1 receptors mediate diet-induced insulin resistance by increasing de novo synthesis of long-chain ceramides. Hepatology. 2014;59(1):143–53. https://doi.org/10.1002/hep.26606.

    Article  CAS  PubMed  Google Scholar 

  107. Rodríguez de Fonseca F, Navarro M, Gómez R, et al. An anorexic lipid mediator regulated by feeding. Nature. 2001;414(6860):209–12. https://doi.org/10.1038/35102582.

    Article  PubMed  Google Scholar 

  108. Fu J, Gaetani S, Oveisi F, et al. Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature. 2003;425(6953):90–3. https://doi.org/10.1038/nature01921.

    Article  CAS  PubMed  Google Scholar 

  109. Schwartz GJ, Fu J, Astarita G, et al. The lipid messenger OEA links dietary fat intake to satiety. Cell Metab. 2008;8(4):281–8. https://doi.org/10.1016/j.cmet.2008.08.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. LoVerme J, Guzmán M, Gaetani S, Piomelli D. Cold exposure stimulates synthesis of the bioactive lipid oleoylethanolamide in rat adipose tissue. J Biol Chem. 2006;281(32):22815–8. https://doi.org/10.1074/jbc.M604751200.

    Article  CAS  PubMed  Google Scholar 

  111. Guzmán M, Lo Verme J, Fu J, Oveisi F, Blázquez C, Piomelli D. Oleoylethanolamide stimulates lipolysis by activating the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-alpha). J Biol Chem. 2004;279(27):27849–54. https://doi.org/10.1074/jbc.M404087200.

    Article  CAS  PubMed  Google Scholar 

  112. Fu J, Oveisi F, Gaetani S, Lin E, Piomelli D. Oleoylethanolamide, an endogenous PPAR-alpha agonist, lowers body weight and hyperlipidemia in obese rats. Neuropharmacology. 2005;48(8):1147–53. https://doi.org/10.1016/j.neuropharm.2005.02.013.

    Article  CAS  PubMed  Google Scholar 

  113. Laleh P, Yaser K, Abolfazl B, et al. Oleoylethanolamide increases the expression of PPAR-Α and reduces appetite and body weight in obese people: A clinical trial. Appetite. 2018;128:44–9. https://doi.org/10.1016/j.appet.2018.05.129.

    Article  PubMed  Google Scholar 

  114. Payahoo L, Khajebishak Y, Asghari Jafarabadi M, Ostadrahimi A. Oleoylethanolamide Supplementation Reduces Inflammation and Oxidative Stress in Obese People: A Clinical Trial. Adv Pharm Bull. 2018;8(3):479–87. https://doi.org/10.15171/apb.2018.056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Tutunchi H, Ostadrahimi A, Saghafi-Asl M, et al. Oleoylethanolamide supplementation in obese patients newly diagnosed with non-alcoholic fatty liver disease: Effects on metabolic parameters, anthropometric indices, and expression of PPAR-α, UCP1, and UCP2 genes. Pharmacol Res. 2020;156:104770. https://doi.org/10.1016/j.phrs.2020.104770.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Research reported in this publication was supported by the National Institute on Drug Abuse (NIDA) of the National Institutes of Health (NIH) under award number P50DA044118 (to D.P.) and the UC Tobacco-Related Disease Research Program (TRDRP) under award number T29IR0618/26IP-0043 (to D.P.).

Author information

Authors and Affiliations

  1. Department of Anatomy and Neurobiology, University of California, Irvine, 3101 Gillespie NRF, Irvine, CA, 92697-1275, USA

    Kwang-Mook Jung, Lin Lin & Daniele Piomelli

  2. Department of Pharmacology, University of California, Irvine, Irvine, CA, 92697, USA

    Daniele Piomelli

  3. Department of Biological Chemistry, University of California, Irvine, Irvine, CA, 92697, USA

    Daniele Piomelli

Authors
  1. Kwang-Mook Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lin Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniele Piomelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniele Piomelli.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jung, KM., Lin, L. & Piomelli, D. The endocannabinoid system in the adipose organ. Rev Endocr Metab Disord 23, 51–60 (2022). https://doi.org/10.1007/s11154-020-09623-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11154-020-09623-z

Keywords

Search

Navigation