Cellular and Molecular Life Sciences

, Volume 76, Issue 7, pp 1341–1363 | Cite as

Multiple endocannabinoid-mediated mechanisms in the regulation of energy homeostasis in brain and peripheral tissues

  • Inigo Ruiz de AzuaEmail author
  • Beat Lutz


The endocannabinoid (eCB) system is widely expressed in many central and peripheral tissues, and is involved in a plethora of physiological processes. Among these, activity of the eCB system promotes energy intake and storage, which, however, under pathophysiological conditions, can favour the development of obesity and obesity-related disorders. It is proposed that eCB signalling is evolutionary beneficial for survival under periods of scarce food resources. Remarkably, eCB signalling is increased both in hunger and in overnutrition conditions, such as obesity and type-2 diabetes. This apparent paradox suggests a role of the eCB system both at initiation and at clinical endpoint of obesity. This review will focus on recent findings about the role of the eCB system controlling whole-body metabolism in mice that are genetically modified selectively in different cell types. The current data in fact support the notion that eCB signalling is not only engaged in the development but also in the maintenance of obesity, whereby specific cell types in central and peripheral tissues are key sites in regulating the entire body’s energy homeostasis.


Endocannabinoid system 2-Arachidonoyl glycerol Anandamide Cannabinoid type 1 receptor Energy balance Energy expenditure Feeding behaviour Rimonabant Peripheral CB1 antagonist Obesity, Type-2 diabetes Metabolic syndrome 



I. R. de A. was partly funded the Boehringer Ingelheim Foundation.


  1. 1.
    Addy C, Wright H, Van Laere K, Gantz I, Erondu N, Musser BJ, Lu K, Yuan J, Sanabria-Bohórquez SM, Stoch A, Stevens C, Fong TM, De Lepeleire I, Cilissen C, Cote J, Rosko K, Gendrano IN 3rd, Nguyen AM, Gumbiner B, Rothenberg P, de Hoon J, Bormans G, Depré M, Eng WS, Ravussin E, Klein S, Blundell J, Herman GA, Burns HD, Hargreaves RJ, Wagner J, Gottesdiener K, Amatruda JM, Heymsfield SB (2008) The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake. Cell Metab 7:68–78CrossRefPubMedGoogle Scholar
  2. 2.
    Agudo J, Marin M, Roca C, Molas M, Bura AS, Zimmer A, Bosc F, Maldonado R (2010) Deficiency of CB2 cannabinoid receptor in mice improves insulin sensitivity but increase food intake and obesity with age. Diabetologia 53:2629–2640CrossRefPubMedGoogle Scholar
  3. 3.
    Alhouayek M, Lambert DM, Delzene NM, Cani PD (2011) Increasing endogenous 2-arachidonoylglycerol levels counteracts colitis and related systemic inflammation. FASEB J 25:2711–2721CrossRefPubMedGoogle Scholar
  4. 4.
    Alvheim AR, Malde MK, Osei-Hyiaman D, Lin YH, Pawlosky RJ, Madsen L, Kristiansen K, Froyland L, Hibbeln JR (2012) Dietary linoleic acid elevates endogenous 2-AG and anandamide and induces obesity. Obesity 20:194–1994CrossRefGoogle Scholar
  5. 5.
    Bäckhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI (2004) The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 101:15718–15723CrossRefPubMedGoogle Scholar
  6. 6.
    Bacci A, Huguernard JR, Prince DA (2004) Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids. Nature 431:312–316CrossRefPubMedGoogle Scholar
  7. 7.
    Barutta F, Corbelli A, Mastrocola R, Gambino R, Di Marzo V, Pinach S, Rastaldi MP, Perin PC, Gruden G (2010) Cannabinoid receptor 1 blockade ameliorates albuminuria in experimental diabetic nephrophaty. Diabetes 59:1046–1054CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bashashati M, Storr MA, Wood JT, Godlewski G, Liu J, Ho W, Keenan CM, Zhang H, Alapafuja SO, Cravatt BF, Lutz B, Mackie K, Kunos G, Patel KD, Makriyannis A, Davison JS, Sharkley KA (2012) Inhibiting fatty acid amide hydrolase normalizes endotoxin-induced enhanced gastrointestinal motility in mice. Br J Pharmacol 165:1556–1571CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Baye TM, Zhang Y, Smith E, Hillard CJ, Gunnell J, Mykleust J, James R, Kissebah AH, Olivier M, Wilke RA (2008) Genetic variation in cannabinoid receptor 1 (CNR1) is associated with derangements in lipid homeostasis, independent of body mass index. Pharmacogenomics 9:1647–1656CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Belendiuk KA, Baldini LL, Bonn-Miller OMO (2015) Narrative review of the safety and efficacy of marijuana for the treatment of commonly state-approved medical and psychiatric disorders. Addict Sci Clin Pract 10:1–10CrossRefGoogle Scholar
  11. 11.
    Bellocchio L, Cervino C, Vicennati V, Pasquali R, Pagotto U (2008) Cannabinoid type 1 receptor: another arrow in the adipocytes’ bow. J Neuroendocrinol 1:130–138CrossRefGoogle Scholar
  12. 12.
    Bellocchio L, Lafenetre P, Cannich A, Cota D, Puente N, Grandes P, Chaouloff F, Piazza PV, Marsicano G (2010) Bimodal control of stimulated food intake by endocannabinoid system. Nat Neurosci 13:281–283CrossRefPubMedGoogle Scholar
  13. 13.
    Bénard G, Massa F, Puente N, Lourenço J, Bellocchio L, Soria-Gómez E, Matias I, Delamarre A, Metna-Laurent M, Cannich A, Hebert-Chatelain E, Mulle C, Ortega-Gutiérrez S, Martín-Fontecha M, Klugmann M, Guggenhuber S, Lutz B, Gertsch J, Chaouloff F, López-Rodríguez ML, Grandes P, Rossignol R, Marsicano G (2012) Mitochondrial CB1 receptors regulate neuronal energy metabolism. Nat Neurosci 15:558–564CrossRefPubMedGoogle Scholar
  14. 14.
    Bensaid M, Gary-BoboM Esclangon A, Maffrand JP, Le Fur G, Oury-Donat F, Soubrie P (2003) 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 63:908–914CrossRefPubMedGoogle Scholar
  15. 15.
    Berger WT, Ralph BP, Kaczocha M, Sun J, Balius TE, Rizzo RC, Haj-Dahmane S, Ojima I, Deutsch DG (2012) Targeting FABP anandamide transporters—a novel strategy for development of anti-inflammatory and anti-nociceptive drugs. PLoS One 7:e50968CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Bermúdez-Silva FJ, Suárez J, Baixeras E, Cobo N, Bautista D, Cuesta-Muñoz AL, Fuentes E, Juan-Pico P, Castro MJ, Milman G, Mechoulam R, Nadal A, Rodríguez de Fonseca F (2008) Presence of functional cannabinoid receptors in human endocrine pancreas. Diabetologia 51:476–487CrossRefPubMedGoogle Scholar
  17. 17.
    Blankman JL, Simon GM, Cravatt BF (2007) A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol 14:1347–1356CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Blüher M, Engeli S, Klöting N, Berndt J, Fasshauer M, Batkai S, Pacher P, Schön MR, Jordan J, Stmvoll M (2006) Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes 55:3053–3060CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Bordicchia M, Battistoni I, Mancinelli L, Giannini E, Refi G, Minardi D, Muzzonigro G, Mazzucchelli R, Montironi R, Piscitelli F, Petrosino S, Dessì-Fulgheri P, Rappelli A, Di Marzo V, Sarzani R (2010) 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 59:734–741CrossRefPubMedGoogle Scholar
  20. 20.
    Bouaboula M, Hilariet S, Marchand J, Fajas L, Le Fur G, Casellas P (2005) Anandamide induced PPAR-gamma transcriptional activation and 3T3-L1 preadipocyte differentiation. Eur J Pharmacol 517:174–181CrossRefPubMedGoogle Scholar
  21. 21.
    Boyd AM, Sturgill JF, Poo C, Isaacson JS (2012) Cortical feedback control of olfactory bulb circuits. Neuron 76:1161–1174CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Bowles NP, Karatsoreos IN, Li X, Vemuri VK, Wood JA, Li Z, Tamashiro KI, Schwartz GJ, Makriyannis AM, Kunos G, Hillard CJ, McEwen BS, Hill MN (2015) A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolism syndrome. Proc Natl Acad Sci USA 112:285–290CrossRefPubMedGoogle Scholar
  23. 23.
    Brestoff JR, Artis D (2015) Immune regulation of metabolic homeostasis in health and disease. Cell 161:146–160CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Busquets-Garcia A, Gomis-González M, Srivastava RK, Cutando L, Ortega-Alvaro A, Ruehle S, Remmers F, Bindila L, Bellocchio L, Marsicano G, Lutz B, Maldonado R, Ozaita A (2016) Peripheral and central CB1 cannabinoid receptors control stress-induced impairment of memory consolidation. Proc Natl Acad Sci USA 113:9904–9909CrossRefPubMedGoogle Scholar
  25. 25.
    Cardinal P, Bellocchio L, Clark S, Cannich A, Klugman M, Lutz B, Marsicano G, Cota D (2012) Hypothalamic CB1 cannabinoid receptors regulate energy balance in mice. Endocrinology 153:1–8CrossRefGoogle Scholar
  26. 26.
    Cardinal P, Andre C, Quarta C, Bellocchio L, Clark S, Elie M, Leste-Laserre T, Maire M, Gonzales D, Cannich A, Pagotto U, Marsicano G, Cota D (2014) CB1 cannabinoid receptor on SF-1-expressing neurons of the ventromedial hypothalamus determines metabolic responses to diet and leptin. Mol Metab 3:705–716CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Cardinal P, Bellocchio L, Guzman-Quevedo O, Andre C, Clark S, Elie M, Leste-Laserre T, Maire M, Gonzales D, Cannich A, Marsicano G, Cota D (2015) Cannabinoid type 1 (CB1) receptor in Sim1-expressing neurons regulate energy expenditure in male mice. Endocrinology 156:411–418CrossRefPubMedGoogle Scholar
  28. 28.
    Cavuoto P, McAinch AJ, Hatzinikolas G, Janovska A, Game P, Wittert GA (2007) The expression of receptors for endocannabinoids in human and rodent skeletal muscle. Biochem Biophys Res Comm 364:105–110CrossRefPubMedGoogle Scholar
  29. 29.
    Cavuoto P, McAinch AJ, Hatzinikolas G, Cameron-Smith D, Wittert GA (2007) Effects of cannabinoid receptors on skeletal muscle oxidative pathways. Mol Cell Endocrinol 267:63–69CrossRefPubMedGoogle Scholar
  30. 30.
    Chan O, Sherwin RS (2012) Hypothalamic regulation of glucose-stimulated insulin secretion. Diabetes 61:564–565CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Chen Z, Guo L, Zhang Y, Walzem RL, Pendergast JS, Printz R, Morris LC, Matafonova E, Sien X, Kang L, Coulon D, McGuinness OP, Niswender KD (2014) Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity. J Clin Invest 8:3391–3406CrossRefGoogle Scholar
  32. 32.
    Choi Y, Fujikawa T, Lee J, Reuter A, Kim KW (2013) Revisiting the ventral medial nucleus of the hypothalamus of the roles of SF-1 neurons in energy homeostasis. Fronti Neurosci 7:1–9Google Scholar
  33. 33.
    Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A (2007) Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 370:1706–1713CrossRefPubMedGoogle Scholar
  34. 34.
    Cluny NL, Vemuri VK, Chambers AP, Limebeer CL, Bedard H, Wood JT, Lutz B, Zimmer A, Parker LA, Makriyannis A, Sharkey KA (2010) A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents. Br J Pharmacol 161:629–642CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8:571–578CrossRefPubMedGoogle Scholar
  36. 36.
    Cota D, Marsicano G, Tschöp M, Grübler Y, Flachskamm C, Schubert M, Auer D, Thöne-ReineckeC Ortmann S, Cervino C, Linthorst A, Pasquali R, Lutz B, Stalla GK, Pagotto U (2003) Decreased fat mass in mice deficient for cannabinoid receptor 1 is due to decreased orexigenic drive and impaired adipocyte differentiation. J Clin Invest 112:423–431CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Cote M, Matias I, Lemieux I, Petrosino S, Almeras N, Despres JP, Di Marzo V (2007) Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes 31:692–699CrossRefGoogle Scholar
  38. 38.
    Coutts AA, Pertwee RG (1997) Inhibition by cannabinoid receptor agonists of acetylcholine release from guinea-pig myenteric plexus. Br J Pharmacol 121:1557–1566CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Craft R, Marusich JA, Wiley JL (2013) Sex differences in cannabinoid pharmacology: a reflection of differences in endocannabinoid system? Life Sci 19:476–481CrossRefGoogle Scholar
  40. 40.
    Crespillo A, Suárez J, Bermúdez-Silva FJ, Rivera P, Vida M, Alonso M, Palomino A, Lucena MA, Serrano A, Pérez-Martín M, Macias M, Fernández-Llébrez P, Rodríguez de Fonseca F (2011) Expression of the cannabinoid system in muscle. Effects of a high-fat diet and CB1 receptor blockade. Biochem J 433:175–185CrossRefPubMedGoogle Scholar
  41. 41.
    D’Eon TM, Pierce KA, Roix JJ, Tyler A, Chen H, Teixeiras SR (2008) Therole of adipocyte insulin resistance in the pathogenesis of obesity-related elevations in endocannabinoids. Diabetes 57:1262–1268CrossRefPubMedGoogle Scholar
  42. 42.
    Despres JP, Golay A, Sjostrom L (2005) Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 353:2121–2134CrossRefPubMedGoogle Scholar
  43. 43.
    Devane WA, Hanus L, Breuer A, Pertwee RG, Sevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949CrossRefPubMedGoogle Scholar
  44. 44.
    Di Marzo V, Goparajau SK, Wang L, Liu J, Batkai S, Jarai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G (2001) Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410:822–825CrossRefPubMedGoogle Scholar
  45. 45.
    Di Marzo V, De Petrocellis L (2010) Endocannabinoids as regulators of transient receptor potential (TRP) channels. A further opportunity to develop new endocannabinoid-based therapeutic drugs. Curr Med Chem 17:1430–1449CrossRefPubMedGoogle Scholar
  46. 46.
    Di Patrizio NV, Astarita G, Schwartz G, Li X, Piomelli D (2011) Endocanabinoid signal in the gut controls dietary fat intake. Proc Natl Acad Sci USA 108:12904–12908CrossRefGoogle Scholar
  47. 47.
    Di Patrizio NV, Piomelli D (2012) The thrifty lipids: endocannabinoids and the neural control of energy conservation. Trends in Neurosci 35:403–411CrossRefGoogle Scholar
  48. 48.
    Di Patrizio NV, Joslin A, Jung KM, Piomelli D (2013) Endocanabinoid signal in the gut mediates preference for dietary unsaturated fats. FASEB J 27:2513–2520CrossRefGoogle Scholar
  49. 49.
    Di Patrizio NV, Igarashi M, Narayanaswami V, Murray C, Gancayco J, Russell A, Jung KM, Piomelli D (2015) Fasting stimulates 2-AG biosynthesis in the small intestine: role of cholinergic pathways. Am J Physiol Regul Integr Comp Physiol 309:R805–R813CrossRefGoogle Scholar
  50. 50.
    Dhopeshwarkar A, Mackie K (2014) CB2 Cannabinoid receptors as a therapeutic target-what does the future hold? Mol Pharmacol 86:430–437CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Dodd GT, Mancini G, Lutz B, Luckman SM (2010) The peptide hemopressin acts through CB1 cannabinoid receptors to reduce food intake in rats and mice. J Neurosci 30:7369–7376CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Eckardt K, Sell H, Taube A, Koenen M, Platzbecker B, Cramer A, Horrighs A, Lehtonen M, Tennagels N, Eckel J (2009) Cannabinoid type 1 receptors in human skeletal muscle cells participate in the negative crosstalk between fat and muscle. Diabetologia 52:664–674CrossRefPubMedGoogle Scholar
  53. 53.
    Engeli S, Lehmann AC, Kaminski J, Hass V, Janke J, Zoerner AA, Luft FC, Tsikas D, Jordan J (2014) Influence of dietary fat intake on the endocannabinoid system in lean and obese subjects. Obesity 22:E70–E76CrossRefPubMedGoogle Scholar
  54. 54.
    Esposito I, Proto MC, Gazzerro P, Laezza C, Miele C, Alberobello AT, D’Esposito V, Beguinot F, Formisano P, Rifulco M (2008) The cannabinoid CB1 receptor antagonist rimonabant stimulates 2-Deoxyglucose uptake in skeletal muscle cells by regulating the expression of phosphatidylinositol-3-kinase. Mol Pharmacol 74:1678–1686CrossRefPubMedGoogle Scholar
  55. 55.
    Esposito G, Capoccia E, Turco F, Palumbo I, Lu J, Steardo A, Cuomo R, Sarnelli G, Steardo L (2014) Palmitoyethanolamide improves colon inflammation through an enteric glial/Toll like receptor 4-dependent PPAR-alpha activation. Gut 63:1300–1312CrossRefPubMedGoogle Scholar
  56. 56.
    Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, Guiot Y, Derrien M, Muccioli GG, Delzenne NM, de Vos WM, Cani PD (2013) Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci USA 110:9066–9071CrossRefPubMedGoogle Scholar
  57. 57.
    Ferrante C, Recinella L, Leone S, Chiavaroli A, Di Nisio C, Martinotti S, Mollica A, Macedonio G, Stefanucci A, Dvorácskó S, Tömböly C, De Petrocellis L, Vacca M, Brunetti L, Orlando G (2017) Anorexigenic effects induced by RVD-hemopressin(α) administration. Pharmacol Rep 69:1402–1407CrossRefPubMedGoogle Scholar
  58. 58.
    Fischer K, Ruiz HH, Jhun K, Finan B, Oberlin DJ, van der Heide V, Kalinovich AV, Petrovic N, Wolf Y, Clemmensen C, Shin AC, Divanovic S, Brombacher F, Glasmacher E, Keipert S, Jastroch M, Nagler J, Schramm KW, Medrikova D, Collden G, Woods SC, Herzig S, Homann D, Jung S, Nedergaard J, Cannon B, Tschöp MH, Müller TD, Buettner C (2017) Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis. Nat Med 23:623–630CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Fisette A, Tobin S, Decarie-Spain L, Bouyakdan K, Peyot ML, Madiraju M, Prentki M, Fulton S, Alquier T (2014) α/β-hydrolase domain 6 in the ventromedial hypothalamus controls energy metabolism flexibility. Cell Rep 17:1217–1226CrossRefGoogle Scholar
  60. 60.
    Fu J, Astarita G, Gaetani S, Kim J, Cravatt BJ, Mackie K, Piomelli D (2007) Food intake regulates oleoylethanolamide formation and degradation in the proximal small intestine. J Biol Chem 282:1518–1528CrossRefPubMedGoogle Scholar
  61. 61.
    Fu J, Di Patrizio NV, Guijarro A, Schwartz GJ, Li Gaetani S, Astarita G, Piomelli D (2011) Sympathetic activity controls fat-induced oleoylethanolamide signalling in small intestine. J Neurosci 31:5730–5736CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Fuss J, Steinle J, Bindila L, Auer MK, Kirchherr H, Lutz B, Gass P (2015) A runner’s high depends on cannabinoid receptors in mice. Proc Natl Acad Sci USA 112:13105–13108CrossRefPubMedGoogle Scholar
  63. 63.
    Gary-Bobo M, Elachouri G, Scatton B, Le Fur G, Oury-Donat F, Bensaid M (2006) The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits cell proliferation and increases markers of adipocyte maturation in cultured mouse 3T3 F442A preadipocytes. Mol Pharmacol 69:471–478CrossRefPubMedGoogle Scholar
  64. 64.
    Gary-Bobo M, Elachouri G, Gallas JF, Janiak P, Marini P, Ravinet-Trillou C, Chabbert M, Cruccioli N, Pfersdorff C, Roque C, Arnone M, Croci T, Soubrie P, Oury-Donat F, Maffrand JP, Scatton B, Lacheretz F, LeFur G, Herbert JM, Bensaid M (2007) Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology 46:122–129CrossRefPubMedGoogle Scholar
  65. 65.
    Gatta-Cherifi B, Matias I, Vallee M, Tabarin A, Marsicano G, Piazza PV, Cota D (2012) Simultaneous postprandial deregulation of the orexigenic endocannabinoid anandamide and anorexigenic peptide YY in obesity. Int J Obes 36:880–885CrossRefGoogle Scholar
  66. 66.
    Gatta-Cherifi B, Cota D (2016) New insights on the role of the endocannabinoid system in the regulation of energy balance. Int J Obes 40:210–219CrossRefGoogle Scholar
  67. 67.
    Geurts L, Everard A, Van Hul M, Essaghir A, Duparc T, Matamoros S, Plovier H, Castel J, Denis RG, Bergiers M, Druart C, Alhouayek M, Delzenne NM, Muccioli GG, Demoulin JB, Luquet S, Cani PD (2015) Adipose tissue NAPE-PLD control fat mass development by altering the browning process and gut microbiota. Nat Commun 6:1–15CrossRefGoogle Scholar
  68. 68.
    Gillum MP, Zhang D, Zhang XM, Erion DM, Jamison RA, Choi C, Dong J, Shanabrough M, Duenas HR, Frederick DW, Hsiao JJ, Horvath TL, Lo CM, Cline GW, Shulman GI (2008) N-acylphosphatidylethanolamine, a gu-derived circulating factor induced by fat ingestion, inhibits food intake. Cell 135:813–824CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Gomez R, Navarro M, Ferrer B, Trigo JM, Bilbao A, Del Arco IO, Cippielli A, Nava F, Piomelli D, Rodriguez de Fonseca F (2002) A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci 22:9612–9617CrossRefPubMedGoogle Scholar
  70. 70.
    Gutiérrez-Rodríguez A, Bonilla-Del Río I, Puente N, Gómez-Urquijo SM, Fontaine CJ, Egaña-Huguet J, Elezgarai I, Ruehle S, Lutz B, Robin LM, Soria-Gómez E, Bellocchio L, Padwal JD, van der Stelt M, Mendizabal-Zubiaga J, Reguero L, Ramos A, Gerrikagoitia I, Marsicano G, Grandes P (2018) Localization of the cannabinoid type-1 receptor in subcellular astrocyte compartments of mutant mouse hippocampus. Glia 66:1417–1431CrossRefPubMedGoogle Scholar
  71. 71.
    Gyires K, Zadori ZS (2016) Role of cannabinoids in gastrointestinal mucosa defense and inflammation. Curr Neuropharmacol 14:935–951CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Häring M, Enk V, Aparisi Rey A, Loch S, Ruiz de Azua I, Weber T, Bartsch D, Monory K, Lutz B (2015) Cannabinoid type-1 receptor signalling in central serotonergic neurons regulates anxiety-like behavior and sociability. Front Behav Neurosci 3:235Google Scholar
  73. 73.
    Heimann AS, Gomes I, Dale CS, Pagano RL, Gupta A, de Souza LL, Luchessi AD, Castro LM, Giorgi R, Rioli V, Ferro ES, Devi LA (2007) Hemopressin is an inverse agonist of CB1 cannabinoid receptors. Proc Natl Acad Sci USA 104:20588–20593CrossRefPubMedGoogle Scholar
  74. 74.
    Herling AW, Kilp S, Elvert R, Haschke G, Kramer W (2008) Increased energy expenditure contributes more to the body weight-reducing effect of rimonabant than reduced food intake in candy-fed Wistar rats. Endocrinology 149:2557–2566CrossRefPubMedGoogle Scholar
  75. 75.
    Herling AW, Kilp S, Juretschke HP, Neumann-Haefelin C, Gerl M, Kramer W (2008) Reversal of visceral adiposity in candy-diet fed female Wistar rats by the CB1 receptor antagonist rimonabant. Int J Obes 32:1363–1372CrossRefGoogle Scholar
  76. 76.
    Heyman E, Gamelin FX, Goekint M, Di Piscitelli F, Roelands B, Leclair E, Di Marzo V, Meeusen R (2012) Intense exercise increases circulating endocannabinoid and BDNF levels in humans-possible implications for reward and depression. Psychoneuroendocrinology 37:844–851CrossRefPubMedGoogle Scholar
  77. 77.
    Higgs S, Barber DJ, Cooper AJ, Terry P (2005) Differential effects of two cannabinoid receptor agonists on progressive ratio responding for food and free-feeding in rats. Behav Pharmacol 16:389–393CrossRefPubMedGoogle Scholar
  78. 78.
    Hinden L, Udi S, Drori A, Gammal A, Nemirovski A, Hadar R, Baraghitghy S, Permyakova A, Geron M, Cohen M, Tsytkin-Kirschenzweig A, Riahi Y, Leibowitz G, Nahmias Y, Priel A, Tam J (2018) Modulation of renal GLUT2 by the cannabinoid-1 receptor: implications for the treatment of diabetic nephrophaty. J Am Soc Nephrol 29:434–448CrossRefPubMedGoogle Scholar
  79. 79.
    Hons IM, Storr MA, Mackie K, Lutz B, Pittman QJ, Mawe GM, Sharkey KA (2012) Plasticity of mouse enteric synapses mediated through endocannabinoid and purinergic signalling. Neurogastroenterol Motil 24:e113–e124CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Hotamisligil G (2017) Inflammation, metaflammation and immunometabolic disorders. Nature 177:177–185CrossRefGoogle Scholar
  81. 81.
    Hu SS, Mackie K (2015) Distribution of the endocannabinoid system in the central nervous system. Handb Exp Pharmacol 231:59–93CrossRefPubMedGoogle Scholar
  82. 82.
    Huang H, McIntosh AL, Martin GG, Landrock D, Chung S, Landrock KK, Dangott LJ, Li S, Kier AB, Schroeder F (2016) FABP1: a novel hepatic endocannabinoid and cannabinoid binding protein. Biochemistry 55:5243–5255CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Huang L, Ramirez J, Frampton GA, Golden LE, Quinn MA, Pae HY, Horvat D, Liang L, DeMorrow S (2011) Anandamide exerts its antiproliferative actions on cholangiocarcinoma by activation of the GPR55 receptor. Lab Invest 91:1007–1017CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Hui X, Gu P, Zhang J, Nie T, Pan Y, Wu D, Feng T, Zhong C, Wang Y, Lam KS, Xu A (2015) Adiponectin enhances cold-induced browning of subcutaneous adipose tissue via promoting M2 macrophage proliferation. Cell Metab 22:279–290CrossRefPubMedGoogle Scholar
  85. 85.
    Izzo AA, Piscitelli F, Capasso R, Aviello G, Romano B, Borrelli F, Petrosino S, Di Marzo V (2009) Peripheal endocannabinoid dysregulation in obesity: relation to intestinal motility and energy processing induced by food deprivation and re-feeding. B J Pharmacol 158:451–461CrossRefGoogle Scholar
  86. 86.
    Izzo AA, Deutsch DG (2011) Unique pathway for anandamide synthesis and liver regeneration. Proc Natl Acad Sci USA 108:6339–6340CrossRefPubMedGoogle Scholar
  87. 87.
    Jamshidi N, Taylor DA (2001) Anandamiede administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol 134:1151–1154CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Jeffrey E, Berry R, Church CD, Yu S, Shook BA, Horsley V, Rosen ED, Rodeheffer MS (2014) Characterization of Cre recombinase models for the study of adipose tissue. Adipocyte 3:206–211CrossRefGoogle Scholar
  89. 89.
    Jenkin KA, McAinch AJ, Zhang Y, Kelly DK, Hryciw DH (2015) Elevated cannabinoid receptor 1 and G protein-coupled receptor 55 expression in proximal tubule cells and whole kidney exposed to diabetic conditions. Clin Exp Pharmacol Physiol 42:256–262CrossRefPubMedGoogle Scholar
  90. 90.
    Jeong W, Osei-Hyiaman D, Park O, Liu J, Batkai S, Mukhopadhyay P, Horiguchi N, Harvery-White J, Marsicano G, Lutz B, Gao B, Kunos G (2008) Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver. Cell Metab 7:227–235CrossRefPubMedGoogle Scholar
  91. 91.
    Jourdan T, Godlewski G, Cinar E, Bertola A, Szanda G, Liu J, Tam J, Han T, Mukhopadhayay B, Skarulis MC, Ju C, Aouadi M, Czech MP, Kunos G (2013) Activation of the Nlpr3 inflammasome in infiltrating macrophages by endocannabinoids mediate beta cell loss in type 2 diabetes. Nat Med 19:1132–1140CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Jourdan T, Szanda G, Rosenberg AZ, Tam J, Earley BJ, Godlewski G, Cinar E, Liu Z, Liu J, Ju C, Pacher P, Kunos G (2014) Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephrophaty. Proc Natl Acad Sci USA 24:5420–5428CrossRefGoogle Scholar
  93. 93.
    Jourdan T, Szanda G, Cinar E, Godlewski G, Holovac DJ, Park JK, Nicoloro S, Shen Y, Liu J, Rosenberg AZ, Liu Z, Czech MP, Kunos G (2017) Developmental role of macrophage cannabinoid-1 receptor signalling in type 2 diabetes. Diabetes 66:994–1007CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Jourdan T, Nicoloro S, Zhou Z, Shen Y, Liu J, Goffey NJ, Cinar E, Godlewski G, Gao V, Aouadi M, Czech MP, Kunos G (2017) Decreasing CB1 receptor signalling in Kupffer cells improve insulin sensitivity in obese mice. Mol Metab 6:1517–1528CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Jung KM, Clapper JR, Fu J, D’Agostino G, Guijarro A, Thongkham D, Avanesian A, Astarita G, DiPatrizio NV, Frontini A, Cinti S, Diano S, Piomelli D (2012) 2-Arachidonoylglyceraol signaling in forebrain regulates systemic energy metabolism. Cell Metab 15:299–310CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Kaczocha LM, Glaser ST, Deutsch DG (2009) Identification of intracellular carriers for the endocannabinoid anandamide. Proc Natl Acad Sci USA 106:6375–6380CrossRefPubMedGoogle Scholar
  97. 97.
    Kaczocha M, Vivieca S, Sun J, Glaser ST, Deutsch DG (2012) Fatty acid binding proteins transport N-acylethanolamines to nuclear receptors and are targets of endocannabinoid transport inhibitors. J Biol Chem 287:3415–3424CrossRefPubMedGoogle Scholar
  98. 98.
    Kaczocha M, Rebecchi MJ, Ralph BP, Teng YHG, Berger WT, Galbavy W, Elmes MW, Glaser ST, Wang L, Rizzo RC, Deutsch DG, Ojima I (2014) Inhibition of fatty acid binding protein elevates brain anandamide levels and produces analgesia. PLoS One 9:e94200CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Karaliota S, Siafaka-Kapadai A, Gontinou C, Psarra K, Mavri-Vavayanni M (2009) Anadamide increases the differentiation of rat adipocytes and causes PPARgamma and CB1 receptor upregulation. Obesity 17:1830–1838CrossRefPubMedGoogle Scholar
  100. 100.
    Kirkham TC, WilliamsCM Fezza F, Di Marzo V (2002) Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol 136:550–557CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Koch M, Varela L, Kim JG, Kim JD, Hernandez-Nuno F, Simonds SE, Castorena CM, Vienna CR, Elmquist JK, Morozov YM, Rakic P, Bechmann I, Cowley MA, Szigeti-Buck K, Dietrich MO, Gao XB, Diano S, Horvath TL (2015) Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519:45–50CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Kozak KR, Crews BC, Morrow JD, Wang LH, Ma YH, Weinander R, Jakobsson PJ, Marnett LJ (2002) Metabolism of the endocannabinoids, 2-arachidonoylglycerol and anandamide, into prostaglandin, thromboxane, and prostacyclin glycerol ester and ethanolamides. J Biol Chem 277:44877–44885CrossRefPubMedGoogle Scholar
  103. 103.
    Krowicki ZK, Moerschbaecher JM, Winsauer PJ, Digavalli SV, Hornby PJ (1999) Δ9-tetrahydrocannabinol inhibits gastric motility in the rat through cannabinoid CB1 receptors. Eur J Pharmacol 371:187–196CrossRefPubMedGoogle Scholar
  104. 104.
    Larkins RG, Dunlop ME (1992) The link between hyperglycaemia and diabetic nephrophaty. Diabetologia 35:499–504CrossRefPubMedGoogle Scholar
  105. 105.
    Lee KY, Russell SJ, Ussar S, Boucher J, Vernochet C, Mori MA, Smyth G, Rourk M, Cederquist C, Rosen ED, Kahn BB, Kahn CR (2013) Lessons on conditional gene targeting in mouse adipose tissue. Diabetes 62:864–874CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Leone S, Ferrante C, Recinella L, Chiavaroli A, Mollica A, Tömböly C, Stefanucci A, Dimmito MP, Dvorácskó S, Verratti V, De Petrocellis L, Orlando G, Brunetti L (2018) Effects of RVD-hemopressin (α) on feeding and body weight after standard or cafeteria diet in rats. Neuropeptides 72:38–46CrossRefPubMedGoogle Scholar
  107. 107.
    Leung D, Saghatelian A, Simon GM, Cravatt BF (2006) Inactivation of N-acyl phosphatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids. Biochemistry 45:4720–4726CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Li Y, Kim J (2015) Neuronal expression of CB2 cannabinoid receptor mRNAs in the mouse hippocampus. Neuroscience 311:253–267CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Liedhegner ES, Vogt CD, Sem DS, Cunninham CW, Hillard CJ (2014) Sterol carrier protein-2: binding protein for endocannabinoids. Mol Neurobiol 50:149–158CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Lim JC, Lim SK, Han HJ, Park SH (2010) Cannabinoid receptor 1 mediates palmitic acid-induced apoptosis via endoplasmic reticulum stress in human renal proximal tubular cells. J Cell Physiol 225:654–663CrossRefPubMedGoogle Scholar
  111. 111.
    Lim JC, Lim SK, Park MJ, Kim GY, Han HJ, Park SH (2011) Cannabinoid receptor 1 mediates high glucose-induced apoptosis via endoplasmic reticulum stress in primary cultured rat mesangial cells. Am J Physiol Renal Physiol 301:F179–F188CrossRefPubMedGoogle Scholar
  112. 112.
    Lindborg KA, Teachey MK, Jacob S, Henriksen EJ (2010) Effects of in vitro antagonism of endocannabinoid-1 receptors on the glucose transport system in normal and insulin-resistant rat skeletal muscle. Diabetes Obes Metab 12:722–730CrossRefPubMedGoogle Scholar
  113. 113.
    Liu J, Batkai S, Pacher P, Harvey-White J, Wagner JA, Cravatt BF, Gao B, Kunos G (2003) Lipopolysaccharide induces anandamide synthesis in macrophages via CD14/MAPK/phosphoinositide 3-kinase/NF-kB independently of platelet-activating factor. J Biol Chem 278:45034–45039CrossRefPubMedGoogle Scholar
  114. 114.
    Liu YL, Connoley IP, Wilson CA, Stock MJ (2005) Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lep (ob)/Lep(ob) mice. Int J Obes 29:183–187CrossRefGoogle Scholar
  115. 115.
    Liu J, Wang L, Harvey-White J, Osei-Hyiaman D, Razdan R, Gong Q, Chan AC, Zhou Z, Huang BX, Kim H, Kunos G (2006) A biosynthetic pathway for anandamide. Proc Natl Acad Sci USA 103:13345–13350CrossRefPubMedGoogle Scholar
  116. 116.
    Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175–184CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR (2007) Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 56:16–23CrossRefPubMedGoogle Scholar
  118. 118.
    Luo Z, Ma L, Zhao Z, He H, Yang D, Feng X, Ma S, Chen X, Zhu T, Cao T, Liu D, Nilius B, Huang Y, Yan Z, Zhu Z (2012) TRPV1 activation improves exercise endurance and energy metabolism through PGC-1α upregulation in mice. Cell Res 22:551–564CrossRefPubMedGoogle Scholar
  119. 119.
    Maccioni P, Pes D, Carai MAM, Gessa GL, Colombo G (2008) Supression by the cannabinoid receptor antagonist, rimonabant, of the reinforcing and motivational properties of a chocolate-flavoured beverage in rats. Behav Pharmacol 19:197–209CrossRefPubMedGoogle Scholar
  120. 120.
    Malenczyk K, Jazurek M, Keimpema E, Silvestri C, Janikiewicz J, Mackie K, Di Marzo V, Redowicz MJ, Harkany T, Dobrzyn A (2013) CB1 cannabinoid receptors couple to focal adhesion kinase to control insulin release. J Biol Chem 288:32685–32699CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Malenczyk K, Keimpema E, Piscitelli F, Calvigioni D, Björklund P, Mackie K, Di Marzo V, Hökfelt TG, Dobrzyn A, Harkany T (2015) Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture. Proc Natl Acad Sci USA 112:E6185–E6194CrossRefPubMedGoogle Scholar
  122. 122.
    Marinelli S, Pacioni S, Bisogno T, Di Marzo V, Prince DA, Huguenard JR, Bacci A (2008) The endocannabinoid 2-arachidonoylglycerol is responsible for the slow self-inhibition in neocortical neurons. J Neurosci 28:13532–13541CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Marinelli S, Pacioni S, Cannich A, Marsicano A, Bacci A (2009) Self-modulation of neocortical pyramidal neurons by endocannabinoids. Nat Neurosci 12:1488–1490CrossRefPubMedGoogle Scholar
  124. 124.
    Maroso M, Szabo GG, Kim HK, Alexander A, Bui AD, Lee SH, Lutz B, Soltesz I (2016) Cannabinoid control of learning and memory through HCN channels. Neuron 89:1059–1073CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Markopoulos F, Rokini D, Gire DH, Murthy VN (2012) Functional properties of cortical feedback projections to the olfactory bulb. Neuron 76:1175–1188CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Martin GG, Chung S, Landrock D, Landrock KK, Huang H, Dangott LJ, Peng X, Kaczocha M, Seeger DR, Murphy EJ, Golovko MY, Kier AB, Schroeder F (2016) FABP1 gene ablation impacts brain endocannabinoid system in male mice. J Neurochem 138:407–422CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Martin GG, Chung S, Landrock D, Landrock K, Dangott LJ, Peng X, Kaczocha M, Murphy EJ, Kier AB, Schroeder F (2016) Female mice are resistant to Fabp1 gene ablation induced alterations in brain endocannabinoid levels. Lipids 51:1007–1020CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Martin GG, Landrock D, Chung S, Dangott LJ, McIntosh AL, Mackie JT, Kier AB, Schroeder F (2017) Loss of fatty acid binding protein-1 alters the hepatic endocannabinoid system response to a high fat diet. J Lip Res 58:2114–2126CrossRefGoogle Scholar
  129. 129.
    Martin GG, Landrock D, Chung S, Dangott LJ, Seeger DR, Murphy EJ, Golovko MY, Kier AB, Schroeder F (2017) Fabp1 gene ablation inhibits high fat diet-induced increase in brain endocannabinoids. J Neurochem 140:294–306CrossRefPubMedGoogle Scholar
  130. 130.
    Martin GG, Landrock D, Dangott LJ, McIntosh AL, Kier AB, Schroeder F (2018) Human liver fatty acid binding FABP1 T94A variant, nonalcohol fatty liver disease, and hepatic endocannabinoid system. Lipids 53:27–40CrossRefPubMedGoogle Scholar
  131. 131.
    Massa F, Monory K (2006) Endocannabinoids and the gastrointestinal tract. J Endocrinol Invest 29:47–57PubMedGoogle Scholar
  132. 132.
    Matias I, Gonthier MP, Orlando P, Martiadis V, De Petrocellis L, Cervino C, Petrosino S, Hoareau L, Festy F, Pasquali R, Roche R, Maj M, Pagotto U, Monteleone P, Di Marzo V (2006) Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab 91:3171–3180CrossRefPubMedGoogle Scholar
  133. 133.
    Matias I, Di Marzo V (2007) Endocannabinoids and the control of energy balance. Trends Endocrinol Metab 18:27–37CrossRefPubMedGoogle Scholar
  134. 134.
    Matias I, Gatta-Cherifi B, Tabarin A, Clark S, Leste-Lasserre T, Marsicano G, Piazza PV, Cota D (2012) Endocannabinoids measurement in human saliva as potential biomarker of obesity. PLoS One 7:e42399CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Marks J, Carvou NJ, Debnam ES, Srai SK, Unwin RJ (2003) Diabetes increases facilitative glucose uptake and GLUT2 expression at the rat proximal tubule brush border membrane. J Physiol 553:137–145CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Martins C, Genelhu V, Pimentel M, Celoria B, Mangia R, Aveta T, Silvestri C, Di Marzo V, Francischetti E (2015) Circulating endocannabinoids and the polymorphism 385C > A in fatty acid amide hydrolase (FAAH) Gene may identify the obesity phenotype related to cardiometabolic risk: a study conducted in a Brazilian population of complex interethnic admixture. PLoS ONE 10:e0142728CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Matsuda LA, Lolait SJ, Browntein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564CrossRefPubMedGoogle Scholar
  138. 138.
    Mattace Raso G, Satoro A, Russo R, Simeoli R, Paciello O, Di Carlo C, Diano S, Calignano A, Meli R (2014) Palmitoyethanolamide prevents metabolic alterations and restores leptin sensitivity in ovariectomized rats. Endocrinology 155:1291–1301CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    McIntosh AL, Huang H, Storey SM, Landrock K, Landrock D, Petrescu AD, Gupta S, Atshaves BP, Kier AB, Schroeder F (2014) Human FABP1 T94A variant impacts fatty acid metabolism and PPAR-activation in cultured human female hepatocytes. Am J Physiol Gastrointest Liver Physiol 307:G164–G176CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    McIntosh AL, Huang H, Landrock D, Martin G, Li S, Kier AB, Schroeder F (2018) Impact of Fabp1 gene ablation on uptake and degradation of endocannabinoids in mouse hepatocytes. Lipids 53:561–580CrossRefPubMedGoogle Scholar
  141. 141.
    McIntosh AL, Martin GG, Huang H, Landrock D, Kier AB, Schroeder F (2018) Delta-9-tetrahydrocannabinol induces endocannabinoid accumulation in mouse hepatocytes: antagonism by Fabp1 gene ablation. J Lipid Res 59:646–657CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almong S, Martin BR, Compton DR, Pertwee RG, Griffin G, Bayewitch M, Barg J, Vogel Z (1992) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Phamacol 50:83–90CrossRefGoogle Scholar
  143. 143.
    Mendizabal-Zubiaga J, Melser S, Bernard G, Ramos A, Reguero L, Arrabal S, Elezgarai I, Gerrikagoitia I, Suarez J, Rodiguez De Fonseca F, Puene N, Marsicano G, Grandes P (2016) Cannabinoid CB1 receptor are localized in striated muscle mitochondria and regulate mitochondrial respiration. Front Physiol 7:1–10CrossRefGoogle Scholar
  144. 144.
    Metna-Laurent M, Marsicano G (2015) Rising stars: modulation of brain functions by astroglial type-1 cannabinoid receptors. Glia 63:353–364CrossRefPubMedGoogle Scholar
  145. 145.
    Monory K, Massa F, Egertová M, Eder M, Blaudzun H, Westenbroek R, Kelsch W, Jacob W, Marsch R, Ekker M, Long J, Rubenstein JL, Goebbels S, Nave KA, During M, Klugmann M, Wölfel B, Dodt HU, Zieglgänsberger W, Wotjak CT, Mackie K, Elphick MR, Marsicano G, Lutz B (2006) The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51:455–466CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Moreira FA, Grieb M, Lutz B (2009) Central side-effects of therapies based on CB1 cannabinoid receptor agonists and antagonists: focus on anxiety and depression. Best Pract Res Clin Endocrinol Metab 23:133–144CrossRefPubMedGoogle Scholar
  147. 147.
    Muccioli GG (2010) Endocannabinoid biosynthesis and inactivation, from simple to complex. Drug Discov Today 15:474–483CrossRefPubMedGoogle Scholar
  148. 148.
    Muccioli GG, Naslain D, Bäckhed F, Reigstad CS, Lambert DM, Delzenne NM, Cani PD (2010) The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol 6:1–15CrossRefGoogle Scholar
  149. 149.
    Mukhopadhyay B, Cinar R, Yin S, Liu J, Tam J, Godlewski G, Harvey-White J, Mordi I, Cravatt BF, Lotersztajn S, Gao B, Yuan Q, Schuebel K, Goldman D, Kunos G (2011) Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB1) receptors in the regenerating liver. Proc Natl Acad Sci USA 108:6323–6328CrossRefPubMedGoogle Scholar
  150. 150.
    Mullican SE, Tomaru T, Gaddis CA, Peed LC, Sundaram A, Lazar MA (2013) A novel adipose-specific gene deletion model demonstrates potential pitfalls of existing methods. Mol Endocrinol 27:127–134CrossRefPubMedGoogle Scholar
  151. 151.
    Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65CrossRefPubMedGoogle Scholar
  152. 152.
    Nam DH, Lee MH, Kin JE, Song HK, Kang YS, Lee JE, Kim HW, Cha JJ, Hyun YY, Kim SH, Han KH, Han JY, Cha DR (2012) Blockade of cannabinoid receptor 1 improves insulin resistance, lipid metabolism, and diabetic nephropathy in db/db mice. Endocrinology 153:1387–1396CrossRefPubMedGoogle Scholar
  153. 153.
    Naughton SS, Mathai ML, Hryciw DH, McAinch AJ (2013) Fatty acid modulation of the endocannabinoid system and the effect on food intake and metabolism. Int J Endocrinol 2013:1–11CrossRefGoogle Scholar
  154. 154.
    Nguyen KD, Qiu Y, Cui X, Goh YP, Mwangi J, David T, Mukundan L, Brombacher F, Locksley RM, Chawla A (2011) Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480:104–108CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Njoo C, Agarwal N, Lutz B, Kuner R (2015) The cannabinoid receptor CB1 interacts with the WAVE1 complex and plays a role in actin dynamics and structural plasticity in neurons. PLoS Biol 13:e1002286CrossRefPubMedPubMedCentralGoogle Scholar
  156. 156.
    Nyiri G, Szabadits E, Cserep C, Mackie K, Shigemoto R, Freund TF (2005) GABAB and CB1 cannabinoid receptor expression identified two types of septal cholinergic neurons. Eur J Neurosci 21:3034–3042CrossRefPubMedGoogle Scholar
  157. 157.
    Oddi S, Fezza F, Pasquariello N, D’Agostino A, Catanzaro G, De Simone C, Rapino C, Finazzi-Agro A, Macarrone (2009) Molecular identification of albumin and Hsp70 as cytosolic anandamide-binding proteins. Chem Biol 16:624–632CrossRefPubMedGoogle Scholar
  158. 158.
    Osei-Hyiaman D, DePetrillo M, Patcher P, Liu J, Radaeva S, Bakai S, Harvey-White K, Mackie K, Offertaler L, Wang L, Kunos G (2005) Endocannabinoids activation at hepatic CB1 receptor stimulates fatty acid synthesis and contributes to diet induced obesity. J Clin Invest 115:1298–1305CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Osei-Hyiamann D, Liu J, Zhou L, Godlewski G, Harvey-White J, Joeng W, Batkai S, Marsicano G, Lutz B, Buettner C, Kunos G (2008) Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. J Clin Invest 118:3160–3169CrossRefGoogle Scholar
  160. 160.
    Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R (2006) The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev 27:73–100CrossRefPubMedGoogle Scholar
  161. 161.
    Parsons LH, Hurd YL (2015) Endocannabinoid signalling in reward and addiction. Nat Rev Neurosci 16:579–594CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Pekala P, Kawakami M, Vine M, Lane MD, Cerami A (1983) Studies of insulin resistance in adipocytes induced by macrophage mediator. J Exp Med 157:1360–1365CrossRefPubMedGoogle Scholar
  163. 163.
    Peng XE, Wu YL, Lu QQ, Hu ZJ, Lin X (2012) Two genetic variants in FABP1 and susceptibility to non-alcoholic fatty liver disease in a Chinese population. Gene 500:54–58CrossRefPubMedGoogle Scholar
  164. 164.
    Pertwee RG (2001) Cannabinoids in the gastrointestinal tract. Gut 48:859–867CrossRefPubMedPubMedCentralGoogle Scholar
  165. 165.
    Pertwee RG (2005) Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sci 76:1307–1324CrossRefPubMedGoogle Scholar
  166. 166.
    Piazza V, Cota D, Marsicano G (2017) The CB1 receptor as the cornerstone of exostasis. Neuron 93:1252–1274CrossRefPubMedGoogle Scholar
  167. 167.
    Pirzgalska RM, Seixas E, Seidman JS, Link VM, Martinez Sanchez N, Mahu I, Mendes R, Gres V, Kubasova N, Morris I, Arus BA, Larabee CM, Vasques M, Tortosa F, Sousa AL, Anandan S, Tranfield E, Hahn MK, Iannacone M, Spann NJ, Glass CK, Domingos A (2017) Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat Med 23:1309–1318PubMedCrossRefGoogle Scholar
  168. 168.
    Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J (2006) Effec of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: IO, North America: a randomized controlled trial. JAMA 295:761–775CrossRefPubMedGoogle Scholar
  169. 169.
    Quarta C, Bellocchio L, Mancini G, Mazza R, Cervino C, Braulke LJ, Fekete C, Latorre R, Nanni C, Bucci M, Clemens LE, Heldmaier G, Watanabe M, Leste-Lassere T, Maitre M, Tedesco L, Fanelli F, Reuss S, Klaus S, Srivastava RK, Monory K, Valerio A, Grandis A, De Giorgio R, Pasquali R, Nisoli E, Cota D, Lutz B, Marsicano G, Pagotto U (2010) CB1 signalling in forebrain and sympathetic neurons is a key determinant of endocannabinoid actions on energy balance. Cell Metab 11:273–285CrossRefPubMedGoogle Scholar
  170. 170.
    Qiu Y, Nguyen KD, Odergaard JI, Cui X, Tian X, Locksley RM, Palmiter RD, Chawla A (2014) Eosinophils and type 2 cytokine signalling in macrophages orchestrate development of functional beige fat. Cell 157:1292–1308CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Ramírez-López MT, Vázquez M, Bindila L, Lomazzo E, Hofmann C, Blanco RN, Alén F, Antón M, Decara J, Ouro D, Orio L, Suarez J, Lutz B, Rodríguez de Fonseca F, Gómez de Heras R (2016) Exposure to a highly caloric palatable diet during progestational and gestational periods affects hypothalamic and hippocampal endocannabinoid levels at birth and induces adiposity and anxiety-like behaviors in male rat offspring. Front Behav Neurosci 9:339CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    Ramírez-López MT, Vázquez M, Bindila L, Lomazzo E, Hofmann C, Blanco RN, Alén F, Antón M, Decara J, Arco R, Ouro D, Orio L, Suárez J, Lutz B, Gómez de Heras R, Rodríguez de Fonseca F (2016) Maternal caloric restriction implemented during the preconceptional and pregnancy period alters hypothalamic and hippocampal endocannabinoid levels at birth and induces overweight and increased adiposity at adulthood in male rat offspring. Front Behav Neurosci 10:208PubMedPubMedCentralGoogle Scholar
  173. 173.
    Rao RR, Long JZ, White JP, Svensson KJ, Lou J, Lokurkar J, Jedrchowski MP, Ruas JL, Wrann CD, Lo JC, Camera DM, Lachey J, Gygi S, Seehra J, Hawley JA, Spiegelman BM (2014) Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 157:1279–1291CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrie P (2004) CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Int J Obes Relat Metab Disord 28:640–648CrossRefPubMedGoogle Scholar
  175. 175.
    Recinella L, Chiavaroli A, Ferrante C, Mollica A, Macedonio G, Stefanucci Dimmito MP, Dvorácskó S, Tömböly C, Brunetti L, Orlando G, Leone S (2018) Effects of central RVD-hemopressin(α) administration on anxiety, feeding behavior and hypothalamic neuromodulators in the rat. Pharmacol Rep 70:650–657CrossRefPubMedGoogle Scholar
  176. 176.
    Roche R, Hoareau L, Bes-Houtmann S, Gonthier MP, Laborde C, Braon JF, Haffaf Y, Cesari M, Festy F (2007) Presence of the cannabinoid receptors, CB1 and CB2, in human and subcutaneous adipocytes. Histochem Cell Biol 4:1–11Google Scholar
  177. 177.
    Rodriguez de Fonseca F, Navarro M, Gomez R, Escudero L, Nava F, Fu J, Murillo-Rodriguez E, Giuffrida A, LoVerme J, Gaetani S, Katuria S, Gall C, Piomelli D (2001) An anorexic lipid mediator regulated by feeding. Nature 414:189–196CrossRefGoogle Scholar
  178. 178.
    Rousseaux C, Thuru X, Gelot A, Barnich N, Neut C, Dubuquoy L, Dubuquoy C, Merour E, Geboes K, Chamaillard M, Ouwehand A, Leyer G, Carcano D, Colombel JF, Ardid D, Desreumaux P (2007) Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med 13:35–37CrossRefPubMedGoogle Scholar
  179. 179.
    Rubino T, Parolaro D (2011) Sexually dimorphic effects of cannabinoid compounds on emotion and cognition. Front Behav Neurosci 5:64CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Ruiz de Azua I, Mancini G, Srivastava RK, Rey AA, Cardinal P, Tedesco L, Zingaretti CM, Sassmann A, Quarta C, Schwitter C, Conrad A, Wettschureck N, Vemuri VK, Makriyannis A, Hartwig J, Mendez-Lago M, Bindila L, Monory K, Giordano A, Cinti S, Marsicano G, Offermanns S, Nisoli E, Pagotto U, Cota D, Lutz B (2017) Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages. J Clin Invest 127:4148–4162CrossRefPubMedPubMedCentralGoogle Scholar
  181. 181.
    Salem N, Pawlosky R, Wegher B, Hibbeln J (1999) In vivo conversion of linoleic acid to arachidonic acid in human adults. Prostaglandins Leukot Esent Fatty acids 60:407–410CrossRefGoogle Scholar
  182. 182.
    Sarzani R, Bordicchia M, Marcucci P, Bedetta S, Santini S, Giovagnoli A, Scappini L, Minardi D, Muzzonigro G, Dessi-Fulgheri P, Rappelli A (2009) Altered pattern of cannabinoid type 1 receptor expression in adipose tissue of dysmetabolic and overweight patients. Metabolism 58:361–367CrossRefPubMedGoogle Scholar
  183. 183.
    Sassman A, Offermanns S, Wettschureck N (2010) Tamoxifen-inducible Cre-mediated recombination in adipocytes. Genes 48:618–625Google Scholar
  184. 184.
    Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF, For the RIO-Diabetes Study Group (2006) Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 368:1660–1672CrossRefPubMedGoogle Scholar
  185. 185.
    Sharkey KA, Wiley JW (2016) The role of the endocannabinoid system in the brain-gut axis. Gastroenterology 151:252–266CrossRefPubMedPubMedCentralGoogle Scholar
  186. 186.
    Sharma MK, Machhi J, Murumkar P, Yadav MR (2018) New role of phenothiazine derivatives as peripherally acting CB1 receptor antagonizing anti-obesity agents. Sci Rep 8:1–17CrossRefGoogle Scholar
  187. 187.
    Siegmund SV, Qian T, de Minicis S, Harvey-White J, Kunos G, Vinod KY, Hungund B, Scwabe RF (2007) The endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells via mitochondrial reactive oxygen species. FASEB J 21:2798–2806CrossRefPubMedGoogle Scholar
  188. 188.
    Simon GM, Cravatt BF (2010) Characterization of mice lacking candidate N-acyl ethanolamide biosynthetic enzymes provides evidence for multiple pathways that contribute to endocannabinoid production in vivo. Mol BioSyst 6:1411–1418CrossRefPubMedPubMedCentralGoogle Scholar
  189. 189.
    Simon V, Cota D (2017) Endocannabinoids and metabolism: past, present and future. Eur J Endocrinol 176:R309–R324CrossRefPubMedGoogle Scholar
  190. 190.
    Sipe JC, Scott TM, Murray S, Harismendy O, Simon GM, Cravatt BF, Waalen J (2010) Biomarkers of endocannabinoid system activation in severe obesity. PLoS One 5:e8792CrossRefPubMedPubMedCentralGoogle Scholar
  191. 191.
    Silvestri C, Di Marzo V (2013) The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disordes. Cell Metab 17:475–490CrossRefPubMedGoogle Scholar
  192. 192.
    Solinas M, Goldberg SR (2005) Motivational effects of cannabinoids and opioids on food reinforcement depend on simultaneous activation of cannabinoid and opioid systems. Neuropsychopharmacology 30:2035–2040CrossRefPubMedGoogle Scholar
  193. 193.
    Solinas M, Justinova Z, Goldberg SR, Tanda G (2006) Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats. J Neurochem 98:408–419CrossRefPubMedGoogle Scholar
  194. 194.
    Soria-Gomez E, Matias I, Rueda-Orozco PE, Cisneros M, Petrosino S, Navarro L, Di Marzo V, Prospero-Garcia O (2007) Pharmacological enhancement of the endocannabinoid system in the nucleus accumbens shell stimulates food intake and increased c-Fos expression in the hypothalamus. Br J Pharmacol 151:1109–1116CrossRefPubMedPubMedCentralGoogle Scholar
  195. 195.
    Soria-Gómez E, Bellocchio L, Reguero L, Lepousez G, Martin C, Bendahmane M, Ruehle S, Remmers F, Desprez T, Matias I, Wiesner T, Cannich A, Nissant A, Wadleigh A, Pape HC, Chiarlone AP, Quarta C, Verrier D, Vincent P, Massa F, Lutz B, Guzmán M, Gurden H, Ferreira G, Lledo PM, Grandes P, Marsicano G (2014) The endocannabinoid system control food intake via olfactory processes. Nat Neurosci 17:407–415CrossRefPubMedGoogle Scholar
  196. 196.
    Sparling PB, Giuffrida A, Piomelli D, Rosskopf L, Dietrich A (2003) Exercise activates the endocannabinoid system. NeuroReport 14:2209–2211CrossRefPubMedGoogle Scholar
  197. 197.
    Starowicz KM, Cristino L, Matias I, Capasso R, Izzo AA, Di Marzo V (2008) Endocannabinoid dysregulation in the pancreas and adipose tissue of mice fed with hig-fat diet. Obesity 16:553–565CrossRefPubMedGoogle Scholar
  198. 198.
    Storr MA, Bashashati M, Hirota C, Vemuri VK, Keenan CM, Duncan M, Lutz B, Mackie K, Makriyannis A, Macnaughton WK, Sharkey KA (2010) Differential effects of CB1 neutral antagonists and inverse agonists on gastrointestinal motility in mice. Neurogastroenterol Motil 22:787–796CrossRefPubMedPubMedCentralGoogle Scholar
  199. 199.
    Suarez J, Rivera P, Arrabal S, Crespillo A, Serrano A, Baixeras E, Pavon FJ, Cifuentes M, Nogueiras R, Ballesteros J, Dieguez C, Rodriguez de Fonseca F (2014) Oleoylethanolamide enhances β-adrenergic-mediated thermogenesis and white-to-brown adipocyte phenotype in epididymal white adipose tissue in rats. Dis Model Mech 7:129–141CrossRefPubMedGoogle Scholar
  200. 200.
    Suarez-Zamorano N, Fabbiano S, Chevalier C, Stojanovic O, Colin DJ, Stevanovic A, Veyrat-Durebex C, Tarallo V, Rigo D, Germain S, Ilievska M, Montet X, Seimbille Y, Hapfelmeier S, Trajkovski M (2015) Microbiota depletion promotes browning of white adipose tissue and reduces obesity. Nat Med 12:1497–1501CrossRefGoogle Scholar
  201. 201.
    Sumithran P, Prendergast LA, Dlebridge E, Purcell K, Shulkes A, Kriketos A, Proietoo J (2011) Long-term persistence of hormonal adaptations to weight loss. N Engl J Med 365:1597–1604CrossRefPubMedGoogle Scholar
  202. 202.
    Tam J, Vemuri K, Liu J, Batkai S, Mukhopadhyay B, Godlewski G, Osei-Hyiaman D, Ohnuma S, Ambudkar SV, Pickel J, Makriyannis A, Kunos G (2010) Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest 120:2953–2966CrossRefPubMedPubMedCentralGoogle Scholar
  203. 203.
    Tam J, Cinar R, Liu J, Godlewski G, Wesley D, Jourdan T, Szanda G, Mukhopadhyay B, Chedester L, Liow JS, Innis RB, Cheng K, Rice KC, Deschamps JR, Chrovat RJ, McElroy JF, Kunos G (2012) Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab 16:167–179CrossRefPubMedGoogle Scholar
  204. 204.
    Tam J, Szanda G, Drori A, Liu Z, Cinar R, Kashiwaya Y, Reitman ML, Kunos G (2017) Peripheral cannabinoid-1 receptor blockade restores hypothalamic leptin signalling. Mol Metab 6:1113–1125CrossRefPubMedPubMedCentralGoogle Scholar
  205. 205.
    Tedesco L, Valerio A, Cervino C, Cardile A, Pagano C, Vettor R, Pasquali R, Carruba MO, Marsicano G, Lutz B, Pagotto U, Nisoli E (2008) Cannabinoid type 1 receptor blockade promotes mitochondrial biogenesis through endothelial nitric oxide synthase expression in white adipocytes. Diabetes 57:2028–2036CrossRefPubMedPubMedCentralGoogle Scholar
  206. 206.
    Tedesco L, Valerio A, Dossena M, Cardile A, Ragni M, Pagano C, Pagotto U, Carruba MO, Vettor R, Nisoli E (2010) Cannabinoid receptor stimulation impairs mitochondrial biogenesis in mouse white adipose tissue, muscle, and liver: the role of eNOS, p38 MAPK, and AMPK pathways. Diabetes 59:2826–2836CrossRefPubMedPubMedCentralGoogle Scholar
  207. 207.
    Thorens B (2010) Central control of glucose homeostasis: the brain-endocrine pancreas axis. Diabetes Metab 36:S45–S49CrossRefPubMedGoogle Scholar
  208. 208.
    Tolson KP, Genmelli T, Meyer D, Yazdani U, Kozlitina J, Zinn AR (2014) Inducible neuronal ablation of Smi1 in adult mice causes hyperphagic obesity. Endocrinology 155:2436–2444CrossRefPubMedPubMedCentralGoogle Scholar
  209. 209.
    Tontonoz P, Hu E, Spiegelman BM (1994) Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 79:1147–1156CrossRefPubMedGoogle Scholar
  210. 210.
    Troy-Fioramonti S, Demizieux K, Gresti J, Muller T, Verges B, Degrace P (2015) Acute activation of cannabinoid receptors by anandamide reduces gastrointestinal motility and improves postprandial glycemia in mice. Diabetes 64:808–818CrossRefPubMedGoogle Scholar
  211. 211.
    Udi S, Hinden L, Earley B, Drori A, Reuveni N, Hadar R, Gammal A, Cinar R, Nemirovski A, Tam J (2017) Proximal tubular cannabinoid-1 receptor regulates obesity-induced CKD. J Am Soc Nephrol 28:3518–3532CrossRefPubMedPubMedCentralGoogle Scholar
  212. 212.
    Vallée M, Vitiello S, Bellocchio L, Hébert-Chatelain E, Monlezun S, Martin-Garcia E, Kasanetz F, Baillie GL, Panin F, Cathala A, Roullot-Lacarrière V, Fabre S, Hurst DP, Lynch DL, Shore DM, Deroche-Gamonet V, Spampinato U, Revest JM, Maldonado R, Reggio PH, Ross RA, Marsicano G, Piazza PV (2014) Pregnenolone can protect the brain from cannabis intoxication. Science 343:94–98CrossRefPubMedPubMedCentralGoogle Scholar
  213. 213.
    Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S, For the RIO-Europe Sudy Group (2005) 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. Lancet 365:1389–1397CrossRefPubMedGoogle Scholar
  214. 214.
    Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N, Makryannis A, Piomelli D, Davison JS, Marnett LJ, Di Marzo V, Pitman QJ, Patel KD, Sharkey KA (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310:329–332CrossRefPubMedGoogle Scholar
  215. 215.
    Verty AN, McGregor IS, Mallet PE (2005) Paraventricular hypothalamic CB1 cannabinoid receptors are involved in the feeding stimulatory effects of d9-tetrahydrocannabinol. Neuropharmacology 49:1101–1109CrossRefPubMedGoogle Scholar
  216. 216.
    Verty AN, Stefanidis A, McAinch AJ, Hryciw DH, Oldfield B (2015) Anti-obesity effect of the CB2 receptor agonist JWH-015 in diet-induced obese mice. PLoS One 10:e0140592CrossRefPubMedPubMedCentralGoogle Scholar
  217. 217.
    Ward SJ, Dykstra LA (2005) The role of CB1 receptors in sweet versus fat reinforcement: effect of CB1 receptor deletion, CB1 receptor antagonism (SR141716A) and CB1 receptor agonism (CP-55940). Behav Pharmacol 16:381–388CrossRefPubMedGoogle Scholar
  218. 218.
    Wolf Y, Boura-Halfon S, Cortese N, Haimon Z, Sar Shalom H, Kuperman Y, Kalchenko V, Brandis A, David E, Segal-Hayoun Y, Chappell-Maor L, Yaron A, Jung S (2017) Brown-adipsoe-tissue macrophages control tissue innervation and homeostatic energy expenditure. Nat Immunol 18:665–674CrossRefPubMedPubMedCentralGoogle Scholar
  219. 219.
    Xu X, Grijalva A, Skowronski A, van Eijk M, Serlie MJ, Ferrante AW (2013) Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classical activation. Cell Metab 18:816–830CrossRefPubMedPubMedCentralGoogle Scholar
  220. 220.
    Yan ZC, Liu DY, Zhang LL, Shen CY, Ma QL, Cao TB, Wang LJ, Nie H, Zidek W, Tepel M, Zhu ZM (2007) Exercise reduces adipose issue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor-δ. Biochem Biophys Res Commun 354:427–433CrossRefPubMedGoogle Scholar
  221. 221.
    Yoshida R, Ohkuri T, Jyotaki M, Yasuo T, Horio N, Yasumatsu K, Sanematsu K, Shigemura N, Yamamoto T, Margolskee RF, Ninomiya Y (2010) Endocannabinoids selectively enhance sweet taste. Proc Natl Acad Sci USA 107:935–939CrossRefPubMedGoogle Scholar
  222. 222.
    Yuece B, Sibaev A, Broedl UC, Marsicano G, Göke B, Lutz B, Allescher HD, Storr M (2007) Cannabinoid type 1 receptor modulates intestinal propulsion by an attenuation of intestinal motor responses within the myenteric part of the peristaltic reflex. Neurogastroenterol Motil 19:744–753CrossRefPubMedGoogle Scholar
  223. 223.
    Zelber-Sagi S, Azar S, Nemirovski A, Webb M, Halpern Z, Shibolet O, Tam J (2017) Serum levels of endocannabinoids are independently associated with nonalcoholic fatty liver disease. Obesity 25:94–101CrossRefPubMedGoogle Scholar
  224. 224.
    Zhu C, Solorzano C, Sahar S, Realini N, Fung E, Sassone-Corsi P, Piomelli D (2011) Proinflammatory stimuli control N-acylphosphatidylethanolamine-specific phospholipase D expression in macrophages. Mol Pharmacol 79:786–792CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.German Resilience Center (DRZ) and Institute of Physiological ChemistryUniversity Medical Center of the Johannes Gutenberg University MainzMainzGermany

Personalised recommendations