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01.03.2008 | Article

Presence of functional cannabinoid receptors in human endocrine pancreas

verfasst von: F. J. Bermúdez-Silva, J. Suárez, E. Baixeras, N. Cobo, D. Bautista, A. L. Cuesta-Muñoz, E. Fuentes, P. Juan-Pico, M. J. Castro, G. Milman, R. Mechoulam, A. Nadal, F. Rodríguez de Fonseca

Erschienen in: Diabetologia | Ausgabe 3/2008

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Abstract

Aims/hypothesis

We examined the presence of functional cannabinoid receptors 1 and 2 (CB1, CB2) in isolated human islets, phenotyped the cells producing cannabinoid receptors and analysed the actions of selective cannabinoid receptor agonists on insulin, glucagon and somatostatin secretion in vitro. We also described the localisation on islet cells of: (1) the endocannabinoid-producing enzymes N-acyl-phosphatidyl ethanolamine-hydrolysing phospholipase D and diacylglycerol lipase; and (2) the endocannabinoid-degrading enzymes fatty acid amidohydrolase and monoacyl glycerol lipase.

Methods

Real-time PCR, western blotting and immunocytochemistry were used to analyse the presence of endocannabinoid-related proteins and genes. Static secretion experiments were used to examine the effects of activating CB1 or CB2 on insulin, glucagon and somatostatin secretion and to measure changes in 2-arachidonoylglycerol (2-AG) levels within islets. Analyses were performed in isolated human islets and in paraffin-embedded sections of human pancreas.

Results

Human islets of Langerhans expressed CB1 and CB2 (also known as CNR1 and CNR2) mRNA and CB1 and CB2 proteins, and also the machinery involved in synthesis and degradation of 2-AG (the most abundant endocannabinoid, levels of which were modulated by glucose). Immunofluorescence revealed that CB1 was densely located in glucagon-secreting alpha cells and less so in insulin-secreting beta cells. CB2 was densely present in somatostatin-secreting delta cells, but absent in alpha and beta cells. In vitro experiments revealed that CB1 stimulation enhanced insulin and glucagon secretion, while CB2 agonism lowered glucose-dependent insulin secretion, showing these cannabinoid receptors to be functional.

Conclusions/interpretation

Together, these results suggest a role for endogenous endocannabinoid signalling in regulation of endocrine secretion in the human pancreas.

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Devane WA, Dysarz FA 3rd, Johnson M, Melvin LS, Howlett AC (1998) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34:605–613

Devane WA, Hanus L, Breuer A et al (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949PubMedCrossRef

Stella N, Schweitzer P, Piomelli D (1992) A second endogenous cannabinoid that modulates long-term potentiation. Nature 388:773–778

Mechoulam R, Ben-Shabat S, Hanus L et al (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90PubMedCrossRef

Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4:873–884PubMedCrossRef

Di Marzo V, Matias I (2005) Endocannabinoid control of food intake and energy balance. Nat Neurosci 8:585–589PubMedCrossRef

Cota D, Marsicano G, Tschop M et al (2003) The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 112:423–431PubMedCrossRef

Gomez R, Navarro M, Ferrer B et al (2002) A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci 22:9612–9617PubMed

Kirkham TC, Williams CM, 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 136:550–557PubMedCrossRef

10.

Di Marzo V, Goparaju SK, Wang L et al (2001) Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410:822–825PubMedCrossRef

11.

Pavon FJ, Bilbao A, Hernandez-Folgado L et al (2006) Antiobesity effects of the novel in vivo neutral cannabinoid receptor Antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole–LH 21. Neuropharmacology 51:358–366PubMedCrossRef

12.

Osei-Hyiaman D, DePetrillo M, Pacher P et al (2005) Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 115:1298–1305PubMedCrossRef

13.

Engeli S, Bohnke J, Feldpausch M et al (2005) Activation of the peripheral endocannabinoid system in human obesity. Diabetes 54:2838–2843PubMedCrossRef

14.

Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S, RIO-Europe Study 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 365:1389–1397PubMedCrossRef

15.

Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J, RIO-North America Study Group (2006) 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. JAMA 295:761–775PubMedCrossRef

16.

Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF, RIO-Diabetes Study Group (2006) Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 368:1660–1672PubMedCrossRef

17.

Juan-Pico P, Fuentes E, Bermúdez-Silva FJ et al (2006) Cannabinoid receptors regulate Ca2+ signals and insulin secretion in pancreatic β-cells. Cell Calcium 39:155–162PubMedCrossRef

18.

Bermudez-Silva FJ, Serrano A, Diaz-Molina FJ et al (2006) Activation of cannabinoid CB1 receptors induces glucose intolerance in rats. Eur J Pharmacol 531:282–284CrossRef

19.

Bermudez-Silva FJ, Suarez J, Sanchez Vera I et al (2007) Role of cannabinoid CB₂ receptors in glucose homeostasis in rats. Eur J Pharmacol 565:207–211PubMedCrossRef

20.

Matias I, Gonthier MP, Orlando P et al (2006) Regulation, function and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrin Metab 91:3171–3180CrossRef

21.

Ricordi C, Lacy PE, Finke EH, Olack BJ, Scharp DW (1988) Automated method for isolation of human pancreatic islets. Diabetes 37:413–420PubMedCrossRef

22.

Cuesta-Munoz AL, Briones RM, Mellado-Gil JM et al (2005) Internal assessment of a novel islet isolation facility in Spain. Transplant Proc 37:3404–3406PubMedCrossRef

23.

Hansson AC, Bermudez-Silva FJ, Malinen H et al (2007) Genetic impairment of frontocortical endocannabinoid degradation and high alcohol preference. Neuropsychopharmacology 32:117–126PubMedCrossRef

24.

Hillard CJ, Manna S, Greenberg MJ et al (1999) Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). J Pharmacol Exp The 289:1427–1433

25.

Huffman JW, Liddle J, Yu S et al (1999) 3-(1′,1′-Dimethylbutyl)-1-deoxy-delta8-THC and related compounds: synthesis of selective ligands for the CB2 receptor. Bioorg Med Chem 7:2905–2914PubMedCrossRef

26.

Gatley SJ, Lan R, Pyatt B, Gifford AN, Volkow ND, Makriyannis A (1997) Binding of the non-classical cannabinoid CP 55,940, and the diarylpyrazole AM251 to rodent brain cannabinoid receptors. Life Sci 61:PL191–PL197CrossRef

27.

Pettit DAD, Harrison MP, Olson JM et al (1998) Immunohistochemical localization of the neural cannabinoid receptor in rat brain. J Neurosci Methods 51:391–402

28.

Egertová M, Elphick MR (2000) Localisation of cannabinoid receptors in the rat brain using antibodies to the intracellular C-terminal tail of CB1. J Comp Neurol 422:159–171PubMedCrossRef

29.

Ashton JC, Zheng Y, Liu P et al (2004) Immunohistochemical characterisation and localisation of cannabinoid CB1 receptor protein in the rat vestibular nucleus complex and the effects of unilateral vestibular deafferentation. Brain Res 1021:264–271PubMedCrossRef

30.

Roche R, Hoareau L, Bes-Houtmann S et al (2006) Presence of the cannabinoid receptors, CB1 and CB2, in human omental and subcutaneous adipocytes. Histochem Cell Biol 126:177–187PubMedCrossRef

31.

Van Sickle MD, Duncan M, Kingsley PJ et al (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310:329–332PubMedCrossRef

32.

Gong JP, Onaivi ES, Ishiguro H et al (2006) Cannabinoid CB2 receptors: Immunohistochemical localization in rat brain. Brain Res 1071:10–23PubMedCrossRef

33.

Dinh TP, Carpenter D, Leslie FM et al (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci U S A 99:10819–10824PubMedCrossRef

34.

Cravatt BF, Giang DK, Mayfield SP et al (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83–87PubMedCrossRef

35.

Giuffrida A, Rodriguez de Fonseca F, Nava F, Loubet-Lescoulie P, Piomelli D (2000) Elevated circulating levels of anandamide after administration of the transport inhibitor, AM404. Eur J Pharmacol 408:161–168PubMedCrossRef

36.

Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R (2005) The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev 27:73–100PubMedCrossRef

37.

Venance L, Piomelli D, Glowinski J, Giaume C (1995) Inhibition by anandamide of gap junctions and intercellular calcium signalling in striatal astrocytes. Nature 376:590–594PubMedCrossRef

38.

Ravier MA, Guldenagel M, Charollais A et al (2005) Loss of connexin36 channels alters beta-cell coupling, islet synchronization of glucose-induced Ca2+ and insulin oscillations, and basal insulin release. Diabetes 54:1798–1807PubMedCrossRef

39.

Singh V, Brendel MD, Zacharias S et al (2007) Characterization of somatostatin receptor subtype-specific regulation of insulin and glucagon secretion: an in vitro study on isolated human pancreatic islets. J Clin Endocrinol Metab 92:673–680PubMedCrossRef

40.

Tabarin A, Diz-Chaves Y, Carmona M del C et al (2005) Resistance to diet-induced obesity in mu-opioid receptor-deficient mice: evidence for a “thrifty gene”. Diabetes 54:3510–3516PubMedCrossRef

41.

Cota D, Tschop MH, Horvath TL, Levine AS (2006) Cannabinoids, opioids and eating behavior: the molecular face of hedonism? Brain Res Rev 51:85–107PubMedCrossRef

Titel: Presence of functional cannabinoid receptors in human endocrine pancreas
verfasst von: F. J. Bermúdez-Silva
J. Suárez
E. Baixeras
N. Cobo
D. Bautista
A. L. Cuesta-Muñoz
E. Fuentes
P. Juan-Pico
M. J. Castro
G. Milman
R. Mechoulam
A. Nadal
F. Rodríguez de Fonseca
Publikationsdatum: 01.03.2008
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 3/2008
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-007-0890-y

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Presence of functional cannabinoid receptors in human endocrine pancreas