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DOI: 10.1055/s-0030-1255119
© Georg Thieme Verlag KG Stuttgart · New York
Upregulation of the Expression of Inflammatory and Angiogenic Markers in Human Adipocytes by a Synthetic Cannabinoid, JTE-907
Publication History
received 12.01.2010
accepted 31.05.2010
Publication Date:
05 July 2010 (online)
Abstract
Inflammation in adipose tissue is a characteristic of obesity and the metabolic syndrome. It is suggested that the endocannabinoid system is involved in the regulation of inflammatory and angiogenic processes within the tissue. Human subcutaneous preadipocytes (Zen Bio) were used as the source of human preadipocytes or adipocytes. Gene expression was examined by RT-PCR and real-time PCR. The secretion of inflammation-related proteins was determined by an ELISA array. In experiments on adipocytes treated at day 14 post-differentiation, JTE-907, a synthetic cannabinoid, upregulated the expression of key inflammatory markers – IL-6, MCP-1 and IL-1β – and angiogenic factors – VEGF and ANGPTL4 – at 10 μM after 20 h of treatment, having also increased the expression of TRPV1 at 10 μM. JTE-907 showed no effect after 4 h. The ELISA array showed a 2.6-fold increase in IL-6 protein release. The effect of JTE-907 was inhibited by AM251 (CB1 antagonist), and partially by arachidonyl serotonin (TRPV1 and FAAH antagonist). The CB2 antagonist, AM630, partially upregulated the effect of JTE-907. Preadipocytes fed 14 days after 100% confluence exhibited downregulation of CB1, MCP-1, and IL-1β, 20 h after having been exposed to JTE-907. CB1 and TRPV1 receptors participate in the regulation of several inflammatory and angiogenic factors in human adipocytes, indicating their potential value as targets for the treatment of disorders related to obesity.
Key words
endocannabinoid system - inflammation - human adipose tissue - obesity - TRPV1 - CB1
References
- 1 Alexander SP, Mathie A, Peters JA. Guide to Receptors and Channels (GRAC), 3rd ed. Br J Pharmacol. 2008; 153 (S 02) S1-S209
- 2 Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992; 258 1946-1949
- 3 Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, Pertwee RG, Griffin G, Bayewitch M, Barg J, Vogel Z. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995; 50 83-90
- 4 Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun. 1995; 215 89-97
- 5 Brown AJ. Novel cannabinoid receptors. Br J Pharmacol. 2007; 152 567-575
- 6 Pertwee RG. GPR55: a new member of the cannabinoid receptor clan?. Br J Pharmacol. 2007; 152 984-986
- 7 Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov. 2004; 3 771-784
- 8 Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006; 27 73-100
- 9 Roche R, Hoareau L, Bes-Houtmann S, Gonthier MP, Laborde C, Baron JF, Haffaf Y, Cesari M, Festy F. Presence of the cannabinoid receptors, CB1 and CB2, in human omental and subcutaneous adipocytes. Histochem Cell Biol. 2006; 126 177-187
- 10 Geppetti P, Trevisani M. Activation and sensitisation of the vanilloid receptor: role in gastrointestinal inflammation and function. Br J Pharmacol. 2004; 141 1313-1320
- 11 Spoto B, Fezza F, Parlongo G, Battista N, Sgro E, Gasperi V, Zoccali C, Maccarrone M. Human adipose tissue binds and metabolizes the endocannabinoids anandamide and 2-arachidonoylglycerol. Biochimie. 2006; 88 1889-1897
- 12 Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993; 365 61-65
- 13 Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N, Makriyannis A, Piomelli D, Davison JS, Marnett LJ, Di Marzo V, Pittman QJ, Patel KD, Sharkey KA. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005; 310 329-332
- 14 Iwamura H, Suzuki H, Ueda Y, Kaya T, Inaba T. In vitro and in vivo pharmacological characterization of JTE-907, a novel selective ligand for cannabinoid CB2 receptor. J Pharmacol Exp Ther. 2001; 296 420-425
- 15 Maekawa T, Nojima H, Kuraishi Y, Aisaka K. The cannabinoid CB2 receptor inverse agonist JTE-907 suppresses spontaneous itch-associated responses of NC mice, a model of atopic dermatitis. Eur J Pharmacol. 2006; 542 179-183
- 16 Ueda Y, Miyagawa N, Matsui T, Kaya T, Iwamura H. Involvement of cannabinoid CB(2) receptor-mediated response and efficacy of cannabinoid CB(2) receptor inverse agonist, JTE-907, in cutaneous inflammation in mice. Eur J Pharmacol. 2005; 520 164-171
- 17 Ueda Y, Miyagawa N, Wakitani K. Involvement of cannabinoid CB2 receptors in the IgE-mediated triphasic cutaneous reaction in mice. Life Sci. 2007; 80 414-419
- 18 Di Marzo V. Targeting the endocannabinoid system: to enhance or reduce?. Nat Rev Drug Discov. 2008; 7 438-455
- 19 Szallasi A, Cortright DN, Blum CA, Eid SR. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat Rev Drug Discov. 2007; 6 357-372
- 20 Deveaux V, Cadoudal T, Ichigotani Y, Teixeira-Clerc F, Louvet A, Manin S, Nhieu JT, Belot MP, Zimmer A, Even P, Cani PD, Knauf C, Burcelin R, Bertola A, Le Marchand-Brustel Y, Gual P, Mallat A, Lotersztajn S. Cannabinoid CB2 receptor potentiates obesity-associated inflammation, insulin resistance and hepatic steatosis. PLoS One. 2009; 4 e5844
- 21 Di Marzo V. The endocannabinoid system in obesity and type 2 diabetes. Diabetologia. 2008; 51 1356-1367
- 22 Di Marzo V, Despres JP. CB1 antagonists for obesity – what lessons have we learned from rimonabant?. Nat Rev Endocrinol. 2009; 5 633-638
- 23 Rinaldi-Carmona M, Barth F, Heaulme M, Shire D, Calandra B, Congy C, Martinez S, Maruani J, Neliat G, Caput D, Ferrara P, Soubrie P, Breliere JC, Lefur G. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 1994; 350 240-244
- 24 Wexler DJ, Hu FB, Manson JE, Rifai N, Meigs JB. Mediating effects of inflammatory biomarkers on insulin resistance associated with obesity. Obes Res. 2005; 13 1772-1783
- 25 Yudkin JS, Juhan-Vague I, Hawe E, Humphries SE, di Minno G, Margaglione M, Tremoli E, Kooistra T, Morange PE, Lundman P, Mohamed-Ali V, Hamsten A. Low-grade inflammation may play a role in the etiology of the metabolic syndrome in patients with coronary heart disease: the HIFMECH study. Metabolism. 2004; 53 852-857
- 26 Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. 2004; 92 347-355
- 27 Rasouli N, Kern PA. Adipocytokines and the metabolic complications of obesity. J Clin Endocrinol Metab. 2008; 93 S64-S73
- 28 Shah A, Mehta N, Reilly MP. Adipose inflammation, insulin resistance, and cardiovascular disease. J Parenter Enteral Nutr. 2008; 32 638-644
- 29 Trayhurn P, Wood IS. Signalling role of adipose tissue: adipokines and inflammation in obesity. Biochem Soc Trans. 2005; 33 1078-1081
- 30 Sugamura K, Sugiyama S, Nozaki T, Matsuzawa Y, Izumiya Y, Miyata K, Nakayama M, Kaikita K, Obata T, Takeya M, Ogawa H. Activated endocannabinoid system in coronary artery disease and antiinflammatory effects of cannabinoid 1 receptor blockade on macrophages. Circulation. 2009; 119 28-36
- 31 Yao X, Garland CJ. Recent developments in vascular endothelial cell transient receptor potential channels. Circ Res. 2005; 97 853-863
- 32 Wang B, Wood IS, Trayhurn P. Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes. Pflugers Arch. 2007; 455 479-492
- 33 Wang B, Jenkins JR, Trayhurn P. Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: integrated response to TNF-alpha. Am J Physiol Endocrinol Metab. 2005; 288 E731-E740
- 34 Wang B, Trayhurn P. Acute and prolonged effects of TNF-alpha on the expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture. Pflugers Arch. 2006; 452 418-427
- 35 Maione S, De Petrocellis L, de Novellis V, Moriello AS, Petrosino S, Palazzo E, Rossi FS, Woodward DF, Di Marzo V. Analgesic actions of N-arachidonoyl-serotonin, a fatty acid amide hydrolase inhibitor with antagonistic activity at vanilloid TRPV1 receptors. Br J Pharmacol. 2007; 150 766-781
- 36 WHO. . Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser. 2000; 894 (i–xii) 1-253
- 37 Pertwee RG. Pharmacological actions of cannabinoids. Handb Exp Pharmacol. 2005; 1-51
- 38 Pertwee RG. Cannabinoid pharmacology: the first 66 years. Br J Pharmacol. 2006; 147 (S 01) S163-S171
- 39 Nogueiras R, Veyrat-Durebex C, Suchanek PM, Klein M, Tschop J, Caldwell C, Woods SC, Wittmann G, Watanabe M, Liposits Z, Fekete C, Reizes O, Rohner-Jeanrenaud F, Tschop MH. Peripheral, but not central, CB1 antagonism provides food intake-independent metabolic benefits in diet-induced obese rats. Diabetes. 2008; 57 2977-2991
- 40 Dahlman I, Kaaman M, Olsson T, Tan GD, Bickerton AS, Wahlen K, Andersson J, Nordstrom EA, Blomqvist L, Sjogren A, Forsgren M, Attersand A, Arner P. A unique role of monocyte chemoattractant protein 1 among chemokines in adipose tissue of obese subjects. J Clin Endocrinol Metab. 2005; 90 5834-5840
- 41 de Mello VD, Kolehmainen M, Schwab U, Mager U, Laaksonen DE, Pulkkinen L, Niskanen L, Gylling H, Atalay M, Rauramaa R, Uusitupa M. Effect of weight loss on cytokine messenger RNA expression in peripheral blood mononuclear cells of obese subjects with the metabolic syndrome. Metabolism. 2008; 57 192-199
- 42 Skurk T, Mack I, Kempf K, Kolb H, Hauner H, Herder C. Expression and secretion of RANTES (CCL5) in human adipocytes in response to immunological stimuli and hypoxia. Horm Metab Res. 2009; 41 183-189
- 43 Fruhbeck G. Overview of adipose tissue and its role in obesity and metabolic disorders. Methods Mol Biol. 2008; 456 1-22
- 44 Wozniak SE, Gee LL, Wachtel MS, Frezza EE. Adipose tissue: the new endocrine organ? A review article. Dig Dis Sci. 2009; 54 1847-1856
- 45 Smid SD, Bjorklund CK, Svensson KM, Heigis S, Revesz A. The endocannabinoids anandamide and 2-arachidonoylglycerol inhibit cholinergic contractility in the human colon. Eur J Pharmacol. 2007; 575 168-176
- 46 Fioravanti B, De Felice M, Stucky CL, Medler KA, Luo MC, Gardell LR, Ibrahim M, Malan TP, Yamamura HI, Ossipov MH, King T, Lai J, Porreca F, Vanderah TW Jr,. Constitutive activity at the cannabinoid CB1 receptor is required for behavioral response to noxious chemical stimulation of TRPV1: antinociceptive actions of CB1 inverse agonists. J Neurosci. 2008; 28 11593-11602
- 47 Motter AL, Ahern GP. TRPV1-null mice are protected from diet-induced obesity. FEBS Lett. 2008; 582 2257-2262
- 48 Zhang LL, Yan Liu D, Ma LQ, Luo ZD, Cao TB, Zhong J, Yan ZC, Wang LJ, Zhao ZG, Zhu SJ, Schrader M, Thilo F, Zhu ZM, Tepel M. Activation of transient receptor potential vanilloid type-1 channel prevents adipogenesis and obesity. Circ Res. 2007; 100 1063-1070
- 49 Landsman RS, Makriyannis A, Deng H, Consroe P, Roeske WR, Yamamura HI. AM630 is an inverse agonist at the human cannabinoid CB1 receptor. Life Sci. 1998; 62 PL109-PL113
- 50 Ross RA, Brockie HC, Stevenson LA, Murphy VL, Templeton F, Makriyannis A, Pertwee RG. Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656, and AM630. Br J Pharmacol. 1999; 126 665-672
- 51 Hoareau L, Buyse M, Festy F, Ravanan P, Gonthier MP, Matias I, Petrosino S, Tallet F, d’Hellencourt CL, Cesari M, Di Marzo V, Roche R. Anti-inflammatory effect of palmitoylethanolamide on human adipocytes. Obesity (Silver Spring). 2009; 17 431-438
- 52 Villanueva A, Yilmaz SM, Millington WR, Cutrera RA, Stouffer DG, Parsons LH, Cheer JF, Feleder C. Central cannabinoid 1 receptor antagonist administration prevents endotoxic hypotension affecting norepinephrine release in the preoptic anterior hypothalamic area. Shock. 2009; 32 614-620
- 53 Nilsson O, Fowler CJ, Jacobsson SO. The cannabinoid agonist WIN 55,212-2 inhibits TNF-alpha-induced neutrophil transmigration across ECV304 cells. Eur J Pharmacol. 2006; 547 165-173
- 54 Marchalant Y, Rosi S, Wenk GL. Anti-inflammatory property of the cannabinoid agonist WIN-55212-2 in a rodent model of chronic brain inflammation. Neuroscience. 2007; 144 1516-1522
- 55 Kimball ES, Schneider CR, Wallace NH, Hornby PJ. Agonists of cannabinoid receptor 1 and 2 inhibit experimental colitis induced by oil of mustard and by dextran sulfate sodium. Am J Physiol Gastrointest Liver Physiol. 2006; 291 G364-G371
- 56 Cencioni MT, Chiurchiu V, Catanzaro G, Borsellino G, Bernardi G, Battistini L, Maccarrone M. Anandamide suppresses proliferation and cytokine release from primary human T-lymphocytes mainly via CB2 receptors. PLoS One. 2010; 5 e8688
- 57 Vercelli CA, Aisemberg J, Billi S, Cervini M, Ribeiro ML, Farina M, Franchi AM. Anandamide regulates lipopolysaccharide-induced nitric oxide synthesis and tissue damage in the murine uterus. Reprod Biomed Online. 2009; 18 824-831
- 58 Chung S, Lapoint K, Martinez K, Kennedy A, Boysen Sandberg M, McIntosh MK. Preadipocytes mediate lipopolysaccharide-induced inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes. Endocrinology. 2006; 147 5340-5351
- 59 Isakson P, Hammarstedt A, Gustafson B, Smith U. Impaired preadipocyte differentiation in human abdominal obesity: role of Wnt, tumor necrosis factor-alpha, and inflammation. Diabetes. 2009; 58 1550-1557
- 60 Wang B, Wood IS, Trayhurn P. Hypoxia induces leptin gene expression and secretion in human preadipocytes: differential effects of hypoxia on adipokine expression by preadipocytes. J Endocrinol. 2008; 198 127-134
- 61 Wang B, Wood IS, Trayhurn P. PCR arrays identify metallothionein-3 as a highly hypoxia-inducible gene in human adipocytes. Biochem Biophys Res Commun. 2008; 368 88-93
Correspondence
Dr. P. González-Muniesa
Department of Nutrition
Food sciences
Physiology and Toxicology
University of Navarra
31008 Pamplona
Navarra
Spain
Phone: +34/94/8425 600 (ext. 6650)
Fax: +34/94/8425 649
Email: pgonmun@unav.es