Cannabinoid Receptor-1 Blockade Attenuates Acute pancreatitis in Obesity by An adiponectin Mediated Mechanism

  • Nicholas J. Zyromski
  • Abhishek Mathur
  • Henry A. Pitt
  • Terence E. Wade
  • Sue Wang
  • Deborah A. Swartz-Basile
  • Andrew D. Prather
  • Keith D. Lillemoe
2008 SSAT Poster Presentation Manuscript



Obesity is a risk factor for increased severity of acute pancreatitis. Adipocytes produce adiponectin, an anti-inflammatory molecule that is paradoxically decreased in the setting of obesity. We have shown that adiponectin concentration inversely mirrors the severity of pancreatitis in obese mice. Cannabinoid receptor CB-1 blockade increases circulating adiponectin concentration. We, therefore, hypothesize that blockade of CB-1 would increase adiponectin and attenuate pancreatitis severity.


Forty lean (C57BL/6J) and 40 obese (LepDb) mice were studied. Half of the mice in each strain received intraperitoneal injection of the CB-1 antagonist rimonabant (10 mg/kg daily for 7 days); the others received vehicle. Pancreatitis was induced by intraperitoneal injection of cerulein (50 μg/g hourly ×6). Pancreatitis severity was determined by histology. Pancreatic chemokine and proinflammatory cytokine concentrations were measured by ELISA.


Rimonabant treatment significantly increased circulating adiponectin concentration in obese mice (p < 0.03 vs. vehicle). After induction of pancreatitis, obese mice treated with rimonabant had significantly decreased histologic pancreatitis (p < 0.001), significantly lower pancreatic tissue levels of monocyte chemoattractant protein-1 (p = 0.03), tumor necrosis factor-α (p < 0.001), interleukin-6 (p < 0.001), and myeloperoxidase (p = 0.006) relative to vehicle-treated animals.


In obese mice, cannabinoid receptor CB-1 blockade with rimonabant attenuates the severity of acute pancreatitis by an adiponectin-mediated mechanism.


Pancreatitis Cannabinoid Adiponectin Obesity 


  1. 1.
    Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 2006;295(13):1549–1555. doi:10.1001/jama.295.13.1549.PubMedCrossRefGoogle Scholar
  2. 2.
    Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999;116(6):1413–1419. doi:10.1016/S0016-5085(99)70506-8.PubMedCrossRefGoogle Scholar
  3. 3.
    Kistorp C, Faber J, Galatius S, Gustafsson F, Frystyk J, Flyvbjerg A, Hildebrandt P. Plasma adiponectin, body mass index, and mortality in patients with chronic heart failure. Circulation 2005;112(12):1756–1762. doi:10.1161/CIRCULATIONAHA.104.530972.PubMedCrossRefGoogle Scholar
  4. 4.
    Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N, Arita Y, Okamoto Y, Shimomura I, Hiraoka H, Nakamura T, Funahashi T, Matsuzawa Y. Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol 2003;23(1):85–89. doi:10.1161/01.ATV.0000048856.22331.50.PubMedCrossRefGoogle Scholar
  5. 5.
    Mathur A, Megan M, Lu D, Al-Azzawi HH, Swartz-Basile DA, Saxena R, Zyromski NJ, Nakeeb A, Pitt HA. Nonalcoholic fatty pancreas disease. HPB 2007;9(4):312–318. doi:10.1080/13651820701504157.PubMedCrossRefGoogle Scholar
  6. 6.
    Zyromski NJ, Gowda GAN, Mathur A, Swartz-Basile DA, Pitt HA, Raftery D. Metabolomics of the fatty pancreas: implicating fat in pancreatic pathology. Pancreas 2007;35(4):439.CrossRefGoogle Scholar
  7. 7.
    Zyromski NJ, Mathur A, Yancey K, Gripe JT, Walker JJ, Lu D, Swartz-Basile DA, Lillemoe KD, Pitt HA. A murine model of obesity implicates the adipokine milieu in the pathogenesis of severe acute pancreatitis. Am J Physiol Gastrointest Liver Physiol 2008;295:G552–G558. doi:10.1152/ajpgi.90278.2008.PubMedCrossRefGoogle Scholar
  8. 8.
    Segersvard R, Sylvan M, Herrington M, Larsson J, Permert J. Obesity increases the severity of acute experimental pancreatitis in the rat. Scand J Gastroenterol 2001;36(6):658–663. doi:10.1080/003655201750163213.PubMedCrossRefGoogle Scholar
  9. 9.
    Suazo-Barahona J, Carmona-Sanchez R, Robles-Diaz G, Milke-Garcia P, Vargas-Vorackova F, Uscanga-Dominguez L, Pelaez-Luna M. Obesity: a risk factor for severe acute biliary and alcoholic pancreatitis. Am J Gastroenterol 1998;93(8):1324–1328.PubMedGoogle Scholar
  10. 10.
    Papachristou GI, Papachristou DJ, Avula H, Slivka A, Whitcomb DC. Obesity increases the severity of acute pancreatitis: performance of APACHE-O score and correlation with the inflammatory response. Pancreatology 2006;6(4):279–285.PubMedCrossRefGoogle Scholar
  11. 11.
    Martinez J, Johnson CD, Sanchez-Paya J, de Madaria E, Robles-Diaz G, Perez-Mateo M. Obesity is a definitive risk factor of severity and mortality in acute pancreatitis: an updated meta-analysis. Pancreatology 2006;6(3):206–209. doi:10.1159/000092104.PubMedCrossRefGoogle Scholar
  12. 12.
    Tsai CJ. Is obesity a significant prognostic factor in acute pancreatitis? Dig Dis Sci 1998;43(10):2251–2254. doi:10.1023/A:1026666622394.PubMedCrossRefGoogle Scholar
  13. 13.
    Fantuzzi G. Adiponectin and inflammation: Consensus and controversy. J Allergy Clin Immunol 2008;121(2):326–330. doi:10.1016/j.jaci.2007.10.018.PubMedCrossRefGoogle Scholar
  14. 14.
    Wolf AM, Wolf D, Rumpold H, Enrich B, Tilg H. Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochem Biophys Res Commun 2004;323(2):630–635. doi:10.1016/j.bbrc.2004.08.145.PubMedCrossRefGoogle Scholar
  15. 15.
    Klein TW. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol 2005;5(5):400–411. doi:10.1038/nri1602.PubMedCrossRefGoogle Scholar
  16. 16.
    Despres JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005;353(20):2121–2134. doi:10.1056/NEJMoa044537.PubMedCrossRefGoogle Scholar
  17. 17.
    Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomized controlled study. Lancet 2006;368:1660–1672. doi:10.1016/S0140-6736(06)69571-8.PubMedCrossRefGoogle Scholar
  18. 18.
    Rongione AJ, Kusske AM, Kwan K, Ashley SW, Reber HA, McFadden DW. Interleukin 10 reduces the severity of acute pancreatitis in rats. Gastroenterology 1997;112(3):960–967. doi:10.1053/gast.1997.v112.pm9041259.PubMedCrossRefGoogle Scholar
  19. 19.
    Fagenholz PJ, Fernandez-del Castillo C, Harris NS, Pelletier AJ, Camargo CA Jr. Direct medical costs of acute pancreatitis hospitalizations in the United States. Pancreas 2007;35(4):302–307.PubMedCrossRefGoogle Scholar
  20. 20.
    Frossard JL, Steer ML, Pastor CM. Acute pancreatitis. Lancet 2008;371(9607):143–152. doi:10.1016/S0140-6736(08)60107-5.PubMedCrossRefGoogle Scholar
  21. 21.
    Zyromski NJ, Kendrick ML, Sarr MG. Acute and chronic pancreatitis. In Kelly Keith A, Sarr MG, Hinder RA, eds. Mayo Clinic Gastrointestinal Surgery. Philadelphia: Saunders, 2004, pp 321–340.Google Scholar
  22. 22.
    Howard TJ, Patel JB, Zyromski NJ, Sandrasegaran K, Yu J, Nakeeb A, Pitt HA, Lillemoe KD. Declining morbidity and mortality rates in the surgical management of pancreatic necrosis. J Gastrointest Surg 2007;11(1):43–49. doi:10.1007/s11605-007-0112-4.PubMedCrossRefGoogle Scholar
  23. 23.
    Ashley SW, Perez A, Pierce EA, Brooks DC, Moore FD Jr, Whang EE, Banks PA, Zinner MJ. Necrotizing pancreatitis: contemporary analysis of 99 consecutive cases. Ann Surg 2001;234(4):572–579. discussion 579–80. doi:10.1097/00000658-200110000-00016.PubMedCrossRefGoogle Scholar
  24. 24.
    Rodriguez JR, Razo AO, Targarona J, Thayer SP, Rattner DW, Warshaw AL, Fernandez-del Castillo C. Debridement and closed packing for sterile or infected necrotizing pancreatitis. Ann Surg 2008;247(2):294–299.PubMedCrossRefGoogle Scholar
  25. 25.
    Michalski CW, Laukert T, Sauliunaite D, Pacher P, Bergmann F, Agarwal N, Su Y, Giese T, Giese NA, Batkai S, Friess H, Kuner R. Cannabinoids ameliorate pain and reduce disease pathology in caerulein-induced acute pancreatitis. Gastroenterology 2007;132(5):1968–1978. doi:10.1053/j.gastro.2007.02.035.PubMedCrossRefGoogle Scholar
  26. 26.
    Dembinski A, Warzecha Z, Ceranowicz P, Dembinski M, Cieszkowski J, Pawlik WW, Konturek SJ, Tomaszewska R, Hladki W, Konturek PC. Cannabinoids in acute gastric damage and pancreatitis. J Physiol Pharmacol 2006;57(Suppl 5):137–154.PubMedGoogle Scholar
  27. 27.
    Matsuda K, Mikami Y, Takeda K, Fukuyama S, Egawa S, Sunamura M, Maruyama I, Matsuno S. The cannabinoid 1 receptor antagonist, AM251, prolongs the survival of rats with severe acute pancreatitis. Tohoku J Exp Med 2005;207(2):99–107. doi:10.1620/tjem.207.99.PubMedCrossRefGoogle Scholar
  28. 28.
    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. Regulation, function, and dysregulation of endocannabinoids in models of adipose and β-pancreatic cells and in obesity and hyperglycemia. JCEM 2006;91(8):3171–3180.PubMedGoogle Scholar
  29. 29.
    Bensaid M, Gary-Bobo M, Esclangon A, Maffrand JP, Le Fur G, Oury-Donat F, Soubrie P. 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):908–914. doi:10.1124/mol.63.4.908.PubMedCrossRefGoogle Scholar
  30. 30.
    Kumada MS, Kihara Ouchi N, Kobayashi H, Okamoto Y, Ohashi K, Maeda K, Nagaretani H, Kishida K, Maeda N, Nagasawa A, Funahashi T, Matsuzawa Y. Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation 2004;109(17):2046–2049. doi:10.1161/01.CIR.0000127953.98131.ED.PubMedCrossRefGoogle Scholar
  31. 31.
    Wulster-Radcliffe MC, Ajuwon KM, Wang J, Christian JA, Spurlock ME. Adiponectin differentially regulates cytokines in porcine macrophages. Biochem Biophys Res Commun 2004;316(3):924–929.PubMedCrossRefGoogle Scholar
  32. 32.
    Ouchi NS, Kihara Arita Y, Nishida M, Matsuyama A, Okamoto Y, Ishigami M, Kuriyama H, Kishida K, Nishizawa H, Hotta K, Muraguchi M, Ohmoto Y, Yamashita S, Funahashi T, Matsuzawa Y. Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 2001;103(8):1057–1063.PubMedGoogle Scholar
  33. 33.
    Zyromski NJ, Mathur A, Wade T, Pitt HA, Swartz-Basile DA, Lu D, Yancey KW. Adiponectin modulates the cytokine and chemokine milieu in steatopancreatitis. J Surg Res 2008;2(144):304. doi:10.1016/j.jss.2007.12.332.CrossRefGoogle Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2009

Authors and Affiliations

  • Nicholas J. Zyromski
    • 1
  • Abhishek Mathur
    • 1
  • Henry A. Pitt
    • 1
  • Terence E. Wade
    • 1
  • Sue Wang
    • 1
  • Deborah A. Swartz-Basile
    • 1
  • Andrew D. Prather
    • 1
  • Keith D. Lillemoe
    • 1
  1. 1.Department of SurgeryIndiana University School of MedicineIndianapolisUSA

Personalised recommendations