Cannabinoid receptor-1 blockade attenuates acute pancreatitis in obesity by an adiponectin mediated mechanism.
BACKGROUND
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.


METHODS
Forty lean (C57BL/6J) and 40 obese (Lep(Db)) 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 microg/g hourly x 6). Pancreatitis severity was determined by histology. Pancreatic chemokine and proinflammatory cytokine concentrations were measured by ELISA.


RESULTS
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-alpha (p < 0.001), interleukin-6 (p < 0.001), and myeloperoxidase (p = 0.006) relative to vehicle-treated animals.


CONCLUSIONS
In obese mice, cannabinoid receptor CB-1 blockade with rimonabant attenuates the severity of acute pancreatitis by an adiponectin-mediated mechanism.
Zyromski
Nicholas J
NJ
Department of Surgery, Indiana University School of Medicine, 535 Barnhill Dr. RT 130, Indianapolis, IN 46202, USA. nzyromsk@iupui.edu
Mathur
Abhishek
A
Pitt
Henry A
HA
Wade
Terence E
TE
Wang
Sue
S
Swartz-Basile
Deborah A
DA
Prather
Andrew D
AD
Lillemoe
Keith D
KD
D052242:Adiponectin / Q000097:blood; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000097:blood* / Q000150:complications* / Q000473:pathology; D010195:Pancreatitis / Q000097:blood / Q000209:etiology / Q000473:pathology*; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D052242:Adiponectin; C499919:Adipoq protein, mouse; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D015850:Interleukin-6; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D014409:Tumor Necrosis Factor-alpha; D000077285:Rimonabant