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 μg/g hourly ×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-α (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.