Background: Obesity is an independent risk factor for developing severe acute pancreatitis. Adipose tissue produces hormones (adipokines) that regulate metabolism and inflammation. We recently showed that the potent anti-inflammatory adipokine adiponectin inversely mirrors the severity of acute pancreatitis in lean and congenitally obese mice. The endocannabinoid system is also important in regulating appetite and metabolism. Increases in circulating levels of adiponectin are observed after central blockade of the cannabinoid-1 (CB-1) receptor. We therefore hypothesized that CB-1 blockade would attenuate the severity of acute pancreatitis by elevating adiponectin.
Methods: 32 congenitally obese (Lepdb/db) mice were studied at 16 weeks of age. Half were subjected to acute pancreatitis by cerulein injection (50µg/kg IP hourly X 6); the others received saline. For 7 days prior to study, half of the animals in each group (pancreatitis/control) received the CB-1 receptor antagonist rimonabant (10mg/kg IP); the other half received vehicle. Mice were sacrificed 9 hours after pancreatitis induction. Histologic pancreatitis severity was determined by a validated method. Serum levels of adiponectin and tissue levels of the pro-inflammatory cytokine interleukin-6 (IL-6), and the chemoattractant molecule MCP-1 were measured by ELISA. ANOVA and Tukey’s test were applied where appropriate; p<0.05 was considered statistically significant.
Results: CB-1 blockade with rimonabant significantly increased circulating adiponectin levels (p<0.05, Table). In the control group, treatment with rimonabant did not change pancreatic levels of IL-6 or MCP-1. In the pancreatitis group, CB-1 blockade with rimonabant significantly decreased the histologic pancreatitis score (p<0.001) as well as pancreatic IL-6 and MCP-1 expression (p<0.001) compared to vehicle treated animals.
Conclusion: These data demonstrate that CB-1 receptor blockade 1) increases circulating adiponectin and 2) significantly attenuates the severity of acute pancreatitis in congenitally obese mice. We conclude that the adipokine milieu is important in the pathogenesis of severe acute pancreatitis in obesity, and that CB-1 blockade attenuates acute pancreatitis by an adiponectin mediated mechanism.

	CONTROL		PANCREATITIS
	Vehicle	Rimonabant	Vehicle	Rimonabant
Adiponectin (μg/mL)	2.2 ± 0.3	4.1 ± 0.6*	2.9 ± 0.4	4.8 ± 0.8*
Pancreatitis Score	0.2 ± 0.5	0 ± 0	7.6 ± 1.0	2.9 ± 0.9†
IL-6 (pg/mL)	231 ± 58	237 ± 148	3445 ± 1432	373 ± 52†
MCP-1 (pg/mL)	380 ± 51	293 ± 66	7740 ± 1386	2096 ± 239†

*p<0.05 vs vehicle in each group (control/pancreatitis); †p<0.001 vs vehicle within pancreatitis group