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OBJECTIVE--Obesity is associated with an overactive endocannabinoid (EC) system. The mechanisms responsible for increased ECs in obese individuals are poorly understood. Therefore, we examined the role of adipocyte insulin resistance in intracellular EC metabolism. METHODS--We used 3T3-L1 adipocytes and diet-induced obese (DIO) mice to examine the role of obesity and insulin resistance in the regulation and/or dysregulation of intracellular ECs. RESULTS--For the first time, we provide evidence that insulin is a major regulator of EC metabolism. Insulin treatment reduced intracellular ECs (2-arachidonylglycerol [2-AG] and anandamide [AEA]) in 3T3-L1 adipocytes. This corresponded with insulin-sensitive expression changes in enzymes of EC metabolism. In insulin-resistant adipocytes, patterns of insulin-induced enzyme expression were disturbed in a manner consistent with elevated EC synthesis and reduced EC degradation. Expression profiling of adipocytes from DIO mice largely recapitulated in vitro changes, suggesting that insulin resistance affects the EC system in vivo. In mice, expression changes of EC synthesis and degradation enzymes were accompanied by increased plasma EC concentrations (2-AG and AEA) and elevated adipose tissue 2-AG. CONCLUSIONS--Our findings suggest that insulin-resistant adipocytes fail to regulate EC metabolism and decrease intracellular EC levels in response to insulin stimulation. These novel observations offer a mechanism whereby obese insulin-resistant individuals exhibit increased concentrations of ECs. Diabetes 57:1262-1268, 2008, Growing evidence suggests that the endocannabinoid (EC) system plays an important role in obesity and metabolic disease. ECs are endogenous lipid-derived molecules that act similarly to the active ingredient in [...]