== HFD-fed obese Adipo/or Adipo+/+mice received vehicle (1% Tween 80, 4% DMSO, and 95% saline) or rimonabant, 10 mg/kg daily, for 7 days by intraperitoneal (ip) injection. reductions in body weight, serum leptin, free fatty acid, cholesterol, and triglyceride levels in the two strains. Rimonabant treatment improved glucose homeostasis and insulin sensitivity to the same extent in Adipo+/+and Adipo/mice, whereas it reversed the HFD-induced hepatic steatosis, fibrosis, and hepatocellular damage only in the former. The adiponectin-dependent, antisteatotic effect of rimonabant was mediated by reduced uptake and Evista (Raloxifene HCl) increased -oxidation of fatty acids in the liver. We conclude that reversal of the HFD-induced hepatic steatosis and fibrosis by chronic CB1blockade, but not the parallel reduction in adiposity and improved glycemic control, is usually mediated by adiponectin. Keywords:cannabinoid type 1 antagonism, insulin resistance, hepatic steatosis and fibrosis, fatty acid uptake adipose tissue is usually no longer considereda passive energy store but rather a complex and highly active metabolic and endocrine organ that produces and secretes biologically active substances known as adipokines (41). Among them, adiponectin, a 30-kDa polypeptide that circulates at high levels in the blood, has been implicated in the maintenance of energy homeostasis and the prevention of several metabolic diseases. Indeed, serum levels of adiponectin are reduced in individuals with obesity and type 2 diabetes (2,4,33,34,72,76) and are positively correlated with insulin sensitivity (11,16,78), increased fatty acid oxidation in peripheral tissues (25,66,77,79), and protection of the liver from nonalcoholic fatty liver disease (7,40,57,75) and fibrosis Evista (Raloxifene HCl) (32). Endocannabinoids are lipid mediators that interact with G protein-coupled cannabinoid type 1 (CB1) and 2 (CB2) receptors to produce a wide range of biological effects much like those of marijuana (50). Activation of CB1results in increased food intake (20), insulin resistance (13,45,48,60), hepatic lipogenesis (36,49,74), and reduced fatty acid -oxidation (22,35), which points to the important role of the endocannabinoid/CB1system in obesity and its metabolic sequealae. Accordingly, chronic CB1blockade or genetic knockout of CB1results in decreased food intake, body weight, and adiposity, increased insulin and leptin sensitivity, and improvements in glucose and lipid homeostasis, hepatic steatosis, and fibrosis in rodent models of obesity (9,17,24,26,36,37,47,54,55,58,6264), and comparable effects were reported in obese subjects treated with rimonabant (12,18,52,67,69,73). Chronic treatment with either globally acting Evista (Raloxifene HCl) or peripherally restricted CB1antagonists has been shown to reverse the obesity-induced reduction in plasma adiponectin and adiponectin mRNA expression in adipose tissue (10,27,42,62,63,65), suggesting a role for adiponectin in the improved metabolic homeostasis caused by CB1blockade. To test this hypothesis, we examined the metabolic effects of CB1blockade in Evista (Raloxifene HCl) Adipo/and Adipo+/+mice with high-fat diet (HFD)-induced obesity (DIO). The results indicate that this reversal of the HFD-induced hepatic steatosis and fibrosis by CB1blockade requires intact adiponectin signaling, whereas the parallel reduction in body weight, improved hormonal homeostasis, and increased insulin sensitivity are impartial of adiponectin. == MATERIALS AND METHODS == == == == Animals. == The experimental protocol used was approved by the Institutional Animal Care and Use Committee of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH). Male 6-wk-old Adipo/mice and their wild-type littermate C57Bl/6J controls (Adipo+/+) were obtained from the Jackson Laboratory (Bar Harbor, ME). The mice were managed under a 12:12-h light-dark cycle and fed ad libitum either a HFD (D12492; 60% of calories from fat, 20% from protein, and 20% from carbohydrates; Research Diets) or mouse standard diet (STD; NIH no. 31 rodent diet) for 7 mo. == Experimental protocol. == HFD-fed obese Adipo/or Adipo+/+mice received vehicle (1% Tween 80, 4% DMSO, and 95% saline) or rimonabant, 10 mg/kg daily, for 7 days by intraperitoneal (ip) injection. Body weight was monitored daily. Mice were euthanized by cervical dislocation, the livers were removed and weighed, and samples of each liver were either snap-frozen or fixed in 10% buffered formalin. Trunk blood was collected Rabbit polyclonal to A2LD1 for determining endocrine and biochemical parameters. Adiposity index was defined as the ratio of the combined weight of the epididymal, retroperitoneal, and subcutaneous excess fat pads to total body weight (63). == Blood chemistry. == Blood was collected at the time the mice were euthanized. Serum alanine aminotransferases (ALT), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and triglycerides (TGs) were quantified using AMS Vegasys Chemistry Analyzer (Diamond Diagnostics). Blood glucose was decided using the Elite (Bayer) glucometer. Serum insulin was decided using the Ultra-Sensitive Mouse Insulin ELISA kit (Crystal Chem). Serum leptin and adiponectin were determined by ELISA (B-Bridge International). Serum non-sterified free fatty acid (FFA) levels were measured using the HR Series NEFA kit (Wako Diagnostics). == Hepatic TG.