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The effects of the cannabinoid-1 receptor (CB 1 ) antagonist rimonabant on energy metabolism and fasting-induced hypothalamic-pituitary-adrenal (HPA) axis and neuronal activation were investigated. Lean and obese Zucker rats were treated orally with a daily dose of 10 mg/kg rimonabant for 14 days. A comprehensive energy balance profile based on whole-carcass analyses further demonstrated the potential of CB 1 antagonists for decreasing energy gain through reducing food intake and potentially increasing brown adipose tissue thermogenesis. Rimonabant also reduced plasma glucose, insulin, and homeostasis model assessment of insulin resistance, which further confirms the ability of CB 1 antagonists to improve insulin sensitivity. To test the hypothesis that rimonabant attenuates the effect of fasting on HPA axis activation in the obese Zucker model, rats were either ad libitum-fed or food-deprived for 8 h. Contrary to expectation, rimonabant increased basal circulating corticosterone levels and enhanced the HPA axis response to food deprivation in obese rats. Rimonabant also exacerbated the neuronal activation seen in the arcuate nucleus (ARC) after short-term deprivation. In conclusion, the present study demonstrates that CB 1 blockade does not prevent the hypersensitivity to food deprivation occurring at the level of HPA axis and ARC activation in the obese Zucker rats. This, however, does not prevent CB 1 antagonism from exerting beneficial effects on energy and glucose metabolism. Diabetes 55:3403-3410, 2006 O besity results from a prolonged energy imbalance during which intake exceeds expenditure. The difficulty to lose excess weight is tightly linked to the ability of the systems regulating energy balance to defend body weight. The complexity and redundancy within these systems, which involve an intricate network of peripheral signals and neuronal circuits, constitute obstacles to finding potential targets for antiobesity treatments. Currently, one of the most promising targets for the pharmacological treatment of obesity is the cannabinoid-1 receptor (CB 1 ). Rimonabant (SR141716), the first selective CB 1 antagonist (1), acts as a potent antiobesity agent when administered to dietinduced obese mice (2). Rimonabant is presently in phase III clinical trials for the treatment of obesity. The recently published results from clinical trials, known as Rimonabant in Obesity-Europe (3), Rimonabant in ObesityLipids (4), and Rimonabant in Obesity-North America (5), indicate that rimonabant not only reduces body weight but also improves cardiovascular risk factors associated with obesity.The precise mechanism responsible for the antiobesity effect of rimonabant remains unknown. It has been suggested that the hypophagic effect of CB 1 antagonists results from an attenuation of feeding-related reward processes (6,7) that could be under the modulation of hypothalamic centers regulating energy balance. Injection of the endocannabinoid anandamide in the ventromedial hypothalamic nucleus, an area rich in CB 1 mRNA (8), in...

The objectives of this study were to characterize rainbow trout (Oncorhynchus mykiss) corticotropin-releasing factor (CRF)-binding protein (CRF-BP) cDNA and to examine the variations in CRF-BP and CRF mRNA levels in response to different intensities of stress. Trout were physically disturbed by a single or three consecutive periods of chasing until exhaustion followed by 2 h of recovery. The pituitary CRF-BP and preoptic area CRF1 mRNA contents were significantly increased only after repeated chasing events. Physical disturbance increased plasma cortisol levels with the largest change occurring in the group of trout that were exposed to repeated chasing events. Trout were also individually isolated in 120 l tanks or confined to 1·5 l boxes for 4, 24 or 72 h. CRF-BP mRNA levels in confined fish were greater than those of isolated fish at 72 h although there were no differences compared with the control group. CRF1 mRNA levels in the preoptic area were greater and remained elevated for a longer period in confined compared with isolated trout. Isolation led to a transient increase in plasma cortisol levels, but the higher cortisol values developed in the confined fish suggest that this treatment was more stressful than isolation. These results demonstrate that the intensity and duration of stress are important factors regulating CRF and CRF-BP mRNA levels in rainbow trout. We hypothesize that pituitary CRF-BP is involved in regulating the activity of the stress axis, possibly by reducing access to CRF1 receptors in the corticotropes.