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Cannabinoid receptor CB1 is expressed abundantly in the brain and presumably in the peripheral tissues responsible for energy metabolism. It is unclear if the antiobesity effects of rimonabant, a CB1 antagonist, are mediated through the central or the peripheral CB1 receptors. To address this question, we generated transgenic mice with central nervous system (CNS)-specific knockdown (KD) of CB1, by expressing an artificial microRNA (AMIR) under the control of the neuronal Thy1.2 promoter. In the mutant mice, CB1 expression was reduced in the brain and spinal cord, whereas no change was observed in the superior cervical ganglia (SCG), sympathetic trunk, enteric nervous system, and pancreatic ganglia. In contrast to the neuronal tissues, CB1 was undetectable in the brown adipose tissue (BAT) or the liver. Consistent with the selective loss of central CB1, agonist-induced hypothermia was attenuated in the mutant mice, but the agonist-induced delay of gastrointestinal transit (GIT), a primarily peripheral nervous system-mediated effect, was not. Compared to wild-type (WT) littermates, the mutant mice displayed reduced body weight (BW), adiposity, and feeding efficiency, and when fed a high-fat diet (HFD), showed decreased plasma insulin, leptin, cholesterol, and triglyceride levels, and elevated adiponectin levels. Furthermore, the therapeutic effects of rimonabant on food intake (FI), BW, and serum parameters were markedly reduced and correlated with the degree of CB1 KD. Thus, KD of CB1 in the CNS recapitulates the metabolic phenotype of CB1 knockout (KO) mice and diminishes rimonabant's efficacy, indicating that blockade of central CB1 is required for rimonabant's antiobesity actions.

Recent studies suggested the involvement of the endocannabinoid pathway on insulin secretion in RINm5F cells or rat islets. Animal and clinical studies have reported beneficial effects of the selective cannabinoid 1 receptor antagonist rimonabant on glucose homeostasis. The aim of this study was to investigate the in vivo effects of rimonabant on pancreatic function in Zucker Fatty rats. Zucker Fatty rats were treated with rimonabant (10 mg kg(-1) day(-1)) or vehicle for up to 3 months. Pancreatic function was assessed by oral glucose tolerance test and by static incubation of islets in the presence of different glucose concentrations. Islet morphology was assessed by immuno-histochemistry on pancreatic sections. After 3 months, there was no difference in fasting glycaemia or AUC(glucose) during oral glucose tolerance test between rimonabant- and vehicle-treated animals. However, vehicle-treated rats developed a marked hyperinsulinaemia with time in contrast to rimonabant-treated animals, which maintained at 3 months significantly lower fasting insulin levels (7.76+/-0.67 microg l(-1) vs. 5.59+/-0.59 microg l(-1), P<0.01) and lower AUC(insulin) (1380+/-98 microg l(-1)min vs. 926+/-58 microg l(-1)min, respectively, P<0.001). In static incubation, rimonabant significantly decreased insulin secretion in response to low glucose concentration (3 months: 7.68+/-1.29 vs. 12.25+/-2.01 microg l(-1) 5 islets(-1) 45 min(-1) in rimonabant and vehicle respectively, P<0.01), resulting in a trend to increase stimulation index in the presence of 16.7 mM glucose (10.64+/-0.92 vs. 8.52+/-1.70 respectively). Morphological analysis at 3 months showed that rimonabant reduced islet-cell surface (-60%) and the percentage of disorganized islets (-54%).In conclusion, our data suggest that rimonabant has a protective role against the development of hyperinsulinaemia, beta-cell dysfunction and islet modification in Zucker Fatty rats.

The increase in adiponectin levels in obese patients with untreated dyslipidemia and its mRNA expression in adipose tissue of obese animals are one of the most interesting consequences of rimonabant treatment. Thus, part of rimonabant's metabolic effects could be related to an enhancement of adiponectin secretion and its consequence on the modulation of insulin action, as well as energy homeostasis. The present study investigated the effects of rimonabant in adiponectin knockout mice (Ad(-/-)) exposed to diet-induced obesity conditions. Six-week-old Ad(-/-) male mice and their wild-type littermate controls (Ad(+/+)) were fed a high-fat diet for 7 mo. During the last month, animals were administered daily either with vehicle or rimonabant by mouth (10 mg/kg). High-fat feeding induced weight gain by about 130% in both wild-type and Ad(-/-) mice. Obesity was associated with hyperinsulinemia and insulin resistance. Treatment with rimonabant led to a significant and similar decrease in body weight in both Ad(+/+) and Ad(-/-) mice compared with vehicle-treated animals. In addition, rimonabant significantly improved insulin sensitivity in Ad(+/+) mice compared with Ad(+/+) vehicle-treated mice by decreasing hepatic glucose production and increasing glucose utilization index in both visceral and subcutaneous adipose tissue. In contrast, rimonabant failed to improve insulin sensitivity in Ad(-/-) mice, despite the loss in body weight. Rimonabant's effect on body weight appeared independent of the adiponectin pathway, whereas adiponectin seems required to mediate rimonabant-induced improvement of insulin sensitivity in rodents.

The mechanisms by which the CB1 receptor antagonist rimonabant exerts its appetite-suppressing and energy-dissipating effects are still incompletely resolved. To shed further light on the central pathways influenced by CB1 receptor modulation we examined the expression of the immediate early gene c-fos in male Sprague-Dawley rats at 60, 120 and 240 min after intraperitoneal administration of the CB1R antagonist rimonabant (10 mg/kg) and the CB1R agonist WIN55,212-2 (3 mg/kg). Perfusion-fixed brains were processed for immunohistochemistry and the localization of c-Fos immunoreactive neuronal profiles was assessed qualitatively throughout the brain. Nine areas, including specific hypothalamic and brainstem nuclei known to be involved in appetite regulation, were selected for quantitative analyses. Whereas WIN55,212-2 induced c-Fos immunoreactivity in a time-specific manner in the striatum, the central nucleus of amygdala, the hypothalamic paraventricular nucleus and the arcuate nucleus, no significant increases in c-Fos positive nuclei were found in any forebrain areas following rimonabant administration. In contrast, rimonabant and WIN55,212-2 were both found to significantly increase c-Fos immunoreactivity in the brainstem lateral parabrachial nucleus, the nucleus of the solitary tract and the area postrema. To characterize the phenotype of activated neurons in the nucleus of the solitary tract, a triple immunohistochemical staining technique was used to simultaneously label c-Fos protein and tyrosine hydroxylase (TH), GLP-1 or CART. Interestingly, rimonabant was found to significantly increase c-Fos protein expression in TH-positive neurons. Collectively, these results suggest that brainstem areas including ascending catetholaminergic A2/C2 neurons could play a role in rimonabant-induced inhibition of food intake.

(1) We investigated the effect of the cannabinoid CB1 receptor antagonist, SR 141716, on indomethacin-induced small intestine inflammation and Escherichia coli lipopolysaccharide (LPS)-induced plasma TNF-alpha (TNF) release in comparison to the cannabinoid CB2 receptor antagonist, SR 144528, in rodents. (2) In rats, indomethacin induced significant ulcer formation in the small intestine; this was accompanied by an increase in tissue TNF levels and myeloperoxidase (MPO) activity. SR 141716 prevented the ulcers and the rise in TNF levels (ID50 3.3, 0.4 mg kg-1, respectively) and MPO activity. SR 144528 prevented intestinal ulcers only. (3) The effect of SR 141716 against indomethacin-induced ulcers and increase of plasma TNF levels after LPS was also studied in wild-type and CB1 receptor knockout mice. Indomethacin induced intestinal ulcers in mice, but not tissue TNF production and MPO activity. SR 141716 reduced the ulcers to a similar extent in wild-type and CB1 receptor knockout mice. In rats and wild-type mice, but not in CB1 receptor knockout mice, SR 141716 inhibited the LPS-induced increase in plasma TNF levels. (4) These findings provide evidence that the indomethacin model of intestinal lesions differs in rat and mouse and support the existence of several mechanisms for the antiulcer activity of SR141716, the most important involving the inhibition of TNF production. The potent anti-inflammatory activity of SR141716 in rodents indicated its potential therapeutic interest in chronic immune-inflammatory diseases.