This study investigates the effects of SR141716, a selective CB 1 receptor antagonist that reduces food intake and body weight of rodents, on Acrp30 mRNA expression in adipose tissue. Acrp30, a plasma protein exclusively expressed and secreted by adipose tissue, has been shown to induce free fatty acid oxidation, hyperglycemia and hyperinsulinemia decrease, and body weight reduction. We report that N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716) treatment once daily (10 mg/kg/d, i.p.) from 2 to 14 days reduced body weight and stimulated Acrp30 mRNA expression in adipose tissue of obese Zucker (fa/fa) rats. In parallel, the hyperinsulinemia associated with this animal model was reduced by SR141716 treatment. In cultured mouse adipocytes (3T3 F442A), SR141716 (25 to 100 nM) also induced an overexpression of Acrp30 mRNA and protein. In addition, in adipose tissue of CB 1 -receptor knockout mice, SR141716 had no effect on Acrp30 mRNA expression, demonstrating a CB 1 receptor mediating effect. Furthermore, RT-PCR analysis revealed that rat adipose tissue and 3T3 F442A adipocytes expressed CB 1 receptor mRNA. Relative quantification of this expression revealed an up-regulation (3-to 4-fold) of CB 1 receptor mRNA expression in adipose tissue of obese (fa/fa) rats and in differentiated 3T3 F442A adipocytes compared with lean rats and undifferentiated adipocytes, respectively. Western blot analysis revealed the presence of CB 1 receptors in 3T3 F442A adipocytes, and their expression was up-regulated in differentiated cells. These results show that SR141716 stimulated Acrp30 mRNA expression in adipose tissue by an effect on adipocytes, and reduced hyperinsulinemia in obese (fa/fa) rats. These hormonal regulations may participate in the body weight reduction induced by SR141716 and suggest a role of metabolic regulation in the antiobesity effect of SR141716.

This study investigated the effects of rimonabant (SR141716), an antagonist of the cannabinoid receptor type 1 (CB1), on obesity-associated hepatic steatosis and related features of metabolic syndrome: inflammation (elevated plasma levels of tumor necrosis factor alpha [TNFalpha]), dyslipidemia, and reduced plasma levels of adiponectin. We report that oral treatment of obese (fa/fa) rats with rimonabant (30 mg/kg) daily for 8 weeks abolished hepatic steatosis. This treatment reduced hepatomegaly, reduced elevation of plasma levels of enzyme markers of hepatic damage (alanine aminotransferase, gamma glutamyltransferase, and alkaline phosphatase) and decreased the high level of local hepatic TNFalpha currently associated with steatohepatitis. In parallel, treatment of obese (fa/fa) rats with rimonabant reduced the high plasma level of the proinflammatory cytokine TNFalpha and increased the reduced plasma level of the anti-inflammatory hormone adiponectin. Finally, rimonabant treatment also improved dyslipidemia by both decreasing plasma levels of triglycerides, free fatty acids, and total cholesterol and increasing the HDLc/LDLc ratio. All the effects of rimonabant found in this study were not or only slightly observed in pair-fed obese animals, highlighting the additional beneficial effects of treatment with rimonabant compared to diet. These results demonstrate that rimonabant plays a hepatoprotective role and suggest that this CB1 receptor antagonist potentially has clinical applications in the treatment of obesity-associated liver diseases and related features of metabolic syndrome.

Functionalisation of MSN with mannose for PDT applications dramatically improved the efficiency of PDT on breast cancer cells.