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Vol. 63, Issue 4, 908-914, April 2003
CNS Research Department, Sanofi-Synthélabo Recherche,
Montpellier, France
This study investigates the effects of SR141716, a selective
CB1 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 CB1-receptor
knockout mice, SR141716 had no effect on Acrp30 mRNA expression,
demonstrating a CB1 receptor mediating effect. Furthermore, RT-PCR analysis revealed that rat adipose tissue and 3T3 F442A adipocytes expressed CB1 receptor mRNA. Relative
quantification of this expression revealed an up-regulation (3- to
4-fold) of CB1 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 CB1
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.
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