Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats.
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.
Gary-Bobo
Magali
M
Sanofi-Aventis Recherche & Développement, Discovery Research CNS Department, Montpellier, France.
Elachouri
Ghizlane
G
Gallas
Jean François
JF
Janiak
Philip
P
Marini
Pietro
P
Ravinet-Trillou
Christine
C
Chabbert
Michèle
M
Cruccioli
Noël
N
Pfersdorff
Christian
C
Roque
Claude
C
Arnone
Michèle
M
Croci
Tiziano
T
Soubrié
Philippe
P
Oury-Donat
Florence
F
Maffrand
Jean Pierre
JP
Scatton
Bernard
B
Lacheretz
Frederic
F
Le Fur
Gérard
G
Herbert
Jean Marc
JM
Bensaid
Mohammed
M
D000818:Animals; D063387:Cannabinoid Receptor Antagonists; D005234:Fatty Liver / Q000209:etiology / Q000517:prevention & control*; D007249:Inflammation / Q000517:prevention & control; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology / Q000517:prevention & control*; D009765:Obesity / Q000150:complications*; D010880:Piperidines / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D011924:Rats, Zucker; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077285:Rimonabant; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D063387:Cannabinoid Receptor Antagonists; D010880:Piperidines; D011720:Pyrazoles; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D000077285:Rimonabant