Additive action of 11beta-HSD1 inhibition and PPAR-gamma agonism on hepatic steatosis and triglyceridemia in diet-induced obese rats.
Both 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) inhibition and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonism reduce liver and plasma lipids in rodents through partly distinct mechanisms. This study aimed to assess their additivity of action on liver and plasma lipids in a model of diet-induced steatosis. Rats were fed an obesogenic diet and were treated either with an 11beta-HSD1 inhibitor (Compound A, 3 mg kg(-1) day(-1)) or rosiglitazone (RSG, 5 mg kg(-1) day(-1)) or both for 6 weeks. Compound A and RSG reduced liver steatosis and triglyceridemia, and did so additively when given in combination. The 11beta-HSD1 inhibitor had no effect on serum adiponectin, but increased liver adiponectin receptor type 2 (Adipo-R2) mRNA levels. Conversely, RSG increased serum adiponectin, a likely mediator of its antisteatotic action, but had no effect per se on the Adipo-R2 expression. mRNA levels of representative genes of fatty acid oxidation tended to be increased by both compounds. The study shows that combined 11beta-HSD1 inhibition and PPAR-gamma agonism additively reduce liver steatosis and triglyceridemia, which may eventually prove therapeutically useful.
Berthiaume
M
M
Laval Hospital Research Center and Department of Anatomy and Physiology, Faculty of Medicine, Laval University, Québec, QC, Canada.
Laplante
M
M
Festuccia
W T
WT
Berger
J P
JP
Thieringer
R
R
Deshaies
Y
Y
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D052242:Adiponectin / Q000097:blood; D000818:Animals; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D009765:Obesity / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054419:Receptors, Adiponectin / Q000097:blood; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism*
D052242:Adiponectin; D047495:PPAR gamma; D054419:Receptors, Adiponectin; D045162:Thiazolidinediones; D014230:Triazoles; D014280:Triglycerides; C524574:compound A (octyltriazole); D000077154:Rosiglitazone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1