Additive action of 11β-HSD1 inhibition and PPAR-γ agonism on hepatic steatosis and triglyceridemia in diet-induced obese rats

Both 11 beta-hydroxysteroid dehydrogenase (11 beta-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 11 beta-HSD1 inhibitor (Compound A, 3mg kg(-1) day(-1)) or rosiglitazone (RSG, 5mg 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 11 beta-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 11 beta-HSD1 inhibition and PPAR-gamma agonism additively reduce liver steatosis and triglyceridemia, which may eventually prove therapeutically useful. International Journal of Obesity (2009) 33, 601-604; doi:10.1038/ijo.2009.33; published online 17 February 2009