Preliminary report: pharmacologic 11beta-hydroxysteroid dehydrogenase type 1 inhibition increases hepatic fat oxidation in vivo and expression of related genes in rats fed an obesogenic diet.

This study aimed to explore in a model of diet-induced steatosis the impact of pharmacologic 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibition, under conditions of unchanged ingestive behavior, on liver fat oxidation. Male Sprague-Dawley rats were fed an obesogenic diet and were continuously treated or not with an 11beta-HSD1 inhibitor (Compound A, 3 mg/[kg d]; Merck Research Laboratories, Rahway, NJ), after which liver expression of oxidative genes and in vivo hepatic fat oxidation were quantified. Treatment with Compound A reduced liver triglyceride concentration (-28%), increased hepatic expression of several genes coding for enzymes of mitochondrial and peroxisomal beta-oxidation, and concomitantly enhanced in vivo liver fat oxidation (+38%). The study demonstrates, under conditions that avoided changes in food intake seen in gene knockout or higher-dose pharmacologic models, the efficacy of 11beta-HSD1 inhibition to up-regulate hepatic fat oxidation gene expression, which functionally translates into enhanced hepatic lipid oxidation in vivo.