Mechanism and implications of brown adipose tissue proliferation in rats and monkeys treated with the thiazolidinedione darglitazone, a potent peroxisome proliferator-activated receptor-gamma agonist.

Thiazolidinediones represent an established class of insulin sensitizing agents for treating noninsulin-dependent diabetes mellitus. Darglitazone, a thiazolidinedione approximately 200x more potent than ciglitazone, was evaluated in preclinical safety assessment studies using rats (1, 5, and 50 mg/kg/day) and cynomolgus monkeys (50, 75, and 100 mg/kg/day). Darglitazone was a potent adipogenic agent in rats, causing hyperplastic/hypertrophic changes and firmness of white and perirenal, dorsal thoracic (TBAT), and interscapular brown adipose tissue (BAT).