PIOGLITAZONE INDUCES IN-VIVO ADIPOCYTE DIFFERENTIATION IN THE OBESE ZUCKER FA FA RAT/

Thiazolidinediones are potent antidiabetic compounds, in both animal a nd human models, which act by enhancing peripheral sensitivity to insu lin. Thiazolidinediones are high-affinity ligands for peroxisome proli ferator-activated receptor-gamma, a key factor for adipocyte different iation, and they are efficient promoters of adipocyte differentiation in vitro. Thus, it could be questioned whether a thiazolidinedione the rapy aimed at improving insulin sensitivity would promote the recruitm ent of new adipocytes in vivo. To address this problem, we have studie d the in vivo effect of pioglitazone on glucose metabolism and gene ex pression in the adipose tissue of an animal model of obesity with insu lin resistance, the obese Zucker (fa/fa) rat. Pioglitazone markedly im proves insulin action in the obese Zucker (fa/fa) rat, but doubles its weight gain after 4 weeks of treatment. The drug induces a large incr ease of glucose utilization in adipose tissue, where it stimulates the expression of genes involved in lipid metabolism such as the insulin- responsive GLUT, fatty acid synthase, and phosphoenolpyruvate carboxyk inase genes, but decreases the expression of the ob gene. These change s are related to both an enhanced adipocyte differentiation, as shown by the large increase in the number of small adipocytes in the retrope ritoneal fat pad, and a direct effect of pioglitazone on specific gene expression (phosphoenolpyruvate carboxykinase and ob genes) in mature adipocytes.