ISMNT News #26 comes back to the thiazolidinedione compounds which work nicely in obese models but unfortunately seem to have side effects. It is intriguing that these compounds improve insulin sensitivity but also promote the recruitment of new

adipocytes. These adipocytes are small but ... It appears that therapy of obesity linked disorders is one of the most challenging fields in pharmacotherapy.

The key reference is by:

Hallakou S, Doare L, Foufelle F, Kergoat M, Guerre-Millo M, Berthault MF, Dugail I, Morin J, Auwerx J, Ferre P

Institut National de la Sante et de la Recherche Medicale, Unit 465, Paris, France

PIOGLITAZONE INDUCES IN VIVO ADIPOCYTE DIFFERENTIATION IN THE OBESE ZUCKER fa/fa RAT

Diabetes 1997 Sep;46(9):1393-1399

Thiazolidinediones are potent antidiabetic compounds, in both animal and human models, which act by enhancing peripheral sensitivity to insulin. Thiazolidinediones are high-affinity ligands for peroxisome proliferator-activated receptor-gamma, a key

factor for adipocyte differentiation, and they are efficient promoters of adipocyte differentiation in vitro. Thus, it could be questioned whether a thiazolidinedione therapy aimed at improving insulin sensitivity would promote the recruitment of new

adipocytes in vivo.

To address this problem, we have studied the in vivo effect of pioglitazone on glucose metabolism and gene expression in the adipose tissue of an animal model of obesity with insulin resistance, the obese Zucker (fa/fa) rat. Pioglitazone markedly improves insulin action in the obese Zucker (fa/fa) rat, but doubles its weight gain after 4 weeks of treatment. The drug induces a large increase 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 carboxykinase genes, but decreases the expression of the ob gene.