TROGLITAZONE INCREASES THE NUMBER OF SMALL ADIPOCYTES WITHOUT THE CHANGE OF WHITE ADIPOSE-TISSUE MASS IN OBESE ZUCKER RATS

Troglitazone (CS-045) is one of the thiazolidinediones that activate t he peroxisome proliferator-activated receptor gamma (PPAR gamma), whic h is expressed primarily in adipose tissues, To elucidate the mechanis m by which troglitazone relieves insulin resistance in vivo, we studie d its effects on the white adipose tissues of an obese animal model (o bese Zucker rat), Administration of troglitazone for 15 d normalized m ild hyperglycemia and marked hyperinsulinemia in these rats. Plasma tr iglyceride level was decreased by troglitazone in both obese and lean rats, Troglitazone did not change the total weight of white adipose ti ssues but increased the number of small adipocytes (< 2,500 mu m(2)) a pproximately fourfold in both retroperitoneal and subcutaneous adipose tissues of obese rats, It also decreased the number of large adipocyt es (> 5,000 mu m(2)) by similar to 50%. In fact, the percentage of apo ptotic nuclei was similar to 2.5-fold higher in the troglitazone-treat ed retroperitoneal white adipose tissue than control, Concomitantly, t roglitazone normalized the expression levels of TNF-alpha which were e levated by 2- and 1.4-fold in the retroperitoneal and mesenteric white adipose tissues of the obese rats, respectively, Troglitazone also ca used a dramatic decrease in the expression levels of leptin, which wer e increased by 4-10-fold in the white adipose tissues of obese rats. T hese results suggest that the primary action of troglitazone may be to increase the number of small adipocytes in white adipose tissues, pre sumably via PPAR gamma. The increased number of small adipocytes and t he decreased number of large adipocytes in white adipose tissues of tr oglitazone-treated obese rats appear to be an important mechanism by w hich increased expression levels of TNF-alpha and higher levels of pla sma lipids are normalized, leading to alleviation of insulin resistanc e.