PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA ACTIVATION BY THIAZOLIDINEDIONES INDUCES ADIPOGENESIS IN BONE-MARROW STROMAL CELLS

The thiazolidinediones improve insulin sensitivity in animal models an d have promise as potent oral antidiabetic agents. Their clinical use has been limited because of the resulting anemia and cardiac hypertrop hy. Some compounds of this class have been reported to induce bone mar row fat accumulation in animals, and this effect could account for the observed anemia. We examined the biological mechanism contributing to this phenomenon. The thiazolidinediones BRL49653 and pioglitazone ind uced adipocyte differentiation in the BMS2 bone marrow stromal cell li ne in a dose- and time-dependent manner. These actions were further en hanced by the presence of glucocorticoids and other adipogenic agonist s. The thiazolidinediones increased the mRNA levels of adipocyte-speci fic genes, including that of their receptor, the peroxisome proliferat or-activated receptor-gamma (PPAR gamma). In contrast, mRNA levels of genes encoding other PPAR family members (PPAR alpha, PPAR delta, or N UC-1) were unchanged or decreased. Thiazolidinedione treatment of prim ary bone marrow stromal cells elicited a comparable dose-dependent res ponse. Using a polyclonal antibody, PPAR gamma was detected in protein lysates from adipose-rich bone marrow. Thus, thiazolidinedione direct ly regulates bone marrow stromal cell differentiation; induced PPAR ga mma expression may play a key regulatory role in this process.