TROGLITAZONE INCREASES SYSTEM-A AMINO-ACID-TRANSPORT IN 3T3-L1 CELLS

System A is one of the most highly regulated transport systems for tra nsport of neutral amino acids into mammalian cells. Stimulation of upt ake of alpha-[H-3]methylaminoisobutyric acid (MeAIB), a nonmetabolizab le system A substrate, by a novel insulin-sensitizing agent, troglitaz one, in 3T3-L1 adipocytes was investigated. Treating adipocytes with t roglitazone alone resulted in a time-and dose-dependent increase in th e uptake of MeAIB. The peak stimulation appeared about 24 h after trog litazone addition. Both troglitazone- and insulin-stimulated transport activities increased markedly after the induction of differentiation of preadipocytes into adipocytes, and declined to a steady state level in adipocytes. The stimulated MeAIB uptake exhibited substrate specif icity typical of system A and was mediated by a single component as de termined by Eadie-Hofstee plots. The stimulation by troglitazone and t hat by insulin were similarly sensitive to actinomycin D and cyclohexi mide, suggesting that both agents may induce de novo synthesis of the same type of system A transport. Apart from the insulin-independent ef fect, troglitazone also showed an insulin-dependent action characteriz ed by enhanced sensitivity to insulin. The synergistic stimulation of MeAIB uptake by coadministration of insulin and troglitazone was most prominent at the early stages of adipocyte differentiation. Pretreatin g cells with troglitazone during the differentiation attenuated the se nsitivity of insulin to inhibition by actinomycin D, suggesting that t roglitazone may enhance the insulin action by stabilizing messenger RN A involved in system A function.