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MicroRNA let-7 Regulates 3T3-L1 Adipogenesis

Departments of Pharmacology (T.S., A.L.B., S.A.K., D.J.M.) and Molecular Biology (S.A.K.) and the Howard Hughes Medical Institute (D.J.M.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Department of Molecular Biology and Microbiology (M.F.), University of Central Florida, Orlando, Florida 32826

Address all correspondence and requests for reprints to: David J. Mangelsdorf, Department of Pharmacology and the Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390-9050. E-mail: davo.mango{at}utsouthwestern.edu; or Steven A. Kliewer, Departments of Molecular Biology and Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390-9041. E-mail: steven.kliewer{at}utsouthwestern.edu.

Differentiation of 3T3-L1 cells into adipocytes involves a highly orchestrated series of events including clonal expansion, growth arrest, and terminal differentiation. The mechanisms coordinating these different steps are not yet fully understood. Here we investigated whether microRNAs (miRNAs) play a role in this process. Microarray analysis was performed to detect miRNA expression during 3T3-L1 preadipocyte differentiation. Several miRNAs, including let-7, were up-regulated during 3T3-L1 adipogenesis. Ectopic introduction of let-7 into 3T3-L1 cells inhibited clonal expansion as well as terminal differentiation. The mRNA encoding high-mobility group AT-hook 2 (HMGA2), a transcription factor that regulates growth and proliferation in other contexts, was inversely correlated with let-7 levels during 3T3-L1 cell adipogenesis, and let-7 markedly reduced HMGA2 concentrations. Knockdown of HMGA2 inhibited 3T3-L1 differentiation. These results suggest that let-7 plays an important role in adipocyte differentiation and that it does so in part by targeting HMGA2, thereby regulating the transition from clonal expansion to terminal differentiation.