The KLF2 Transcription Factor Does Not Affect the Formation of Preadipocytes but Inhibits Their Differentiation into Adipocytes

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Abstract
Kruppel-like transcription factor 2 (KLF2), a critical gene for mouse embryogenesis, was recently identified as an inhibitor of adipogenesis. However, it is still unknown whether KLF2 is a natural repressor of adipocyte differentiation and if KLF2 affects the formation of preadipocytes. It may also be important for preadipocyte formation, as KLF2 is crucial for lung development and blood vessel formation. In this study, we show that differentiation of preadipocytes not only results in a concomitant decrease in the levels of KLF2 protein but also significantly reduces KLF2 promoter activity. We have generated tet-responsive lines of 3T3L1 that express physiological levels of KLF2 and show that reexpression of KLF2 prevents preadipocyte differentiation, thereby confirming the inhibition of adipogenesis by KLF2, partially via the restoration of Pref-1. In addition, we studied the contribution of KLF2-negative cells to the formation and subsequent differentiation of preadipocytes. We demonstrate that embryoid bodies derived from KLF2-/- ES cells can differentiate into adipocytes as evidenced by the accumulation of lipids and expression of several biochemical markers. Moreover, mouse embryonic fibroblasts (MEFs) derived from KLF2-/- mouse embryos differentiate efficiently into adipocytes. Interestingly, quantification of lipid accumulation in MEFs indicated that KLF2-/- cells are more prone to differentiate at the early stage of the process, suggesting that KLF2 is a natural repressor of differentiation in vivo. Taken together, these studies demonstrate that KLF2 does not affect the commitment of multipotent stem cells into the preadipocytic lineage but rather maintains their preadipocyte state and thereby negatively regulates their transition into adipocytes.